Clinical trial NCT01297309
Conditions: Hypoparathyroidism
Keywords: PTH 1-84 Hypoparathyroidism Parathyroid Hormone 1-84 NPSP558
Sponsor: Shire
Start date: 2011-04-06; Completion date: 2018-06-08
Enrollment: 51 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is a long-term, open-label study using NPSP558 for the treatment of adult patients with Hypoparathyroidism.

Detailed description:
Patients with a history of Hypoparathyroidism will be enrolled to receive study drug for up to 80 months, which will be injected daily in either thigh. During that time they will be monitored for safety (specifically calcium levels in blood or urine). In addition, the patients' intake of Vitamin D and Calcium will be measured.

Arms: arm 1: titration of 25, 50, 75 or 100 μg
Interventions: intervention 1: NPSP558
Intervention descriptions: intervention 1: All patients will inject NPSP558 individual titration of 25, 50, 75 or 100 μg SC QD into alternating thighs in the morning via a multidose injection pen device.

Protocol documents:
SAP_006.pdf: 
STATISTICAL ANALYSIS PLAN 
 
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 
 
SAP Version:   
SAP Amendment 1 
 
SAP Version Date: 
22 March 2018 


 
 
  
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
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 No. PAR-C10-008 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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Prot_003.pdf: 
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 3 
 
Protocol Version Date: 15 Mar 2012 


 
 
 
 
 
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 
 
 
 
NPS Pharmaceuticals, Inc.  
550 Hills Drive, 3rd Floor 
Bedminster, NJ 07921 
 
 
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


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Clinical Protocol PAR-C10-008 Amendment 3 
 
 
NPSP558 (rhPTH[1-84]) powder for subcutaneous injection 
 
 
Page 3 of 79 
 
 
 
 
 
 
 
Amendment 3_Final v4.0 
15 March 2012 
SUMMARY 
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 3  
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 as hormone replacement therapy for the treatment of adult 
subjects with hypoparathyroidism. 
Secondary Objectives: 
• To evaluate the impact of different preparations of calcium and calcitriol on the 
response to NPSP558 replacement therapy 
• To demonstrate that dosing with NPSP558 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 NPSP558.  
Study Design 
This study is a long-term, open-label study using NPSP558 for the treatment of adult 
male and female subjects with hypoparathyroidism. Subjects can enroll if they either 
previously completed the NPSP558 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 NPSP558 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 NPSP558 and to the 
calcium/calcitriol supplements and safety monitoring of calcium levels are explained in 
Appendix 2, NPSP558 and Supplement Titration Guideline.   
• 
The starting dose of NPSP558 for this study will be 25 or 50 µg SC once daily (QD). 


Clinical Protocol PAR-C10-008 Amendment 3 
 
 
NPSP558 (rhPTH[1-84]) powder for subcutaneous injection 
 
 
Page 4 of 79 
 
 
 
 
 
 
 
Amendment 3_Final v4.0 
15 March 2012 
• 
Subjects may have their NPSP558 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 NPSP558, 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 and any time following the Week 16 (Visit 4), subjects who are on a stable dose of 
NPSP558 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 at least October 2013.  During this time, subjects will return to the clinic for 
interim visits every 2 months (Months 14, 16, 18, etc).   
• 
During the week following the last visit (End of Treatment visit or early termination), 
subjects will have their total serum calcium levels 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 phosphorus checked. 
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 NPSP558 RELAY study (8 weeks of active therapy) and/or 
previously completed the NPSP558 REPLACE study (Visit 18) 


Clinical Protocol PAR-C10-008 Amendment 3 
 
 
NPSP558 (rhPTH[1-84]) powder for subcutaneous injection 
 
 
Page 5 of 79 
 
 
 
 
 
 
 
Amendment 3_Final v4.0 
15 March 2012 
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 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 treatment, which was initially 12 months, is being extended until 
October 2013 with further definition to be made by the sponsor at that time.  However, 
after the last study visit, subjects will have follow-up visits or contact during the month 
following the last dose of study drug.  See Protocol Section 6.2 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 NPSP558 25 or 50 µg SC QD in an 
open-label fashion as described in Section 3.1.  Subjects may have their NPSP558 dose 
adjusted upwards in increments of 25 µg to a maximum of 100 µg SC QD.  NPSP558 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; 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 
o Hematology (hematocrit, hemoglobin, white blood cells, red blood cells, 
platelets, differential) 
o Serum chemistries (standard Chem-20 panel) 
o Serum 25(OH) vitamin D levels 
o Serum 1,25-dihydroxyvitamin D levels 
o Creatinine clearance 
o Serum bone turnover markers 
o Urinalysis 
o 24-hour urine calcium, phosphate, sodium, and creatinine excretion 
o PTH and Escherichia coli protein antibodies 
• Bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) 
• Electrocardiogram (ECG) parameters 


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• Physical examinations (including vital signs) 
• Reason for termination from the study 
Efficacy:   
Efficacy variables will be assessed by one or more of the following evaluations: 
• Laboratory test results 
o Total serum calcium  
o 24-hour urinary calcium excretion 
o Serum phosphate (calcium-phosphate ratio)  
• Supplement usage 
o Concomitant supplemental oral calcium dosage 
o 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 


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• 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 (≥7.5 mg/dL) 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        
• Distribution of subjects by NPSP558 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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PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE 
Protocol PAR-C10-008 Amendment 3 
I agree: 
To assume responsibility for the proper conduct of this clinical study at this center and to 
conduct the study in compliance with this protocol, any future amendments, and with any 
other study conduct procedures provided by the sponsor, 
That I am aware of, and will comply with, the internationally recognized code of Good 
Clinical Practice and all other applicable regulatory requirements to obtain written and 
dated approval from the Institutional or Central Review Board (IRB) or Independent 
Ethics Committee (IEC) for the study protocol and any amendments thereof, written 
informed consent or updates thereof, subject recruitment procedures (eg, advertisements), 
and any other written information to be provided to the subjects, before initiating this 
clinical study, 
Not to implement any changes to, or deviations from the protocol without prior 
agreement from the sponsor and review and documented approval from the IRB/IEC, 
except to eliminate an immediate hazard to the study subjects, or when change(s) 
involves only logistical or administrative aspects of the clinical study, 
To permit direct monitoring and auditing by the sponsor or sponsor’s representatives and 
inspection by the appropriate regulatory authority(ies), 
That I am thoroughly familiar with the appropriate use of the investigational product(s), 
as described in this protocol, and any other information provided by the sponsor or 
designee, including, but not limited to, the current Investigator’s Brochure or equivalent 
document and approved product label (if applicable), 
To provide sufficient time and an adequate number of qualified staff and facilities for the 
foreseen duration of the clinical study in order to conduct the study properly, ethically, 
and safely, 
To ensure that all persons assisting in this study are adequately informed about the 
protocol, investigational product(s), and their clinical study-related duties and functions, 
To 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.   
 
 
Principal Investigator (Print Name) 
 
 
 
 
Principal Investigator (Signature) 
 
Date (DD MMM YYYY) 


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TABLE OF CONTENTS 
TITLE PAGE .....................................................................................................................1 
KEY SPONSOR CONTACTS ..........................................................................................2 
SUMMARY ........................................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................15 
1 INTRODUCTION......................................................................................................17 
1.1 Background .........................................................................................................17 
1.2 Rationale for the Clinical Study ..........................................................................20 
1.3 Rationale for Study Design .................................................................................24 
2 OBJECTIVES ............................................................................................................24 
2.1 Primary Objective ...............................................................................................24 
2.2 Secondary Objectives..........................................................................................24 
2.3 Endpoints ............................................................................................................25 
2.3.1 
Safety Endpoints ..................................................................................25 
2.3.2 
Efficacy Endpoints ...............................................................................25 
2.3.3 
Other Efficacy Endpoints .....................................................................26 
3 STUDY DESIGN ........................................................................................................26 
3.1 Overall Design and Control Methods .................................................................26 
3.2 Study Duration ....................................................................................................31 
4 SUBJECT SELECTION AND PARTICIPATION ................................................31 
4.1 Number of Subjects.............................................................................................31 
4.2 Inclusion Criteria ................................................................................................31 
4.3 Exclusion Criteria ...............................................................................................32 
4.4 Subject Withdrawal Criteria ...............................................................................32 
5 TREATMENTS AND TREATMENT PLAN .........................................................33 
5.1 Treatments Administered ....................................................................................33 
5.1.1 
Identification of Investigational Product(s) .........................................33 
5.1.2 
Packaging and Labeling .......................................................................34 
5.1.3 
Storage, Accountability, and Stability .................................................34 


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5.2 Methods of Assigning Subjects to Treatment Groups ........................................35 
5.3 Dose Regimens ...................................................................................................35 
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.....................................................36 
5.4 Prior and Concomitant Medications ...................................................................36 
5.4.1 
Exclusionary Prior/Concomitant Medications .....................................36 
5.4.2 
Active Calcitriol, Calcium, Native Vitamin D, and Magnesium 
Supplementation ..................................................................................37 
6 STUDY EVALUATIONS AND PROCEDURES ...................................................38 
6.1 Efficacy Evaluations ...........................................................................................38 
6.2 Safety Evaluations ..............................................................................................39 
6.2.1 
Adverse Events ....................................................................................40 
6.2.1.1 Adverse Event Definition .....................................................40 
6.2.1.2 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 ..............................................................................47 
6.2.6 
Physical Examinations .........................................................................47
 
6.2.7 
Dual-energy X-ray Absorptiometry .....................................................47 
6.2.8 
Women of Childbearing Potential .......................................................48 
6.2.9 
Pregnancy Reporting ............................................................................48 
6.3 Schedule of Evaluations and Procedures ............................................................49 
6.4 Description of Study Procedures ........................................................................54 
6.4.1 
Visit 1 Baseline Procedures .................................................................54 
6.4.2 
Week 1 Interim Safety Check ..............................................................55 
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 


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6.4.5 
Long-term Extension Visits .................................................................58 
6.4.6 
End of Treatment Visit or Early Termination ......................................59 
6.4.7 
Poststudy Interim Safety Check ...........................................................59 
6.4.8 
Follow-up Safety Visit .........................................................................60 
6.4.9 
Follow-up Telephone Contact ..............................................................60 
6.4.10 
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 ...................................62 
8.1 Demographic and Baseline Variables .................................................................62 
8.2 Safety Variables ..................................................................................................62 
8.3 Efficacy Variables ...............................................................................................62 
8.4 Other Variables ...................................................................................................63 
8.5 Analysis Populations, Data Sets, and Time Points .............................................64 
8.5.1 
Analysis Populations ............................................................................64 
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 ............................................................65 
9 ADMINISTRATIVE AND ETHICAL REQUIREMENTS ..................................65 
9.1 Declaration of Helsinki and Ethical Review .......................................................65 
9.2 Subject Information and Consent........................................................................65 
9.3 Subject Data Protection.......................................................................................66 
9.4 Financial Disclosure............................................................................................66 


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9.5 Changes to the Protocol ......................................................................................67 
9.6 Investigator Obligations ......................................................................................67 
9.7 Confidentiality/Publication of the Study ............................................................68 
9.8 Selection of a Primary Principal Investigator .....................................................68 
9.9 Study Termination ..............................................................................................69 
10 REFERENCES ...........................................................................................................70 
APPENDIX 1 
INSTRUCTIONS FOR USE FOR THE PTH HASELMEIER 
PEN INJECTOR SYSTEM ..............................................................72 
APPENDIX 2 
NPSP558 AND SUPPLEMENT TITRATION GUIDELINE ........75 
APPENDIX 3    METHOD OF BIRTH CONTROL ..................................................79 
 
 
LIST OF FIGURES AND TABLES  
Figure 3-1 
Study Design – First 12 Months of Study ..................................................30 
Figure 3-2 
Study Design – Long-term Extension ........................................................30 
 
Table 5-1 
Prohibited Medications or Therapies .........................................................37 
Table 6-1 
Schedule of Evaluations and Procedures – First 12 Months of Study .......50 
Table 6-2 
Schedule of Evaluations and Procedures – Long-term Extension .............52 
Table 6-3 
Schedule of Follow-up Visits and Procedures for Subjects with 
PTH-specific Antibodies at Final Visit ......................................................54 
 


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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 
β-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 
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 as hormone replacement therapy for the treatment of adult 
subjects with hypoparathyroidism. 
1.1 
Background 
Compound 
NPSP558 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 


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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, 
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 


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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, 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 


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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).  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  
Hypoparathyroidism is one of the few hormonal deficiency syndromes in which 
replacement therapy using the native hormone is not clinically available.  Treatment of 
hypoparathyroidism is also 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 


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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 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 


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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 NPSP558 is not identical to the full 
84 amino acid sequence. 
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 


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for 12 months with 100 µg 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, 2008c, 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 NPSP558 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 NPSP558 
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 NPSP558 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, 


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because NPSP558 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 µg QOD SC in patients with hypoparathyroidism provide a 
framework of information that supports the safety and potential clinical utility of PTH 
replacement therapy in hypoparathyroidism.   
1.3 
Rationale for Study Design  
Dose 
In a phase 2 study of NPSP558 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 purpose of the RACE study is to assess the safety and tolerability 
of varying doses of NPSP558 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.  
NPSP558 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.   
2 
OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to demonstrate the long-term safety and tolerability 
of SC NPSP558 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 and calcitriol on the 
response to NPSP558 replacement therapy 


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• To demonstrate that dosing with NPSP558 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 
o Hematology (hematocrit, hemoglobin, white blood cells, red blood cells, 
platelets, differential) 
o Serum chemistries (standard Chem-20 panel, including calcium, phosphorus, 
and albumin) 
o Serum 25(OH) vitamin D levels 
o Serum 1,25-dihydroxyvitamin D levels 
o Creatinine clearance 
o Serum bone turnover markers 
o Urinalysis 
o 24-hour urine calcium, phosphate, sodium, and creatinine excretion 
o PTH and E. coli protein (ECP) antibodies 
• Bone mineral density by dual-energy x-ray absorptiometry (DXA)  
• Electrocardiogram (ECG) parameters 
• Physical examinations (including vital signs) 
• Reason for termination from the study 
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: 


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• 
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 (≥7.5 mg/dL) 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 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        
• Distribution of subjects by NPSP558 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) 
3 
STUDY DESIGN 
3.1 
Overall Design and Control Methods 
This study is a long-term, open-label study using NPSP558 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 (Visit 18). 


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The goal of this study is to optimize NPSP558 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, NPSP558 and Supplement 
Titration Guideline).   
• 
The starting dose of NPSP558 for this study will be 25 or 50 µg 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: 
o 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 µg SC QD.  
o Subjects who are taking minimal or no supplemental calcium (< 500 mg) 
and no calcitriol will have a starting dose of 25 µg 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 at least October 2013.  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 NPSP558 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 NPSP558 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 NPSP558, after any 
significant change in doses of calcium and/or and calcitriol supplements, or at any 


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other time at the discretion of the investigator.  Results of local total serum calcium 
levels will be entered on the electronic case report form (eCRF). 
• 
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 NPSP558.      
• 
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, NPSP558 can be 
reintroduced.  The NPSP558 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 NPSP558 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 NPSP558 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 NPS Pharmaceuticals (NPS) medical monitor.   
• 
At and any time following the Week 16 (Visit 4), subjects who are on a stable dose of 
NPSP558 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. 


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• 
During the week following the last visit (End of Treatment or early termination visit), 
subjects will have their total serum calcium levels 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 phosphorus checked. 
• 
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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3.2 
Study Duration 
The duration of treatment, which was initially 12 months, is being extended until October 
2013 with further definition to be made by the sponsor at that time.   However, at the 
conclusion of the study, subjects will have a follow-up visit one week after the last dose 
of study drug and will be contacted by telephone 3 weeks later, approximately 30 days 
after the final dose of study drug, in order to follow up on any SAE or study drug-related 
AE.  See Table 6-3 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 
8. Serum 25(OH) vitamin D ≤ 1.5 times the ULN within approximately 16 weeks prior 
to enrollment 


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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 NPS, 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 
In all cases, the reason for withdrawal must be recorded in the (eCRF) and 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 
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. 


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5 
TREATMENTS AND TREATMENT PLAN 
5.1 
Treatments Administered  
Subjects will self-administer an SC injection of NPSP558 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)  
NPSP558  is manufactured using a strain of E. coli modified by DNA technology and is 
identical to native human PTH.  NPSP558 is a single-chain polypeptide containing 
84 amino acid residues.  The drug substance is clear and colorless to light straw-colored. 
NPSP558 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.   


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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 cartridges to provide daily doses for the duration of the study.  Drug 
cartridges will be provided 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.   
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 have a maximum shelf-life of 36 months and 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.  Additional data on the 
reconstituted solution demonstrates that it is stable for up to 7 days when stored at 25°C, 
which provides assurance of product quality during any unexpected excursions.  
Cartridges must be replaced 14 days after reconstitution.  Cartridges should not be 


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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 NPSP558.  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 
• 
quantity removed from stock but not dispensed (eg, damaged, dropped, spilled) 
• 
quantity remaining at the end of the study and retained, returned, or destroyed, 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 or disposed of 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 NPSP558 25 or 50 µg 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 NPSP558 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).    


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5.3.1 
Selection of Doses in Study 
rhPTH(1-84) given as a daily SC injection of 100 µg 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 µg/kg.  The phase 2 and 3 studies alone exposed 2891 subjects with 
PMO to doses ranging between 50 to 100 µg of NPSP558.    
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 µg SC QD with the potential for upward adjustments in increments of 25 µg to a 
maximum dose of 100 µg 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 NPSP558 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.  Calcium and/or vitamin D should be taken in the morning as normal after the 
NPSP558 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 the end of the study 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. 


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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 
 
In addition, concomitant active vitamin D supplements from outside sources are 
prohibited.  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 signing the ICF through study exit), including administration dates and 
dosage, are to be recorded on the appropriate eCRF.  Any medication which contains 
either calcium or vitamin D must be recorded on the eCRF 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 entered on the appropriate 
eCRF. 
 
5.4.2 
Active Calcitriol, Calcium, Native Vitamin D, and Magnesium 
Supplementation 
Calcitriol 
Subjects enrolled in this study will be taking calcitriol 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 


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study.  Prescribed doses of calcitriol will be entered on the appropriate eCRF.  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, including the long-term extension; 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 
entered on the appropriate eCRF.   
In the case that extra calcium supplementation is taken by the subject due to symptoms of 
hypocalcemia, the dose/time and associated symptoms should be recorded by the subject 
in 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 on the concomitant medication eCRF. 
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 on the 
concomitant medication eCRF. 
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 
o Total serum calcium  
o 24-hour urinary calcium excretion 
o Serum phosphate (calcium-phosphate ratio)  
• Supplement usage 
o Concomitant supplemental oral calcium dosage 


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o 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 
o Hematology (hematocrit, hemoglobin, white blood cells, red blood cells, 
platelets, differential) 
o Serum chemistries (standard Chem-20 panel, including calcium, phosphorus, 
and albumin) 
o Serum 25-hydroxyvitamin D levels 
o Serum 1,25-dihydroxyvitamin D levels 
o Creatinine clearance 
o Serum bone turnover markers 
o Urinalysis 
o 24-hour urine calcium, phosphate, sodium, and creatinine excretion 
o PTH and ECP antibodies  (If any subject tests positive for PTH-specific 
antibodies at the final visit, they will have follow-up blood draws for PTH 
antibodies at Months 2, 3, and 6 poststudy.  If a subject’s results are negative 
at 2 successive visits within this timeframe, follow-up may be terminated.  If 
at the end of 6 months the subject is still determined to have PTH-specific 
antibodies, the PI and the sponsor will determine if additional follow-up may 
be required.  During this time, subjects also will be evaluated for AEs or SAEs 
related to immunogenicity, which will be collected in the Pharmacovigilance 
database.)  Subjects may remain on study if they develop 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) 


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• Reason for termination from the study 
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 
Overdose 
Defined as an accidental or intentional administration of an excessive dose of a product, 
an overdose should be reported to the sponsor using the SAE form.  This information will 
be shared with the Safety Management Team (SMT) and medical monitor. 


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6.2.1.2 
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 completion of the study.  
AE/SAEs will be monitored by the site with a telephone call approximately 30 days 
following the last dose of study drug.     
At each visit, new AEs will be recorded sequentially on the AE page of the eCRF.  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) 
o Mild:  usually transient, requiring no special treatment and generally not 
interfering with usual daily activities 
o Moderate:  usually ameliorated by simple therapeutic maneuvers and 
impairs usual activities 
o Severe:  requires vigorous therapeutic intervention and interrupts usual 
activities.  Hospitalization may or may not be required. 
• 
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 


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• 
Fulfill SAE criteria, and/or 
• 
Cause subject discontinuation from the study. 
6.2.2 
Serious Adverse Events 
A serious event must be reported as described in Section 6.2.2.2.  An SAE requires 
expeditious handling to comply with regulatory requirements.  
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 
• 
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 


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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 enter the SAE information into InForm and fax supplemental data (e.g., 
medical records or lab values, if applicable) to 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 sponsor or designee will provide a FAX cover sheet for the investigators in the Study 
Reference Manual. 
Autopsy reports, if applicable, will be forwarded as they become available.  All pertinent 
laboratory results should be entered on the sponsor’s SAE form. 
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 6.2.1.2).  A causality assessment should always be included on 
the sponsor’s 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) 


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• 
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 determined that there is an unanticipated signal, the NPS 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).   


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NPS Pharmaceuticals (sponsor) 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  the 
sponsor 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 phosphorus, 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 phosphorus (every visit through Week 52; calcium 
and phosphorus only at every long-term extension visit and at the 1-week follow-up 
visit) 


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• 
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) 
• 
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 (β-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, 


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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 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 and the eCRF.  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 


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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, 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 an 
SAE supplemental form will be completed to capture potential drug exposure during 
pregnancy and will be 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, an additional SAE form will be 
completed and submitted to the sponsor or designee within 24 hours as discussed above.  
An SAE supplemental 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. 


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Amendment 3_Final v4.0 
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6.3 
Schedule of Evaluations and Procedures 
All clinical study evaluations will be performed according to Table 6-1 and Table 6-2.  
Details of the exact date and time of medical assessments (day/month/year) will be 
documented in the eCRF.  Any deviations from protocol requirements will be 
documented in the eCRF.   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 6-3.


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Amendment 3_Final v4.0 
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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, phosphorus, 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 
 
 


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Amendment 3_Final v4.0 
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Table 6-1  
Schedule of Evaluations and Procedures – First 12 Months of Study (continued) 
 
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/administration/accountability of study drug and pen 
injectors/ancillary supplies  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
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 Interim total serum calcium for all subjects 3 to 5 days (±2 days) after baseline  
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 
Study Procedures / Proposed Study Montha 
Month 
14 
Month 
16 
Month 
18 
Month 
20 
Month 
22 
Month 
24** 
 
End of 
Treatment 
Poststudy 
Int.b 
 
F/upc  
F/up 
Phoned 
 
 
Visit Windows 
± 2 weeks 
± 2 weeks 
± 2 weeks 
± 2 weeks 
± 2 weeks 
± 2 weeks 
± 1 week 
± 2 days 
± 3 days 
± 7 days 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse event monitoring  
X 
X 
X 
X 
X 
X 
X 
 
X 
Xl 
Assessment of clinical episodes of hypocalcemia and 
hypercalcemia  
X 
X 
X 
X 
X 
X 
X 
 
 
 
Physical examination  
 
 
Xe 
 
 
Xe 
X 
 
 
 
Vital signsf and weight 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Electrocardiogram (12-lead)  (local) 
 
 
 
 
X 
 
 
 
Bone mineral density by DXAg      
 
 
 
 
 
X 
Xh 
 
 
 
Hematologyi  
 
 
 
 
 
X 
X 
 
 
 
Serum chemistry (20-panel)i 
 
 
 
 
 
X 
X 
 
 
 
Serum calcium (local)* 
 
 
 
 
 
 
 
X 
 
 
Serum calcium, phosphorus 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Serum calcium, potassium, sodiumj 
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 antibodiesk 
 
 
X 
 
 
X 
Xl 
 
 
 
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 m 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Dispense/administration/accountability of study drug, 
calcium, and pen injectors/ancillary supplies  
X 
X 
X 
X 
X 
X 
X 
 
 
 
Collect used/unused study drug and pen injectorsn 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 


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Amendment 3_Final v4.0 
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Table 6-2 
Schedule of Evaluations and Procedures – Long-term Extension (continued) 
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:  Any adjustment of study drug or supplemental calcium and calcitriol 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 will repeat starting with 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 (at least 
until October 2013). 
b Interim total serum calcium (local) for all subjects 3 to 5 days (±2 days) after last dose of study drug 
c A follow-up safety visit (local) will be conducted 1 week after the last dose of study drug. 
d Follow-up phone contact 30 days after the last dose of study medication to check on any ongoing or new drug-related AEs or SAEs.  
e Brief physical exams will be conducted at 6-month intervals. 
f Vital signs should be done prior to blood draws. 
g 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. 
h DXA will be performed at End of Treatment visit ONLY if the previous DXA was ≥3 months prior.   
i Fasting for at least 6 to 8 hours prior to test 
j 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.   
k Blood draw for PTH and ECP antibodies will be done predose. 
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 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.   
  n 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 Follow-up Visits and Procedures for Subjects with 
PTH-specific Antibodies at Final Visit 
Follow-up Proceduresa,b 
Follow-up  
(Month 2) 
Follow-up  
(Month 3) 
Follow-up  
(Month 6) 
Visit Number: 
F2 
F3 
F4 
Visit Window (± Days) 
±7 
±7 
±7 
Antibodies to PTH 
X 
X 
X 
Adverse events 
X 
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 end of the End of Study visit (or at the time of discontinuation). See Section 6.2. 
b Blood samples for antibody determination may be collected locally.  Occurrence of any AEs during the 
follow-up period may be determined via phone 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 


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• 
Blood samples for serum chemistries (including calcium, phosphorus, and albumin), 
hematology, serum 25(OH) vitamin D, creatinine clearance, and bone turnover 
markers.  The 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 β-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: 
o Study medication cartridges in sufficient number to supply daily doses until 
the next scheduled clinic visit  
o Two pen injectors 
o Ancillary injection supplies (ie, alcohol swabs, needles, etc.) 
o Paper diaries  
o 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, NPSP558 and Supplement Titration Guideline) 
based on this value.  If further adjustments are made to the NPSP558 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. 


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Amendment 3_Final v4.0 
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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) 
• 
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, phosphorus, and albumin (all visits) 
• 
Serum bone turnover markers (Weeks 8, 16, 24, and 40) 
• 
Serum β-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: 
o Study medication cartridges in sufficient number to supply daily doses until 
the next scheduled clinic visit  
o Ancillary injection supplies (ie, alcohol swabs, needles, etc.) 


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Amendment 3_Final v4.0 
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o Calcium (carbonate or citrate) and calcitriol supplements in sufficient 
quantity to supply daily doses until the next scheduled clinic visit 
o 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 
• 
Physical examination 
• 
12-lead electrocardiogram 
• 
Blood samples for serum chemistries (including calcium, phosphorus, 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 β-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: 
o Study medication cartridges in sufficient number to supply daily doses until 
the next scheduled clinic visit  
o Calcium (carbonate or citrate) supplements in sufficient quantity to supply 
daily doses until the next scheduled clinic visit 


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Amendment 3_Final v4.0 
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o Ancillary injection supplies (ie, alcohol swabs, needles, etc.) 
o Paper diaries 
o 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 phosphorus  
• 
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: 


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Amendment 3_Final v4.0 
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o Study medication cartridges in sufficient number to supply daily doses until 
the next scheduled clinic visit  
o Ancillary injection supplies (ie, alcohol swabs, needles, etc.) 
o Calcium (carbonate or citrate) supplements in sufficient quantity to supply 
daily doses until the next scheduled clinic visit 
o 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 phosphorus), 
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 β-HCG pregnancy test (WOCBP only) 
• 
Review the subject’s diary  
• 
Collect used and unused drug cartridges and pen injectors, for assessment of 
accountability, and subject diaries. 
 
6.4.7 
Poststudy Interim Safety Check  
Subjects will have a total serum calcium level drawn locally between 3 to 5 days 
(± 2 days) following the last dose of study drug.  Poststudy adjustments of supplemental 
calcium and calcitriol will be made (see Appendix 2, NPSP558 and Supplement Titration 
Guideline) based on this value.   


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6.4.8 
Follow-up Safety Visit  
One week following the last dose of study drug, subjects will have blood drawn for total 
serum calcium, and phosphorus levels which will be done locally.  Further adjustment of 
subjects’ supplemental calcium and calcitriol doses will be made based on these values 
(see Appendix 2, NPSP558 and Supplement Titration Guideline).  Subjects will also be 
monitored for 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 Telephone Contact  
Subjects will be contacted approximately 30 days 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. 
   
6.4.10 
Follow-up assessment for PTH antibodies 
If any subject tests positive for PTH-specific antibodies at the final visit, they will have 
follow-up blood draws for PTH antibodies at Months 2, 3, and 6 poststudy.  If a subject’s 
results are negative at 2 successive visits within this timeframe, follow-up may be 
terminated.  If at the end of 6 months the subject is still determined to have PTH-specific 
antibodies, the PI and the sponsor will determine if additional follow-up may be required.  
During this time, subjects also will be evaluated for AEs or SAEs related to 
immunogenicity, which will be collected in the Pharmacovigilance database (see 
Section 6.2). 
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 


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responsible for submitting the data to 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. 


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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).  
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, 
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 


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• 
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 (≥7.5 mg/dL) and does not exceed the 
ULN of the central laboratory 
In addition, the following efficacy variables will be summarized:  
• 
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        
• 
Distribution of subjects by NPSP558 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:  
• 
Subject accounting 
• 
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.  


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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. 
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 study report will be completed to look at safety and efficacy compiled through 
31 May 2012.    
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.  


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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). 
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 NPS 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 


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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 
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 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 


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• 
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 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: 


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• 
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 “Principal Investigator Protocol Agreement 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. 
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 


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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. 
Rubin MR, Sliney J Jr, McMahon DJ, Silverberg SJ, Bilezikian JP.  Therapy of 
hypoparathyroid with intact parathyroid hormone.  Osteoporos Int. 2010;21(11):1927-34. 
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. 


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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 
NPSP558 AND SUPPLEMENT TITRATION 
GUIDELINE 
In this study the goal is to continue NPSP558 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 NPSP558.  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, NPSP558 
(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 NPSP558 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 


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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 NPSP558 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, NPSP558 
can be reintroduced with clinically appropriate doses of calcitriol and oral calcium, with 
the aim to avoid further episodes of abnormal serum calcium.   
 
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 
NPSP558 reviewed with the subject to ensure proper administration.  At planned study 
visits (Week 4, 8 etc) the NPSP558 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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Visit number 
Serum calcium (mg/dL) 
NPSP558 dose 
Supplement dose adjustment 
Visit 1 (Baseline) 
> 9.5 mg/dL and  
< 500 mg supplemental oral  
calcium and no calcitriol 
Start at 25 µg 
Receive no supplemental calcitriol and oral calcium 
> 9.5 mg/dL on any dose of 
supplemental calcitriol or 
≥ 500 mg oral calcium 
Start at 50 µg 
Stop supplemental calcitriol and oral calcium 
≤ 9.5 mg/dL on any dose of 
supplemental calcitriol or 
oral calcium 
Start at 50 µg 
Maintain supplemental calcitriol and oral calcium 
Interim Safety Check: 
* 3-5 days post Visit 1 
 
AND 
* after significant 
change in supplements 
*or after any adjustment 
in NPSP558 dose 
*or if clinically indicated  
< 8.0 mg/dL 
Maintain 
Increase calcitriol dose or oral calcium dose as required* 
8.0 - 9.0 mg/dL 
Maintain 
No change in calcitriol dose; no change in oral calcium dose 
9.1 - 10.5 mg/dL 
Maintain 
Reduce calcitriol dose by up to 50%; if no longer receiving calcitriol then 
reduce oral calcium dose by up to 50% * 
10.6 - 11.9 mg/dL 
Maintain 
Reduce by up to 50% or eliminate calcitriol dose and/or oral calcium dose * 
> 11.9 mg/dL 
Stop Study Drug until serum 
calcium is in the normal range 
on at least daily retesting 
STOP calcitriol AND oral calcium dosing  
until serum calcium is in the normal range on at least daily retesting 
 
At baseline, the starting dose should be 25 or 50 µg/d, as no experience is available with a higher starting dose.  A stepwise dose 
increase of NPSP558 is advised if needed after an observation of the initial response to 25 or 50 µg/d.  
 


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Visit number 
Serum calcium 
(mg/dL) 
NPSP558 dose 
Supplement dose adjustment 
 Weeks 4 to End of Study 
  
< 8.0 mg/dL 
Uptitrate 
Reduce calcitriol dose by up to 50% (if not receiving calcitriol, reduce oral 
calcium dose by up to 50% as required) * 
8.0 - 9.0 mg/dL 
Maintain 
No change in calcitriol dose; no change in oral calcium dose 
9.1 - 10.5 mg/dL 
Maintain 
Once both calcitriol and calcium doses have been reduced by ≥50% from 
Baseline, further reduction or elimination of calcitriol and reduction of oral 
calcium to 500mg/day can be made at the investigator’s discretion based on 
serum calcium levels* 
10.6 - 11.9 mg/dL 
Maintain 
> 11.9 mg/dL 
Stop NPSP558 until serum 
calcium is in the normal 
range on at least daily 
retesting 
 STOP calcitriol AND oral calcium dosing  
until serum calcium is in the normal range on at least daily retesting 
 
* Any changes in the NPSP558 dose or calcitriol and/or oral calcium supplement dose must be followed by a safety laboratory check 
for total serum calcium 3 to 5 days afterwards (or earlier if deemed clinically necessary).  The safety laboratory checks can be 
performed using a local laboratory. 
 


Clinical Protocol PAR-C10-008 Amendment 3 
 
 
NPSP558 (rhPTH[1-84]) powder for subcutaneous injection 
 
 
Page 79 of 79 
 
 
 
 
 
 
Amendment 3_Final v4.0 
15 March 2012 
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.   
 

Prot_005.pdf: 
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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Shire
CONFIDENTIAL
Page 7
PAR-C10-008 Protocol Amendment 6
SHP634 (Natpara)
24 Oct 2016
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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CONFIDENTIAL
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PAR-C10-008 Protocol Amendment 6
SHP634 (Natpara)
24 Oct 2016

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


Shire
CONFIDENTIAL
Page 9
PAR-C10-008 Protocol Amendment 6
SHP634 (Natpara)
24 Oct 2016
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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PAR-C10-008 Protocol Amendment 6
SHP634 (Natpara)
24 Oct 2016
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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PAR-C10-008 Protocol Amendment 6
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24 Oct 2016
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


Shire
CONFIDENTIAL
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PAR-C10-008 Protocol Amendment 6
SHP634 (Natpara)
24 Oct 2016

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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PAR-C10-008 Protocol Amendment 6
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24 Oct 2016
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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PAR-C10-008 Protocol Amendment 6
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24 Oct 2016
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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PAR-C10-008 Protocol Amendment 6
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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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24 Oct 2016
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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PAR-C10-008 Protocol Amendment 6
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24 Oct 2016
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 
significant change in doses of calcium and/or and calcitriol supplements, or at any other time 


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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 
cartridges to provide daily doses for the duration of the study.  Drug cartridges will be provided 


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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.  



Prot_002.pdf: 
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 2 
 
Protocol Version Date: 05 Oct 2011 


 
CONFIDENTIAL 
 
 
 
 
NPSP558 
 
A 12-Month 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) 
 
 
 
Clinical Protocol PAR-C10-008 
US IND Number: 76,514 
 
 
 
NPS Pharmaceuticals, Inc.  
550 Hills Drive, 3rd Floor 
Bedminster, NJ 07921 
 
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 
 


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Clinical Protocol PAR-C10-008 Amendment 2 
 
 
NPSP558 (rhPTH[1-84]) powder for subcutaneous injection 
 
 
Page 3 of 73 
 
 
 
 
 
 
 
Amendment 2v3.0_Final 
05 October 2011 
SUMMARY 
Title:  A 12-Month 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 2 
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 as hormone replacement therapy for the treatment of adult 
subjects with hypoparathyroidism. 
Secondary Objectives: 
• To evaluate the impact of different preparations of calcium and calcitriol on the 
response to NPSP558 replacement therapy 
• To demonstrate that dosing with NPSP558 across a dose range of 25 to 100 μg SC 
can be implemented in a safe and effective manner and can be maintained 
throughout 12 months (52 weeks) of treatment 
• To evaluate the impact of calcium-sparing diuretics on serum and urinary calcium 
Study Rationale 
This study is designed to evaluate 12-month treatment with NPSP558.  
Study Design 
This study is a 12-month, open-label study using NPSP558 for the treatment of adults 
with hypoparathyroidism. Subjects can enroll if they either previously completed the 
NPSP558 RELAY study (8 weeks of active therapy) and/or completed the REPLACE 
study (Visit 18). 
The goal of this study is to optimize NPSP558 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 NPSP558 and to the 
calcium/calcitriol supplements and safety monitoring of calcium levels are explained in 
Appendix 2, NPSP558 and Supplement Titration Guideline.   
• 
The starting dose of NPSP558 for this study will be 25 or 50 µg SC once daily 


Clinical Protocol PAR-C10-008 Amendment 2 
 
 
NPSP558 (rhPTH[1-84]) powder for subcutaneous injection 
 
 
Page 4 of 73 
 
 
 
 
 
 
 
Amendment 2v3.0_Final 
05 October 2011 
• 
Subjects may have their NPSP558 dose adjusted by the investigator at any time 
through Week 48 of 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 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 NPSP558, 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 will be conducted at Weeks 1 (baseline), 4, 8, and then every 8 weeks 
thereafter up to Week 48 (Visit 8).  The End of Treatment Visit (Week 52, Visit 9) is 
scheduled 4 weeks later followed by a safety visit at Week 53 (Visit 10) and a follow-
up telephone contact at Week 56 (Visit 11).   See 6.2 for additional follow-up for 
subjects who develop antibodies specific to PTH. 
• 
At the Week 16 (Visit 4), subjects who are on a stable dose of NPSP558 and have a 
24-hour urine calcium > 300 mg may be treated for hypercalciuria with calcium-
sparing diuretics. 
• 
During Week 53, subjects will have their total serum calcium levels 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 Week 53 
(Visit 10) in order to have serum calcium, phosphorus, and albumin checked.   
Number of Subjects Planned:  Approximately 40 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 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 levels (> 40 IU/L); (2) surgically 


Clinical Protocol PAR-C10-008 Amendment 2 
 
 
NPSP558 (rhPTH[1-84]) powder for subcutaneous injection 
 
 
Page 5 of 73 
 
 
 
 
 
 
 
Amendment 2v3.0_Final 
05 October 2011 
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 
8. Serum 25(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 total duration of treatment will be 12 months (52 weeks).   Subjects will have a 
follow-up visit at Week 53 and will also be contacted by telephone at Week 56.  See 6.2 
for additional follow-up for subjects who develop antibodies specific to PTH.    
Test Product, Dose, and Mode of Administration:  
At the beginning of the study, subjects will receive NPSP558 25 or 50 µg SC QD in an 
open-label fashion as described in Section 3.1.  Subjects may have their NPSP558 dose 
adjusted upwards in increments of 25 µg to a maximum of 100 µg SC QD.  NPSP558 is 
to be administered into alternating thighs each morning via a multidose pen injector 
device.  


Clinical Protocol PAR-C10-008 Amendment 2 
 
 
NPSP558 (rhPTH[1-84]) powder for subcutaneous injection 
 
 
Page 6 of 73 
 
 
 
 
 
 
 
Amendment 2v3.0_Final 
05 October 2011 
Supplements:  
Calcium citrate, calcium carbonate, and calcitriol will be supplied by the sponsor.  
Criteria for Evaluation:  
Safety:  
Safety variables will be assessed by the following evaluations:  
• Adverse events and serious adverse events 
• Incidence of adverse events 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 
o Hematology (hematocrit, hemoglobin, white blood cells, red blood cells, 
platelets, differential) 
o Serum chemistries (standard Chem-20 panel) 
o Serum 25-hydroxyvitamin D levels 
o Creatinine clearance 
o Serum bone turnover markers 
o Urinalysis 
o 24-hour urine calcium, phosphate, sodium, and creatinine excretion 
o PTH 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 
Efficacy:   
Efficacy variables will be assessed by one or more of the following evaluations: 
• Laboratory test results 
o Total serum calcium  
o 24-hour urinary calcium excretion 
o Serum phosphate (calcium-phosphate ratio)  


Clinical Protocol PAR-C10-008 Amendment 2 
 
 
NPSP558 (rhPTH[1-84]) powder for subcutaneous injection 
 
 
Page 7 of 73 
 
 
 
 
 
 
 
Amendment 2v3.0_Final 
05 October 2011 
• Supplement usage 
o Concomitant supplemental oral calcium dosage 
o 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, if available.   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 condition.  
Efficacy Variables Summary 
Primary Efficacy Endpoint: 
The proportion of subjects in whom the following three conditions are fulfilled at 
Week 52 (Visit 9) 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 (≥7.5 mg/dL) and does not exceed the 
ULN for the central laboratory 
Secondary Efficacy Endpoints:  
• Mean percentage changes from baseline in supplemental oral calcium and 
supplemental calcitriol dosages at each visit 


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• Proportion of subjects achieving the primary endpoint 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        
• Distribution of subjects by NPSP558 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 adverse events 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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05 October 2011 
 
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE 
Protocol PAR-C10-008 Amendment 2 
I agree: 
To assume responsibility for the proper conduct of this clinical study at this center and to 
conduct the study in compliance with this protocol, any future amendments, and with any 
other study conduct procedures provided by the sponsor, 
That I am aware of, and will comply with, the internationally recognized code of Good 
Clinical Practice and all other applicable regulatory requirements to obtain written and 
dated approval from the Institutional or Central Review Board (IRB) or Independent 
Ethics Committee (IEC) for the study protocol and any amendments thereof, written 
informed consent or updates thereof, subject recruitment procedures (eg, advertisements), 
and any other written information to be provided to the subjects, before initiating this 
clinical study, 
Not to implement any changes to, or deviations from the protocol without prior 
agreement from the sponsor and review and documented approval from the IRB/IEC, 
except to eliminate an immediate hazard to the study subjects, or when change(s) 
involves only logistical or administrative aspects of the clinical study, 
To permit direct monitoring and auditing by the sponsor or sponsor’s representatives and 
inspection by the appropriate regulatory authority(ies), 
That I am thoroughly familiar with the appropriate use of the investigational product(s), 
as described in this protocol, and any other information provided by the sponsor or 
designee, including, but not limited to, the current Investigator’s Brochure or equivalent 
document and approved product label (if applicable), 
To provide sufficient time and an adequate number of qualified staff and facilities for the 
foreseen duration of the clinical study in order to conduct the study properly, ethically, 
and safely, 
To ensure that all persons assisting in this study are adequately informed about the 
protocol, investigational product(s), and their clinical study-related duties and functions, 
To 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.   
 
 
Principal Investigator (Print Name) 
 
 
 
 
Principal Investigator (Signature) 
 
Date (DD MMM YYYY) 


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TABLE OF CONTENTS 
TITLE PAGE .....................................................................................................................1 
SPONSOR KEY CONTACTS ..........................................................................................2 
SUMMARY ........................................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................16 
1 INTRODUCTION......................................................................................................18 
1.1 Background .........................................................................................................18 
1.2 Rationale for the Clinical Study ..........................................................................21 
1.3 Rationale for Study Design .................................................................................25 
2 OBJECTIVES ............................................................................................................25 
2.1 Primary Objective ...............................................................................................25 
2.2 Secondary Objectives..........................................................................................25 
2.3 Endpoints ............................................................................................................26 
2.3.1 
Safety Endpoints ..................................................................................26 
2.3.2 
Efficacy Endpoints ...............................................................................26 
2.3.2.1 Primary Efficacy Endpoint ...................................................26 
2.3.2.2 Secondary Efficacy Endpoints ..............................................27 
3 STUDY DESIGN ........................................................................................................27 
3.1 Overall Design and Control Methods .................................................................27 
3.2 Study Duration ....................................................................................................30 
4 SUBJECT SELECTION AND PARTICIPATION ................................................30 
4.1 Number of Subjects.............................................................................................30 
4.2 Inclusion Criteria ................................................................................................30 
4.3 Exclusion Criteria ...............................................................................................31 
4.4 Subject Withdrawal Criteria ...............................................................................31 
5 TREATMENTS AND TREATMENT PLAN .........................................................32 
5.1 Treatments Administered ....................................................................................32 
5.1.1 
Identification of Investigational Product(s) .........................................32 
5.1.2 
Packaging and Labeling .......................................................................33 


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5.1.3 
Storage, Accountability, and Stability .................................................33 
5.2 Methods of Assigning Subjects to Treatment Groups ........................................34 
5.3 Dose Regimens ...................................................................................................35 
5.3.1 
Selection of Doses in Study .................................................................35 
5.3.2 
Selection and Timing of Dose for Each Subject ..................................35 
5.3.3 
Compliance With Dosing Regimens ....................................................36 
5.4 Prior and Concomitant Medications ...................................................................36 
5.4.1 
Exclusionary Prior/Concomitant Medications .....................................36 
5.4.2 
Active Calcitriol, Calcium, Native Vitamin D, and Magnesium 
Supplementation ..................................................................................37 
6 STUDY EVALUATIONS AND PROCEDURES ...................................................38 
6.1 Efficacy Evaluations ...........................................................................................38 
6.2 Safety Evaluations ..............................................................................................38 
6.2.1 
Adverse Events ....................................................................................39 
6.2.1.1 Adverse Event Definition .....................................................39 
6.2.1.2 Procedures for Reporting Adverse Events ............................40 
6.2.2 
Serious Adverse Events .......................................................................41 
6.2.2.1 Serious Adverse Event Definition ........................................42 
6.2.2.2 Procedures for Reporting Serious Adverse Events ...............42 
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 .........................................................................46 
6.2.7 
Dual-energy X-ray Absorptiometry .....................................................47 
6.2.8 
Women of Childbearing Potential .......................................................47 
6.2.9 
Pregnancy Reporting ............................................................................47 
6.3 Schedule of Evaluations and Procedures ............................................................48 
6.4 Description of Study Procedures ........................................................................51 
6.4.1 
Visit 1 Baseline Procedures .................................................................51 
6.4.2 
Week 1 Interim Safety Check ..............................................................52 


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6.4.3 
Weeks 4, 8, 16, 24, 32, 40, and 48 (Visits 2 through 8) Study 
Clinic Visits .........................................................................................52 
6.4.4 
Week 52 (Visit 9) End of Study Visit ..................................................53 
6.4.5 
Week 53 Interim Safety Check ............................................................54 
6.4.6 
End of Week 53 (Visit 10) Follow-up Safety Visit .............................54 
6.4.7 
Week 56 (Visit 11) Follow-up Telephone Contact ..............................54 
6.4.8 
Follow-up assessment for PTH antibodies ..........................................54 
7 DATA MANAGEMENT ...........................................................................................54 
7.1 Data Collection ...................................................................................................54 
7.2 Record Retention ................................................................................................56 
8 STATISTICAL METHODOLOGY AND SAMPLE SIZE ...................................56 
8.1 Demographic and Baseline Variables .................................................................56 
8.2 Safety Variables ..................................................................................................57 
8.2.1 
Efficacy Variables ................................................................................57 
8.3 Other Variables ...................................................................................................58 
8.4 Analysis Populations, Data Sets, and Time Points .............................................58 
8.4.1 
Analysis Populations ............................................................................58 
8.5 Statistical/Analytical Issues ................................................................................58 
8.5.1 
Adjustments for Covariates..................................................................58 
8.5.2 
Handling of Dropouts or Missing Data ................................................58 
8.5.3 
Interim Analyses and Data Monitoring................................................59 
8.5.4 
Multiple Comparisons/Multiplicity .....................................................59 
8.5.5 
Use of a Pharmacokinetic Subset of Subjects ......................................59 
8.5.6 
Examination of Subgroups ...................................................................59 
8.6 Determination of Sample Size ............................................................................59 
8.7 Changes to Planned Statistical Analyses ............................................................59 
9 ADMINISTRATIVE AND ETHICAL REQUIREMENTS ..................................59 
9.1 Declaration of Helsinki and Ethical Review .......................................................59 
9.2 Subject Information and Consent........................................................................60 
9.3 Subject Data Protection.......................................................................................60 


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9.4 Financial Disclosure............................................................................................61 
9.5 Changes to the Protocol ......................................................................................62 
9.6 Investigator Obligations ......................................................................................62 
9.7 Confidentiality/Publication of the Study ............................................................63 
9.8 Selection of a Primary Principal Investigator .....................................................63 
9.9 Study Termination ..............................................................................................63 
10 REFERENCES ...........................................................................................................64 
APPENDIX 1 
INSTRUCTIONS FOR USE FOR THE PTH HASELMEIER 
PEN INJECTOR SYSTEM ......................................................................................66 
• INSTRUCTIONS FOR USE .....................................................................................67 
• REMOVE THE CAP FROM THE PEN INJECTOR BY PULLING.  SAVE 
THE CAP FOR LATER USE. ..................................................................................68 
• UNSCREW THE ROD PROTECTOR. DO NOT DISCARD THE ROD 
PROTECTOR BECAUSE YOU MAY USE IT TO PROTECT THE ROD 
WHEN A MEDICATION CARTRIDGE IS NOT INSTALLED. ........................68 
STEP 4A:  REMOVE THE MEDICATION CARTRIDGE FROM THE 
MIXING DEVICE .....................................................................................................68 
 ..................................................................................68 
• WHEN YOU ATTACH A NEW MEDICATION CARTRIDGE TO THE 
PEN INJECTOR, YOU MUST PRIME THE PEN INJECTOR PRIOR TO 
THE FIRST INJECTION. ........................................................................................68 
• HOLD THE PEN INJECTOR WITH THE NEEDLE CAP POINTING UP. .....68 


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STEP 7A:  DISCARD THE NEEDLE ...........................................................................68 
STEP 7B:  STORE THE PEN INJECTOR ...................................................................68 
....................................................................................................................68 
APPENDIX 2 
NPSP558 AND SUPPLEMENT TITRATION GUIDELINE ........69 
APPENDIX 3   METHOD OF BIRTH CONTROL .....................................................73 
 
 
LIST OF FIGURES AND TABLES  
Figure 3-1 
Study Design ..............................................................................................30 
 
Table 5-1 
Prohibited Medications or Therapies .........................................................36 
Table 6-1 
Schedule of Evaluations and Procedures ...................................................49 
 


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05 October 2011 
  
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
25(OH) vitamin D 
25-hydroxyvitamin D 
1,25(OH)2 vitamin D 
1,25-dihydroxyvitamin D 
β-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 
ECG 
Electrocardiogram 
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 
Information for Use 
IRB 
Institutional Review Board 
ITT 
Intention to treat 
IV 
Intravenous 
mm Hg 
Millimeters of mercury 
NPS 
NPS Pharmaceuticals 
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 
RELAY 
NPSP558 Study PAR-C10-007 
REPLACE 
NPSP558 Study C1-11-040 
rhPTH 
Recombinant human parathyroid hormone 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
SC 
Subcutaneous 
s-CTx 
Serum carboxy-terminal telopeptide of type I collagen 
SMT 
Safety Management Team  
SOC 
System organ class  
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 as hormone replacement therapy for the treatment of adult 
subjects with hypoparathyroidism. 
1.1 
Background 
Compound 
NPSP558 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).  hPTH 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 
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 


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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, 
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 


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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, 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 


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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).  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  
Hypoparathyroidism is one of the few hormonal deficiency syndromes in which 
replacement therapy using the native hormone is not clinically available.  Treatment of 
hypoparathyroidism is also 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 


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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 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 


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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 et al, 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 NPSP558 is not identical to the full 
84 amino acid sequence. 
One prospective, open-label clinical trial of PTH in the treatment of hypoparathyroidism 
is ongoing (Bilezikian et al, 2008).  In that study, patients with hypoparathyroidism were 


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treated for 12 months with 100 µg 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.  
An investigator-initiated open-label study evaluating the utility of PTH(1-84) 100 µg 
QOD for 24 months as hormone-replacement therapy in 30 patients with 
hypoparathyroidism is also ongoing (Rubin et al, 2010).  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, 2008c, 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 patients with 
hypoparathyroidism is currently ongoing (CL1-11-040, REPLACE).  This study is 
investigating 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 phase 1 pharmacokinetic/ 
pharmacodynamic study is also being conducted to assess these aspects of NPSP558 
administered as single SC doses of 50 and 100 μg in patients with hypoparathyroidism. 
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 NPSP558 is identical in structure to endogenous human PTH(1-84), the potential 
for hypersensitivity reactions would be low as compared to nonbiologically identical 


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peptides.  Results from studies of rhPTH(1-34) twice daily SC and from an open-label 
study of rhPTH(1-84) 100 µg QOD SC in patients with hypoparathyroidism provide a 
framework of information that supports the safety and potential clinical utility of PTH 
replacement therapy in hypoparathyroidism.   
1.3 
Rationale for Study Design  
Dose 
In a phase 2 study of NPSP558 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 ongoing 
REPLACE study is evaluating these same doses in hypoparathyroid patients.  An 8-week 
study of fixed doses of 25 and 50 µg (RELAY) is currently being undertaken to explore a 
broader range of treatment dose options.  The purpose of this study is to assess the 
12-month safety and tolerability of varying doses of NPSP558 in reducing requirements 
for supplemental oral calcium and calcitriol, while 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.  
NPSP558 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.   
2 
OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to demonstrate the long-term safety and tolerability 
of SC NPSP558 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 and calcitriol on the 
response to NPSP558 replacement therapy 
• To demonstrate that dosing with NPSP558 across a dose range of 25 to 100 μg SC 
can be implemented in a safe and effective manner and can be maintained 
throughout 12 months (52 weeks) of treatment 
• To evaluate the impact of calcium-sparing diuretics on serum and urinary calcium 


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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 adverse events 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 
o Hematology (hematocrit, hemoglobin, white blood cells, red blood cells, 
platelets, differential) 
o Serum chemistries (standard Chem-20 panel, including calcium, phosphorus, 
and albumin) 
o Serum 25-hydroxyvitamin D levels 
o Creatinine clearance 
o Serum bone turnover markers 
o Urinalysis 
o 24-hour urine calcium, phosphate, sodium, and creatinine excretion 
o PTH antibodies 
• Bone mineral density by dual-energy x-ray absorptiometry (DXA) Electrocardiogram 
(ECG) parameters 
• Physical examinations (including vital signs) 
• Reason for termination from the study 
2.3.2 
Efficacy Endpoints 
2.3.2.1 
Primary Efficacy Endpoint 
The proportion of subjects in whom the following three conditions are fulfilled at 
Week 52 (Visit 9) 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 


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AND 
• 
An albumin-corrected total serum calcium concentration that is normalized or 
maintained compared to the baseline value (≥7.5 mg/dL) and does not exceed the 
ULN for the central laboratory 
2.3.2.2 
Secondary Efficacy Endpoints  
• Mean percentage changes from baseline in supplemental oral calcium and 
supplemental calcitriol dosages at each visit. 
• Proportion of subjects achieving the primary endpoint 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        
• Distribution of subjects by NPSP558 doses at the End of Treatment Visit 
• Change from baseline in bone turnover markers (bone-specific alkaline phosphatase 
[BSAP], serum carboxy-terminal telopeptide of type I collagen [P1NP], serum 
procollagen type 1 amino-terminal propeptide [s-CTx], and osteocalcin), PTH 
antibodies, and BMD by DXA  
• Additional subgroup analyses that are specified in the Statistical Analysis Plan (SAP) 
3 
STUDY DESIGN 
3.1 
Overall Design and Control Methods 
This study is a 12-month, open-label study using NPSP558 for the treatment of adult 
male and female subjects with hypoparathyroidism. Either subjects must have previously 
completed the NPSP558 RELAY study (8 weeks of active therapy) and/or previously 
completed the NPSP558 REPLACE study (Visit 18). 
The goal of this study is to optimize NPSP558 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, NPSP558 and Supplement 
Titration Guideline).   
• 
The starting dose of NPSP558 for this study will be 25 or 50 µg SC once daily.  
• 
Subjects with a total serum calcium value of ≤ 9.5 mg/dL will have a starting dose of 
50 μg.   


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• 
Subjects with a total serum calcium value of > 9.5 mg/dL will have a starting dose as 
follows: 
o 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 µg SC QD.  
o Subjects who are taking minimal or no supplemental calcium (< 500 mg) 
and no calcitriol will have a starting dose of 25 µg SC QD.   
• 
Study visits will be conducted at Weeks 1 (baseline), 4, 8, and then every 8 weeks 
thereafter up to Week 48 (Visit 8).  The End of Treatment Visit (Week 52, Visit 9) is 
scheduled 4 weeks later followed by a safety visit at Week 53 (Visit 10) and a follow-
up telephone contact at Week 56 (Visit 11).  See 6.2 for additional follow-up for 
subjects who develop antibodies specific to PTH. 
• 
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 NPSP558 dose increased by the investigator at any time 
through Week 48 of 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 NPSP558 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 NPSP558, after any 
significant change in doses of calcium and/or and calcitriol supplements, or at any 
other time at the discretion of the investigator.   
• 
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 NPSP558.      
• 
If ANY predose total serum calcium is > 11.9 mg/dL study drug will be stopped.  
Once total serum calcium returns to the normal range, NPSP558 can be reintroduced.  
The NPSP558 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 
NPSP558 should be reintroduced at the next lowest dose level and supplemental oral 


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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 NPSP558 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 NPS medical monitor.   
• 
At the Week 16 (Visit 4), subjects who are on a stable dose of NPSP558 and have a 
24-hour urine calcium > 300 mg 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 visit.   
• 
Monitoring of urine calcium will be performed at Weeks 16, 32, and 52 (Visits 4, 6, 
and 9) 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 Week 53, subjects will have their total serum calcium levels 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 Week 53 
(Visit 10) in order to have serum calcium, phosphorus, and albumin checked.   
• 
At Week 56 (Visit 11), approximately 4 weeks (30 days) following the End of 
Treatment visit (Week 52), subjects will be contacted by telephone in order to assess 
adverse events (AEs)/serious AEs (SAEs).  
 
A schematic representation of the study design is displayed in Figure 3-1. 




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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 
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 that 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 (IRB/IEC), Health Authority and/or NPS, it is no longer in the subject’s 
best interest to continue in the study 


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• 
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 
In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) and 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 
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 NPSP558 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)  
NPSP558  is manufactured using a strain of E. coli modified by DNA technology and is 
identical to native human PTH.  NPSP558 is a single-chain polypeptide containing 
84 amino acid residues.  The drug substance is clear and colorless to light straw-colored. 
NPSP558 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 currently is 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.   


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The preliminary results of a recent study (PAR-C10-005) comparing the Haselmeier pen 
to the Ypsomed pen, shows that the two pens are bioequivalent.   The Haselmeier pen 
will now replace the Ypsomed pen in this study.    
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 cartridges to provide daily doses for 52 weeks.  Drug cartridges will be 
provided 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.   
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 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 


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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 have a maximum shelf-life of 36 months and 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.  Additional data on the 
reconstituted solution demonstrates that it is stable for up to 7 days when stored at 25°C, 
which provides assurance of product quality during any unexpected excursions.  
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 NPSP558.  Subjects should be reminded to 
return all cartridges, even if empty, at the final 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 
• 
quantity removed from stock but not dispensed (eg, damaged, dropped, spilled) 
• 
quantity remaining at the end of the study and retained, returned, or destroyed, 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 or disposed of 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 


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last 4 digits are the sequential subject number.  Subjects will receive study treatment in an 
open-label fashion at starting doses of NPSP558 25 or 50 µg 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 NPSP558 SC injections will be self-administered into alternating thighs each 
morning using a multidose pen injection device (see Appendix 1, Instructions for Use).    
5.3.1 
Selection of Doses in Study 
rhPTH (1-84) given as a daily SC injection of 100 µg 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 µg/kg.  The phase 2 and 3 studies alone exposed 2891 subjects with 
PMO to doses ranging between 50 to 100 µg of NPSP558.    
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).  The phase 3, randomized, double-blind placebo-controlled 
REPLACE study in subjects with hypoparathyroidism is ongoing.  This registrational 
study is exploring the biologic activity of NPSP558 at doses of 50, 75, or 100 µg 
administered as SC injections to the thigh.  An ongoing pharmacokinetic study (C09-002) 
utilizes two single doses of 50 and 100 µg each, also as SC injections to the thigh.  The 
phase 3 fixed-dose study (RELAY) utilized dose of 25 and 50 µg SC daily.  This current 
study will utilize varying doses starting at either 25 or 50 µg SC QD with the potential for 
upward adjustments in increments of 25 µg to a maximum dose of 100 µg 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 NPSP558 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.  Calcium and/or vitamin D should be taken in the morning as normal after the 
NPSP558 injection.  


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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 the end of the study 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 
 


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In addition, concomitant active vitamin D supplements from outside sources are 
prohibited.  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 signing the ICF through study exit), including administration dates and 
dosage, are to be recorded on the appropriate eCRF.  Any medication which contains 
either calcium or vitamin D must be recorded on the eCRF 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 entered on the appropriate 
eCRF. 
 
5.4.2 
Active Calcitriol, Calcium, Native Vitamin D, and Magnesium 
Supplementation 
Calcitriol 
Subjects enrolled in this study will be taking calcitriol to control serum calcium levels.  
Oral calcitriol supplements will be provided for this study by the sponsor or designee; no 
other sources of calcitriol should be used during the study.  Prescribed doses of calcitriol 
will be entered on the appropriate eCRF. 
Calcium 
Oral calcium supplements (either calcium carbonate or calcium citrate) will be provided 
for 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 entered on the appropriate eCRF. 
In the case that extra calcium supplementation is taken by the subject due to symptoms of 
hypocalcemia, the dose/time and associated symptoms should be recorded by the subject 
in the diary.  


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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 Week 52 (End of Treatment).  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 on the concomitant medication eCRF. 
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 on the 
concomitant medication eCRF. 
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 
o Total serum calcium  
o 24-hour urinary calcium excretion 
o Serum phosphate (calcium-phosphate ratio)  
• Supplement usage 
o Concomitant supplemental oral calcium dosage 
o 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 adverse events 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 


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o Hematology (hematocrit, hemoglobin, white blood cells, red blood cells, 
platelets, differential) 
o Serum chemistries (standard Chem-20 panel, including calcium, phosphorus, 
and albumin) 
o Serum 25-hydroxyvitamin D levels 
o Creatinine clearance 
o Serum bone turnover markers 
o Urinalysis 
o 24-hour urine calcium, phosphate, sodium, and creatinine excretion 
o PTH antibodies  (If any subject tests positive for PTH-specific antibodies at 
the final visit, they will have follow-up blood draws for PTH antibodies at 
Months 2, 3, and 6 poststudy.  If a subject’s results are negative at 
2 successive visits within this timeframe, follow-up may be terminated.  If at 
the end of 6 months the subject is still determined to have PTH-specific 
antibodies, the PI and the sponsor will determine if additional follow-up may 
be required.  During this time, subjects also will be evaluated for AEs or SAEs 
related to immunogenicity, which will be collected in the Pharmacovigilance 
database.) 
• Bone mineral density by DXA  
• Electrocardiogram parameters 
• Physical examinations (including vital signs) 
• Reason for termination from the study 
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. 


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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 
Overdose 
Defined as an accidental or intentional administration of an excessive dose of a product, 
an overdose should be reported to the sponsor using the SAE form.  This information will 
be shared with the Safety Management Team (SMT) and medical monitor. 
6.2.1.2 
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 completion of the study.  
AE/SAEs will be monitored by the site with a telephone call at Week 56, approximately 
30 days following the last dose of study drug.     
At each visit, new AEs will be recorded sequentially on the AE page of the eCRF.  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) 
o Mild:  usually transient, requiring no special treatment and generally not 
interfering with usual daily activities 


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o Moderate:  usually ameliorated by simple therapeutic maneuvers and 
impairs usual activities 
o Severe:  requires vigorous therapeutic intervention and interrupts usual 
activities.  Hospitalization may or may not be required. 
• 
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 
A serious event must be reported as described in Section 6.2.2.2.  An SAE requires 
expeditious handling to comply with regulatory requirements.  


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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 
• 
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 enter the SAE information into InForm and fax supplemental data (e.g., 
medical records or lab values, if applicable) to the sponsor. This ensures timely reporting 
of applicable reports to Health Authorities.   


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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 sponsor or designee will provide a FAX cover sheet for the investigators in the Study 
Reference Manual. 
Autopsy reports, if applicable, will be forwarded as they become available.  All pertinent 
laboratory results should be entered on the sponsor’s SAE form. 
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 6.2.1.2).  A causality assessment should always be included on 
the sponsor’s 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) 


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• 
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 determined that there is an unanticipated signal, the NPS 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).   
NPS Pharmaceuticals (sponsor) 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  the 
sponsor 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.   


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6.2.3 
Laboratory Evaluations  
The following laboratory tests will be performed with subjects in a fasted state (6 to 
8 hours) at baseline and Week 52 (End of Treatment), unless otherwise noted.  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 will be analyzed by a central laboratory, 
with the exception of all urine pregnancy tests and total serum calcium levels obtained at 
baseline, Week 53, 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 outlined in Table 6-1: 
• 
Hematology: hemoglobin concentration, hematocrit, erythrocyte count, platelet count, 
and leukocyte counts with differential 
• 
Serum Chem-20 panel: alanine transaminase, aspartate transaminase, alkaline 
phosphatase, lactate dehydrogenase, inorganic phosphorus, 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  
• 
Urinalysis: specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, 
blood, and microscopic analysis of sediment 
• 
Creatinine clearance  
• 
Total serum calcium (local)  
• 
Total serum calcium, albumin, and phosphorus  
• 
Serum 25-hydroxyvitamin D levels  
• 
24-hour urine calcium, phosphate, sodium, and creatinine  
• 
Serum bone turnover markers (BSAP, s-CTx, P1NP, and osteocalcin)  
• 
Serum beta human chorionic gonadotropin (β-HCG) pregnancy test (women of child-
bearing potential [WOCBP] only) 
• 
An FSH test to confirm postmenopausal status, if necessary. 
• 
Urine pregnancy test (WOCBP only)  
• 
PTH  antibodies  
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 


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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 at baseline and each clinic study visit through Week 52 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 and Week 52, at the study center on the same 
model unit.  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 AE.  All ECGs 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 and the eCRF.  Two copies of the 
ECG tracings should be retained in the subject source record. 
6.2.6 
Physical Examinations 
Physical examinations will be performed at baseline and Week 52 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.  
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. 


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6.2.7 
Dual-energy X-ray Absorptiometry  
DXA scans will be performed at baseline and Week 52 and 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, and 52.  Pregnancy occurring during the trial will necessitate 
immediately 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 an 
SAE supplemental form will be completed to capture potential drug exposure during 
pregnancy and will be 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, an additional SAE form will be 
completed and submitted to the sponsor or designee within 24 hours as discussed above.  
An SAE supplemental 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 


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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.  Details of the 
exact date and time of medical assessments (day/month/year) will be documented in the 
eCRF.  Any deviations from protocol requirements will be documented in the eCRF. 


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Table 6-1 
Schedule of Evaluations and Procedures 
Visit Number 
1* 
Int. 
2 
3 
4 
5 
6 
7 
8 
9 
Int. 
10 
11 
Study Procedures / Proposed Study Weeka 
BLb 
1c 
4 
8 
16 
24 
32 
40 
48 
52 
(EoT) 
53c, d 
53 d 
(F/up) 
56 
(F/up) 
Phone 
 
 
Visit Windows 
± 3 
days 
± 2 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7  
days 
± 2 
days 
± 3 
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 
 
X 
X 
Adverse event monitoring (new) 
X 
 
X 
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 signse and weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Electrocardiogram (12-lead)  
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Bone mineral density by DXAf      
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Hematology  
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Serum chemistry (20-panel)g 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Serum calcium (local)** 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Serum calcium, phosphorus, and albumin 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Serum 25-hydroxyvitamin D 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Serum bone turnover markers 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
 
 
Serum thyroid function testg,h, 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine clearance (estimated GFR) 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
 
PTH antibodiesi 
X 
 
 
 
 
X 
 
X 
 
Xl 
 
 
 
FSH (newly menopausal women only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test  
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Urine pregnancy test 
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  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Continued on next page 
 


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Table 6-1  
Schedule of Evaluations and Procedures (continued) 
Visit Number 
1 
Int. 
2 
3 
4 
5 
6 
7 
8 
9 
Int. 
10 
11 
Study Procedures / Proposed Study Weeka 
BLb 
1c 
4 
8 
16 
24 
32 
40 
48 
52 
(EoT) 
53c, d 
53 d 
(F/up) 
56 
(F/up) 
Phone 
 
 
Visit Windows 
± 3 
days 
± 2 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7  
days 
± 2 
days 
± 3 
days 
± 7 
days 
Dispense/accountability of calcium/calcitriol supplements (see 
guideline)  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Collect used/unused study drug, supplements, and pen injectorsk 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
BL = baseline; DXA = dual-energy x-ray absorptiometry; EoT = end of treatment; FSH = follicle stimulating hormone; F/up = follow up; GFR = glomerular filtration rate; Int.= interim visit;  
PTH = parathyroid hormone 
*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 and 53.  Week 56 is telephone contact only.  
b Week 8 from the RELAY Study; subjects will return all used/unused drug, supplements, and pens from RELAY/REPLACE. 
c Interim total serum calcium for all subjects 3 to 5 days (±2 days) after baseline and after last dose of study drug 
d Week 53 will be comprised of 2 visits:  one interim safety check and one end of week study visit. 
e Vital signs should be done prior to blood draws 
f 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 1 of the previous studies (all subjects will have 
a DXA performed at the end of the study Visit 9) 
g Fasting for at least 6 to 8 hours prior to test 
h Thyroid function tests done for final visit of the RELAY/REPLACE studies only. 
i Blood draw for PTH 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.  Pens will be collected at the final visit.  
 l See Section 6.2 for instructions on follow-up for subjects with PTH-specific antibodies. 
 
 


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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, phosphorus, and albumin), 
hematology, serum 25(OH) vitamin D, creatinine clearance, and bone turnover 
markers.  The blood sample for serum chemistries will be split and a local total serum 
calcium will also be performed. 
• 
Blood sample for PTH antibodies  
• 
Urinalysis and 24-hour urine calcium, phosphate, sodium, and creatinine 
• 
Serum β-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). 


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• 
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: 
o Study medication cartridges in sufficient number to supply daily doses until 
the next scheduled clinic visit  
o Two pen injectors 
o Ancillary injection supplies (ie, alcohol swabs, needles, etc.) 
o Paper diaries  
o 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, NPSP558 and Supplement Titration Guideline) 
based on this value.  If further adjustments are made to the NPSP558 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) 
• 
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 calcium, phosphorus, and albumin (all visits) 
• 
Serum bone turnover markers (Weeks 8, 16, 24, and 40) 
• 
Serum β-HCG pregnancy test (Weeks 16, 24, 32, 40, and 48) 
• 
Urine pregnancy test (WOCBP only) (Weeks 4 and 8) 
• 
Creatinine clearance (Weeks 16 and 32)  


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• 
24-hour urine calcium, phosphate, sodium, and creatinine (Weeks 16 and 32)  
• 
Blood sample for PTH antibodies (predose on Weeks 24 and 40) 
• 
Subjects will be provided with the following study supplies: 
o Study medication cartridges in sufficient number to supply daily doses until 
the next scheduled clinic visit  
o Ancillary injection supplies (ie, alcohol swabs, needles, etc.) 
o Calcium (carbonate or citrate) and calcitriol supplements in sufficient 
quantity to supply daily doses until the next scheduled clinic visit 
o Collection container for 24-hour urine (Weeks 16 and 32) 
6.4.4 
Week 52 (Visit 9) End of Study Visit  
Subjects will be instructed to come into the study center after having fasted for 
approximately 6 to 8 hours and prior to taking their last dose of 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 
• 
Physical examination 
• 
12-lead electrocardiogram 
• 
Blood samples for serum chemistries (including calcium, phosphorus, and albumin), 
hematology, serum 25(OH) vitamin D, creatinine clearance, and bone turnover 
markers  
• 
Blood sample for PTH antibodies (predose) (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 
• 
A BMD test by DXA  
• 
Serum β-HCG pregnancy test (females only) 
• 
Review the subject’s diary to assess compliance to protocol procedures and 
dosing/supplement regimens. 


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• 
Collect used and unused drug cartridges, supplements (calcium and calcitriol), and 
pen injectors for assessment of accountability and subject diaries. 
6.4.5 
Week 53 Interim Safety Check 
Subjects will have a total serum calcium level drawn locally between 3 to 5 days 
(± 2 days) following the last dose of study drug.  Poststudy adjustments of supplemental 
calcium and calcitriol will be made (see Appendix 2, NPSP558 and Supplement Titration 
Guideline) based on this value.   
6.4.6 
End of Week 53 (Visit 10) Follow-up Safety Visit  
Subjects will have blood drawn for total serum calcium, phosphorus, and albumin levels.  
This sample will be split in order to provide blood for a local total serum calcium to be 
done at the investigator’s local laboratory.  Further adjustment of subjects’ supplemental 
calcium and calcitriol doses will be made based on these values (see Appendix 2, 
NPSP558 and Supplement Titration Guideline).  Subjects will also be monitored for 
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. 
6.4.7 
Week 56 (Visit 11) Follow-up Telephone Contact  
Subjects will be contacted approximately 30 days 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.\ 
6.4.8 
Follow-up assessment for PTH antibodies 
If any subject tests positive for PTH-specific antibodies at the final visit, they will have 
follow-up blood draws for PTH antibodies at Months 2, 3, and 6 poststudy.  If a subject’s 
results are negative at 2 successive visits within this timeframe, follow-up may be 
terminated.  If at the end of 6 months the subject is still determined to have PTH-specific 
antibodies, the PI and the sponsor will determine if additional follow-up may be required.  
During this time, subjects also will be evaluated for AEs or SAEs related to 
immunogenicity, which will be collected in the Pharmacovigilance database. (see Section 
6.2) 
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, 


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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 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 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  This number is the main identifier for 
subjects. 


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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   
Statistical analyses 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).  
8.1 
Demographic and Baseline Variables 
Demographic variables (such as sex, age, race, birthdate, etc.) will be obtained from the 
REPLACE or RELAY study, if available.   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 and surgical 
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.  


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8.2 
Safety Variables 
Safety data including vital signs assessments, physical examinations, AEs, SAEs, 
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.  
 
8.2.1 
Efficacy Variables 
Primary Efficacy Endpoint: 
The proportion of subjects in whom the following three conditions are fulfilled at 
Week 52 (Visit 9) 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 (≥7.5 mg/dL) and does not exceed the 
ULN of the central laboratory 
In addition, the following efficacy variables will be summarized:  
• 
Mean percentage changes from baseline in supplemental oral calcium and 
supplemental calcitriol dosages at each visit 
• 
Proportion of subjects achieving the primary endpoint 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        
• 
Distribution of subjects by NPSP558 doses at the End of Treatment Visit 


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• 
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. 
8.3 
Other Variables  
Other variables to be analyzed will include the following:  
• 
Subject accounting 
• 
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. 
8.4 
Analysis Populations, Data Sets, and Time Points 
8.4.1 
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. 
8.5 
Statistical/Analytical Issues  
8.5.1 
Adjustments for Covariates 
No preselected covariates are selected for adjustments. 
8.5.2 
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. 


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8.5.3 
Interim Analyses and Data Monitoring 
An interim study report will be completed to look at safety and efficacy at a date to be 
determined.    
8.5.4 
Multiple Comparisons/Multiplicity 
No adjustment for multiplicity in treatment is planned. 
8.5.5 
Use of a Pharmacokinetic Subset of Subjects 
No pharmacokinetic subset of subjects was selected for analysis. 
8.5.6 
Examination of Subgroups 
Subgroup analyses (if any), in addition to the possible ones by gender, will be discussed 
in the SAP.  
8.6 
Determination of Sample Size 
Approximately 40 subjects are anticipated to be enrolled.  Sample sizes were not 
estimated for this extension study.  
8.7 
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). 
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). 


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The investigator will inform the IRB/IEC of subsequent protocol amendments and any 
SUSARs if the NPS 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 
partner of male subjects who is a WOCBP) 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 
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 a secondary unique identifier (ie, hospital/clinic number).  A list of 
subjects who failed screening must also be maintained and be available for inspection. 


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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. 


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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 revised protocol.  Changes to the protocol may require notification 
to or approval by the IRB/IEC 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 
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 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 “Principal Investigator Protocol Agreement Page” of this protocol must be signed 
and dated by the principal investigator for the center. 


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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. 
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. 


Clinical Protocol PAR-C10-008 Amendment 2 
 
 
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Amendment 2v3.0_Final 
05 October 2011 
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 
Aug 4;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. 
Rubin MR, Sliney J Jr, McMahon DJ, Silverberg SJ, Bilezikian JP.  Therapy of 
hypoparathyroid with intact parathyroid hormone.  Osteoporos Int. 2010;21(11):1927-34. 
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 
Sep;88(9):4214-20. 


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Amendment 2v3.0_Final 
05 October 2011 
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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Amendment 2v3.0_Final 
05 October 2011 
APPENDIX 1 
INSTRUCTIONS FOR USE FOR THE PTH 
HASELMEIER PEN INJECTOR SYSTEM






Clinical Protocol PAR-C10-008 Amendment 2 
 
 
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Amendment 2v3.0_Final 
05 October 2011 
 
 
APPENDIX 2 
NPSP558 AND SUPPLEMENT TITRATION 
GUIDELINE 
In this study the goal is to continue NPSP558 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 NPSP558.  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, NPSP558 
(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 NPSP558 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 


Clinical Protocol PAR-C10-008 Amendment 2 
 
 
NPSP558 (rhPTH[1-84]) powder for subcutaneous injection 
 
 
Page 70 of 73 
 
Amendment 2v3.0_Final 
05 October 2011 
 
 
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 NPSP558 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, NPSP558 
can be reintroduced with clinically appropriate doses of calcitriol and oral calcium, with 
the aim to avoid further episodes of abnormal serum calcium.   
 
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 
NPSP558 reviewed with the subject to ensure proper administration.  At planned study 
visits (Week 4, 8 etc until Week 48) the NPSP558 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. 


Clinical Protocol PAR-C10-008 Amendment 2 
 
 
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Page 71 of 73 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amendment 2v3.0_Final 
05 October 2011 
Visit number 
Serum calcium (mg/dL) 
NPSP558 dose 
Supplement dose adjustment 
Visit 1 (Baseline) 
> 9.5 mg/dL and  
< 500 mg supplemental oral  
calcium and no calcitriol 
Start at 25 µg 
Receive no supplemental calcitriol and oral calcium 
> 9.5 mg/dL on any dose of 
supplemental calcitriol or 
≥ 500 mg oral calcium 
Start at 50 µg 
Stop supplemental calcitriol and oral calcium 
≤ 9.5 mg/dL on any dose of 
supplemental calcitriol or 
oral calcium 
Start at 50 µg 
Maintain supplemental calcitriol and oral calcium 
Interim Safety Check: 
* 3-5 days post Visit 1 
 
AND 
* after significant 
change in supplements 
*or after any adjustment 
in NPSP558 dose 
*or if clinically indicated  
< 8.0 mg/dL 
Maintain 
Increase calcitriol dose or oral calcium dose as required* 
8.0 - 9.0 mg/dL 
Maintain 
No change in calcitriol dose; no change in oral calcium dose 
9.1 - 10.5 mg/dL 
Maintain 
Reduce calcitriol dose by up to 50%; if no longer receiving calcitriol then 
reduce oral calcium dose by up to 50% * 
10.6 - 11.9 mg/dL 
Maintain 
Reduce by up to 50% or eliminate calcitriol dose and/or oral calcium dose * 
> 11.9 mg/dL 
Stop Study Drug until serum 
calcium is in the normal range 
on at least daily retesting 
STOP calcitriol AND oral calcium dosing  
until serum calcium is in the normal range on at least daily retesting 
 
At baseline, the starting dose should be 25 or 50 µg/d, as no experience is available with a higher starting dose.  A stepwise dose 
increase of NPSP558 is advised if needed after an observation of the initial response to 25 or 50 µg/d. 


Clinical Protocol PAR-C10-008 Amendment 2 
 
 
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Page 72 of 73 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amendment 2v3.0_Final 
05 October 2011 
 
Visit number 
Serum calcium 
(mg/dL) 
NPSP558 dose 
Supplement dose adjustment 
Visits 2 to 8 
(Weeks 4 to 48)   
  
< 8.0 mg/dL 
Uptitrate 
Reduce calcitriol dose by up to 50% (if not receiving calcitriol, reduce oral 
calcium dose by up to 50% as required) * 
8.0 - 9.0 mg/dL 
Maintain 
No change in calcitriol dose; no change in oral calcium dose 
9.1 - 10.5 mg/dL 
Maintain 
Once both calcitriol and calcium doses have been reduced by ≥50% from 
Baseline, further reduction or elimination of calcitriol and reduction of oral 
calcium to 500mg/day can be made at the Investigator’s discretion based on 
serum calcium levels* 
10.6 - 11.9 mg/dL 
Maintain 
> 11.9 mg/dL 
Stop NPSP558 until serum 
calcium is in the normal 
range on at least daily 
retesting 
 STOP calcitriol AND oral calcium dosing  
until serum calcium is in the normal range on at least daily retesting 
 
* Any changes in the NPSP558 dose or calcitriol and/or oral calcium supplement dose must be followed by a safety laboratory check 
for of total serum calcium 3 to 5 days afterwards (or earlier if deemed clinically necessary).  The safety laboratory checks can be 
performed using a local laboratory. 
 
. 


Clinical Protocol PAR-C10-008 Amendment 2 
 
 
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Page 73 of 73 
 
 
 
 
 
 
Amendment 2v3.0_Final 
05October 2011 
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.   
 

Prot_004.pdf: 
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 5 
 
Protocol Version Date: 03 May 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


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Shire
CONFIDENTIAL
Page 3
PAR-C10-008 Protocol Amendment 5
3 May 2016
SUMMARY
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 5
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 and calcitriol 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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CONFIDENTIAL
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PAR-C10-008 Protocol Amendment 5
3 May 2016

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 at 
December 2016. 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
4. Willingness and ability to understand and comply with the protocol


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CONFIDENTIAL
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PAR-C10-008 Protocol Amendment 5
3 May 2016
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 treatment, which was initially 12 months, is being extended until December 
2016. However, after the last study visit, subjects will have follow-up visits or contact during 
the month following the last dose of study drug. See Section 6.2 for additional follow-up for 
subjects who develop antibodies specific to PTH.   
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: 


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PAR-C10-008 Protocol Amendment 5
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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
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 (calcium-phosphate ratio)


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PAR-C10-008 Protocol Amendment 5
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
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

An albumin-corrected total serum calcium concentration that is normalized or maintained 
compared to the baseline value (≥7.5 mg/dL) 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


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PAR-C10-008 Protocol Amendment 5
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
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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PAR-C10-008 Protocol Amendment 5
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PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE
Protocol PAR-C10-008 Amendment 5
I agree:
To assume responsibility for the proper conduct of this clinical study at this center and to 
conduct the study in compliance with this protocol, any future amendments, and with any other 
study conduct procedures provided by the sponsor,
That I am aware of, and will comply with, the internationally recognized code of Good Clinical 
Practice and all other applicable regulatory requirements to obtain written and dated approval 
from the Institutional or Central Review Board (IRB) or Independent Ethics Committee (IEC) 
for the study protocol and any amendments thereof, written informed consent or updates thereof, 
subject recruitment procedures (eg, advertisements), and any other written information to be 
provided to the subjects, before initiating this clinical study,
Not to implement any changes to, or deviations from the protocol without prior agreement from 
the sponsor and review and documented approval from the IRB/IEC, except to eliminate an 
immediate hazard to the study subjects, or when change(s) involves only logistical or 
administrative aspects of the clinical study,
To permit direct monitoring and auditing by the sponsor or sponsor’s representatives and 
inspection by the appropriate regulatory authority(ies),
That I am thoroughly familiar with the appropriate use of the investigational product(s), as 
described in this protocol, and any other information provided by the sponsor or designee, 
including, but not limited to, the current Investigator’s Brochure or equivalent document and 
approved product label (if applicable),
To provide sufficient time and an adequate number of qualified staff and facilities for the 
foreseen duration of the clinical study in order to conduct the study properly, ethically, and 
safely,
To ensure that all persons assisting in this study are adequately informed about the protocol, 
investigational product(s), and their clinical study-related duties and functions,
To 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.  
Principal Investigator (Print Name)
Principal Investigator (Signature)
Date (DD MMM YYYY)


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TABLE OF CONTENTS
KEY SPONSOR CONTACTS:.......................................................................................................2
SUMMARY.....................................................................................................................................3
SIGNATURE PAGE .......................................................................................................................9
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE .........................................10
TABLE OF CONTENTS...............................................................................................................11
LIST OF IN-TEXT TABLES ........................................................................................................14
LIST OF IN-TEXT FIGURES.......................................................................................................14
LIST OF APPENDICES................................................................................................................14
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................15
1
INTRODUCTION..................................................................................................................17
1.1
Background ..............................................................................................................17
1.2
Rationale for the Clinical Study...............................................................................20
1.3
Rationale for Study Design ......................................................................................23
2
OBJECTIVES.........................................................................................................................23
2.1
Primary Objective ....................................................................................................23
2.2
Secondary Objectives...............................................................................................23
2.3
Endpoints..................................................................................................................24
2.3.1
Safety Endpoints....................................................................................................24
2.3.2
Efficacy Endpoints.................................................................................................24
2.3.3
Other Efficacy Endpoints.......................................................................................25
3
STUDY DESIGN ...................................................................................................................25
3.1
Overall Design and Control Methods.......................................................................25
3.2
Study Duration .........................................................................................................29
4
SUBJECT SELECTION AND PARTICIPATION................................................................29
4.1
Number of Subjects..................................................................................................29
4.2
Inclusion Criteria......................................................................................................29
4.3
Exclusion Criteria.....................................................................................................30
4.4
Subject Withdrawal Criteria.....................................................................................30
5
TREATMENTS AND TREATMENT PLAN........................................................................31
5.1
Treatments Administered .........................................................................................31
5.1.1
Identification of Investigational Product(s) ...........................................................31
5.1.2
Packaging and Labeling.........................................................................................31


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5.1.3
Storage, Accountability, and Stability...................................................................32
5.2
Methods of Assigning Subjects to Treatment Groups .............................................33
5.3
Dose Regimens.........................................................................................................33
5.3.1
Selection of Doses in Study...................................................................................33
5.3.2
Selection and Timing of Dose for Each Subject....................................................33
5.3.3
Compliance with Dosing Regimens.......................................................................34
5.4
Prior and Concomitant Medications.........................................................................34
5.4.1
Exclusionary Prior/Concomitant Medications.......................................................34
5.4.2
Active Vitamin D, Calcium, Native Vitamin D, and Magnesium 
Supplementation ....................................................................................................35
6
STUDY EVALUATIONS AND PROCEDURES.................................................................36
6.1
Efficacy Evaluations ................................................................................................36
6.2
Safety Evaluations....................................................................................................36
6.2.1
Adverse Events ......................................................................................................37
6.2.1.1
Adverse Event Definition.......................................................................37
6.2.1.2
Abuse, Misuse, Overdose, and Medication Error ..................................37
6.2.1.3
Procedures for Reporting Adverse Events .............................................38
6.2.2
Serious Adverse Events .........................................................................................39
6.2.2.1
Serious Adverse Event Definition..........................................................39
6.2.2.2
Procedures for Reporting Serious Adverse Events ................................40
6.2.3
Laboratory Evaluations..........................................................................................42
6.2.4
Vital Signs and Body Weight ................................................................................44
6.2.5
Electrocardiograms ................................................................................................44
6.2.6
Physical Examinations...........................................................................................44
6.2.7
Dual-energy X-ray Absorptiometry.......................................................................45
6.2.8
Women of Childbearing Potential .........................................................................45
6.2.9
Pregnancy Reporting..............................................................................................45
6.3
Schedule of Evaluations and Procedures .................................................................46
6.4
Description of Study Procedures..............................................................................53
6.4.1
Visit 1 Baseline Procedures ...................................................................................53
6.4.2
Week 1 Interim Safety Check................................................................................54
6.4.3
Weeks 4, 8, 16, 24, 32, 40, and 48 (Visits 2 through 8) Study Clinic Visits.........54
6.4.4
Week 52 (Visit 9)...................................................................................................55
6.4.5
Long-term Extension Visits...................................................................................56


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6.4.6
End of Treatment Visit or Early Termination........................................................57
6.4.7
Posttreatment Serum Calcium/Phosphate Follow Up............................................58
6.4.8
Follow-up Telephone Contact................................................................................58
6.4.9
Follow-up assessment for PTH antibodies ............................................................58
7
DATA MANAGEMENT .......................................................................................................58
7.1
Data Collection.........................................................................................................58
7.2
Record Retention......................................................................................................59
8
STATISTICAL METHODOLOGY AND SAMPLE SIZE...................................................59
8.1
Demographic and Baseline Variables ......................................................................59
8.2
Safety Variables .......................................................................................................60
8.3
Efficacy Variables....................................................................................................60
8.4
Other Variables ........................................................................................................61
8.5
Analysis Populations, Data Sets, and Time Points...................................................61
8.5.1
Analysis Populations..............................................................................................61
8.6
Statistical/Analytical Issues......................................................................................61
8.6.1
Adjustments for Covariates....................................................................................61
8.6.2
Handling of Dropouts or Missing Data..................................................................62
8.6.3
Interim Analyses and Data Monitoring..................................................................62
8.6.4
Multiple Comparisons/Multiplicity .......................................................................62
8.6.5
Use of a Pharmacokinetic Subset of Subjects........................................................62
8.6.6
Examination of Subgroups.....................................................................................62
8.7
Determination of Sample Size..................................................................................62
8.8
Changes to Planned Statistical Analyses..................................................................62
9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS ..................................................62
9.1
Declaration of Helsinki and Ethical Review............................................................62
9.2
Subject Information and Consent.............................................................................63
9.3
Subject Data Protection............................................................................................63
9.4
Financial Disclosure.................................................................................................64
9.5
Changes to the Protocol............................................................................................64
9.6
Investigator Obligations ...........................................................................................65
9.7
Confidentiality/Publication of the Study..................................................................65
9.8
Selection of a Primary Principal Investigator ..........................................................66
9.9
Study Termination....................................................................................................66


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10 REFERENCES .......................................................................................................................67
LIST OF IN-TEXT TABLES
Table 5-1
Prohibited Medications or Therapies.............................................................34
Table 6-1
Schedule of Evaluations and Procedures – First 12 Months of Study ..........47
Table 6-2
Schedule of Evaluations and Procedures – Long-term Extension to 
Month 36 .......................................................................................................49
Table 6-3
Schedule of Evaluations and Procedures – Long-term Extension after 
Month 36 .......................................................................................................51
Table 6-4
Schedule of Follow-up Visits and Procedures for Subjects with 
PTH-specific Antibodies at Final Visit .........................................................53
LIST OF IN-TEXT FIGURES
Figure 3-1
Study Design – First 12 Months of Study .....................................................28
Figure 3-2
Study Design – Long-term Extension ...........................................................28
LIST OF APPENDICES
Appendix 1
INSTRUCTIONS FOR USE FOR THE PTH HASELMEIER PEN 
INJECTOR SYSTEM ...................................................................................68
Appendix 2
RHPTH[1-84] AND SUPPLEMENT TITRATION GUIDELINE...............71
Appendix 3
METHOD OF BIRTH CONTROL...............................................................75
Appendix 4
SUMMARY OF CHANGES ........................................................................76


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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
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
SAP
Statistical analysis plan


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
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 


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kidney and bone, PTH is the principal regulator of plasma calcium homeostasis.  In the kidney, 
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 


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function by inducing arrhythmias, hypotension, or heart failure.  Psychiatric symptoms (anxiety, 
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 


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diuretics that decrease urinary calcium excretion, or increased PTH levels (hyperparathyroidism).  
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 


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brain (ie, basal ganglia), kidneys, ocular lens, and other organs leading to structural damage and 
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.  
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 and calcitriol 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


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
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)

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


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
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 (≥7.5 mg/dL) 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 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)
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. 


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
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 
December 2016.  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 
significant change in doses of calcium and/or and calcitriol supplements, or at any other time 
at the discretion of the investigator.  Results of local total serum calcium levels will be 
entered on the electronic case report form (eCRF).

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 


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choices on adaptation of treatment regimens, reinstitution of previous therapy, or 
discontinuation from study will be made in consultation with the NPS Pharmaceuticals (NPS) 
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.

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 treatment, which was initially 12 months, is being extended until December 
2016.   However, at the conclusion of the study, subjects will have a follow-up visit or a 
phone/wellness check one week after the last dose of study drug and will be contacted by 
telephone 3 weeks later, approximately 4 weeks (30 days) after the final dose of study drug, in 
order to follow up on any SAE or study drug-related AE.  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
8. Serum 25(OH) vitamin D ≤ 1.5 times the ULN within approximately 16 weeks prior to 
enrollment


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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 NPS, 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 (eCRF) and 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.
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.


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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 
cartridges to provide daily doses for the duration of the study.  Drug cartridges will be provided 
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 


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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.  
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

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


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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.  
Calcium and/or vitamin D should be taken in the morning as normal after the rhPTH[1-84]
injection. 


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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 
signing the ICF through study exit), including administration dates and dosage, are to be 
recorded on the appropriate eCRF.  Any medication which contains either calcium or vitamin 


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D must be recorded on the eCRF 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 entered on the appropriate eCRF.
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 entered on the appropriate eCRF. 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 entered 
on the appropriate eCRF.  
In the case that extra calcium supplementation is taken by the subject due to symptoms of 
hypocalcemia, the dose/time and associated symptoms should be recorded by the subject in 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 on 
the concomitant medication eCRF.
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 on the concomitant medication eCRF.


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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 (calcium-phosphate ratio)

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.    
At each visit, new AEs will be recorded sequentially on the AE page of the eCRF.  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 CRO/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 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 
SAE form.  The investigator should make the causality assessment based on the information 


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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 
determined that there is an unanticipated signal, the NPS SMT will analyze the data and prepare 


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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).  
NPS Pharmaceuticals (sponsor) 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  the sponsor 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:


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
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)

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 


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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 
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 and the eCRF.  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.


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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, 
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.


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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 eCRF.  Any deviations from protocol requirements will be documented in the 
eCRF.   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. 
lSee 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.
mBlood 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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PAR-C10-008 Protocol Amendment 5
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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.
jSee 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.  
lSubjects 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
Months 
44/56/68
Months 
46/58/70
Months 
48/60/72
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.)


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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
Months 
44/56/68
Months 
46/58/70
Months 
48/60/72
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
*Any adjustment of study drug or oral calcium and active vitamin D doses requires testing of total serum calcium concentrations at interim time points.
a Study visits will be conducted every 2 months and will continue until the subject voluntarily withdraws or until termination of the study (currently extended at least until 
December 2016).  At that time, and periodically following the December 2016 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 5. 
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 Final Visit
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 end of the 
End of Study visit (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)

Collect used and unused drug cartridges and supplements (calcium and calcitriol) for 
assessment of accountability (all visits).


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
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

Physical examination

12-lead electrocardiogram


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
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

Serum 25(OH) vitamin D


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
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)

Review the subject’s diary 


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
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 phone 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 
the sponsor (or designee) in a timely manner, on the eCRFs provided by the sponsor (or 


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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). 
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 


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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 (≥7.5 mg/dL) and does not exceed the ULN of the central 
laboratory
In addition, the following efficacy variables will be summarized: 

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


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
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.
8.6
Statistical/Analytical Issues 
8.6.1
Adjustments for Covariates
No preselected covariates are selected for adjustments.


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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. No other interim analyses are planned. 
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).
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).


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The investigator will inform the IRB/IEC of subsequent protocol amendments and any SUSARs 
if the NPS 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 
a secondary unique identifier (ie, hospital/clinic number).  A list of subjects who failed screening 
must also be maintained and be available for inspection.


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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 
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


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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 “Principal Investigator Protocol Agreement 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.  


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Appendix 4
SUMMARY OF CHANGES
NPS Pharmaceuticals, the original Sponsor of this study, was acquired by Shire Pharmaceuticals 
on 21 February 2015. Under NPS, this study had previously been extended through 
administrative letters to investigators in order to continue to collect long-term safety and efficacy 
data for rhPTH[1-84]. This amendment is to formalize the previous extensions and to clarify that 
the study will end in December 2016, in order to fulfil the previous commitment from NPS. 
The following schedule of changes lists the updates made from Amendment 3 to this update, 
Amendment 5. On 30 May 2013 this protocol was amended specifically for clinical site #1006. 
The amendment initiated for that site, Amendment 4, clarified that the study had been extended. 
The schedule of changes from Amendment 4 to Amendment 5 follows this summary.
Amendment 3 to Amendment 5 Summary of Changes
Additions from the previous version are marked by underline. Deletions from the previous 
amendment are marked by strikethrough.
The following changes were made but are not displayed in the table below:

Sponsor information, key contacts (including SAE reporting contact information), and 
signature page contacts were updated to reflect changes related to Shire’s acquisition of NPS 
Pharmaceuticals.

Changes to the protocol summary are not displayed as they are captured within the changes 
to the body of the protocol.

Minor editorial changes are not displayed. 

Amendment number indicating the current version (Amendment 5)

Many references to NPSP558 were removed and replaced with the compound name, 
rhPTH[1-84].

“Supplemental calcitrol” has been replaced with “active Vitamin D” 
Section
Change
Rationale
1.2 Rationale for 
Clinical Study
Hypoparathyroidism is one of the few hormonal deficiency 
syndromes in which replacement therapy using the native 
hormone is not clinically available.  
The purpose of the present study is to assess the long-term 
safety and efficacy of rhPTH[1-84] to treat 
hypoparathyroidism.
Editorial updates to 
clarify rationale and 
purpose of the study, 
and to acknowledge that 
commercial Natpara has 
been approved and 
treatment for 
hypoparathyroidism is 
clinically available.
1.3 Rationale for 
Study Design
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 
Updated to reflect 
RELAY patients may 
elect to continue on 
NPSP558 through the 
RACE study.


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total serum calcium levels, and controlling hypercalciuria in 
adult subjects with hypoparathyroidism.
2.3.1 Safety 
Endpoints

Immunogenicity analysis (AEs and SAEs related to PTH 
antibodies)

Injection pen-related events and/or complaints
New safety endpoints 
were added. This data 
was collected through 
the duration of the study 
but had not been 
specified in previous 
versions of the protocol.
2.3.3 Other 
efficacy endpoints

Proportion of subjects that maintain a calcium-phosphate 
product in the range of 35 to< 55 mg2/dL2 
(4.4 mmol2/L2).     
The lower limit for 
range was removed as it 
has no known clinical 
significance for this 
patient population and 
is not an endpoint for 
this product. Calcium 
and phosphate are 
assessed as individual 
endpoints for this study.
3.1 Overall 
Design and 
Control Methods

At the end of Week 52, subjects will be invited to extend 
their study participation.  Continuing subjects now will 
receive NPSP558 (rhPTH[1-84]) until at least October 
2013 December 2016.  During this time, subjects will 
return to the clinic for interim visits every 2 months 
(Months 14, 16, 18, etc).

During the week following the last visit (End of 
Treatment or early termination visit), subjects will have 
their total serum calcium levelswho are discontinuing 
NPSP558 (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 phosphorus checked.

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 phosphorus checks as a part of this study, but 
rather should continue follow-up serum calcium and/or 
phosphorus monitoring with a physician under approved
labeling instructions.  These subjects will be contacted 
one week after end of treatment for a wellness check.

Study extension date 
was updated to 
formalize the previous 
extensions that were 
initiated by NPS 
through administrative 
letters to investigators..
Follow-up procedures 
were clarified. Patients 
that do not continue on 
commercial Natpara 
will have oral 
calcium/active vitamin 
D adjusted to 
compensate for the 
cessation of NPSP558. 
Patients that continue 
on commercial Natpara 
will not require serum 
calcium/phosphorus 
checks following 
treatment as a 
component of this study 
but will continue to be 
monitored under the 
care of a physician 
under approved labeling 
instructions.
Figure 3-2
* 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 phosphorus checks, 
but should continue treatment under the supervision of a 
physician under approved labeling instructions.
** Approximately 4 weeks (30 days) following the End of 
Footnotes were added to 
clarify follow-up 
procedures.


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Treatment visit, all subjects will be contacted by telephone in 
order to assess AEs/SAEs.
3.2 Study 
Duration
The duration of treatment, which was initially 12 months, is 
being extended until October 2013December 2016, with 
further definition to be made by the sponsor at that time.  
However, at the conclusion of the study, subjects will have a 
follow-up visit or phone/email wellness check one week after 
the last dose of study drug and will be contacted by telephone 
3 weeks later, approximately 4 Weeks (30 days) after the final 
dose of study drug, in order to follow up on any SAE or study 
drug-related AE.  See Table 6-34 for additional follow-up for 
subjects who develop antibodies specific to PTH.
The study extension 
date was formalized. It 
was clarified that the 
follow-up visit may 
occur through phone or 
email.
4.4 Subject 
Withdrawal  
Criteria

Treatment with commercial drug (Natpara)
Procedure updated due 
to commercial Natpara 
approval in the United 
States. Subjects will be 
withdrawn for use of 
commercial Natpara as 
this could lead to drug 
accountability issues.
5.1.3 Storage, 
Accountability, 
and Stability
Prior to reconstitution, cartridges have a maximum shelf life 
of 36 months and 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 with 
infrequent exposure to room temperature for up to 30 minutes 
per day.Additional data on the reconstituted solution 
demonstrates that it is stable for up to 7 days when stored at 
25°C., which provides assurance of product quality during 
any unexpected excursions.  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 NPSP558 (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

quantity removed from stock but not dispensed (eg, 
damaged, dropped, spilled)

quantity remaining at the end of the study and retained or 
returned, or destroyed, 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 
This section was 
updated to reflect the 
most current Storage 
and Stability 
information. Patients 
are required to 
refrigerate study drug 
during the course of this 
study
Unused study drug must 
now be returned 
according to the 
sponsor’s instructions.


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drug containers will not be combined. Unused study drug will 
be returned or disposed of according to the sponsor’s 
instructions.
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 the end of 
the at monitoring visits study and submitted to the sponsor. 
Study procedures have 
changed. Diaries will 
not be collected at 
monitoring visits.
5.4.1
Exclusionary 
Prior/Concomitant 
Medications
In addition, concomitant active vitamin D supplements 
from outside sources are prohibited.
Sponsor is no longer 
providing active vitamin 
D supplements.
5.4.2 Active 
Vitamin D, 
Calcium, Native 
Vitamin D, and
Magnesium 
Supplementation
6.4.5 Long-term 
Extension Visits
Calcium
Oral calcium supplements (either calcium carbonate or 
calcium citrate) will be provided throughout this study, 
including through approximately May 2014. Calcium citrate 
will continue to be supplied through the long-term extension; 
nocalcium 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 entered on the appropriate eCRF.  
Sponsor stopped 
providing calcium 
carbonate in 
approximately May 
2014.
6.2 Safety 
Evaluation

Laboratory test results
o
PTH and ECP antibodies (If any(Any subject 
who tests positive for PTH-specific antibodies at 
the final visit, theylast 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 2,3 and 6 poststudy. If a subject’s 
results are negative at 2 successive visits within 
this timeframeMonth 3, follow-up may be 
terminated. If at the end of 6 months the subject 
is still determined to have PTH specific 
antibodies, the PI and the sponsor will determine 
if additional follow up may be required.  During 
this time, subjects also will be evaluated for AEs 
or SAEs related to immunogenicity, which will 
be collected in the Pharmacovigilance database.)  
Subjects may remain on study if they develop 
PTH-specific antibodies during the study, 
providing that there are no concurrent AEs 
related to immunogenicity.)

Pen-related events and/or complaints
Antibody follow-up was 
clarified. Patients will 
not be followed for 
PTH-specific antibodies 
beyond 6 months 
poststudy in order to 
eliminate the possibility 
for open-ended follow-
up without a pre-
determined endpoint. 
The Month 2 follow-up 
visit was removed Two 
consecutive visits in 
which a positive PTH-
antibodies are identified 
will confirm a persistent 
presence of antibodies 
before determining if 
follow-up is necessary. 
The Month 2 and Month 
3 visits did not offer a 
duration long enough to 
establish persistent 
antibody presence.


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Pen-related events were 
added as a correction. 
Data has been collected 
through the duration of 
the study.
6.2.1.2 Abuse, 
Misuse, Overdose, 
and Medication 
Error
Defined as an accidental or intentional administration of an 
excessive dose of a product, an overdose should be reported 
to the sponsor using the SAE form.  This information will be 
shared with the Safety Management Team (SMT) and 
medical monitor.
Abuse, misuse, overdose, or medication error (as defined 
below) must be reported to the sponsor according to the SAE 
reporting procedure whether or not they result in an AE/SAE 
as described in Section 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.
Language was updated 
to reflect the Shire 
protocol template.
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 completion of the last
study AE/ visit or the last study required procedure (including 
the follow-up telephone call 4 weeks after end of treatment).
SAEs will be monitored by the site with a telephone call by 
the investigator, as necessary, for approximately 30 days 
following4 weeks after the last dose of study drug or until 
resolution or the SAE is judged by the investigator to have 
stabilized.
It was clarified that the 
4 week follow-up will 
be conducted by 
telephone. Post-study 
SAE monitoring process 
was clarified.


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6.2.2 Serious 
Adverse Events
AAll serious eventevents 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 CRO/Shire Medical Monitor within 24 hours after the 
investigator is made aware of the event.
SAE reporting details 
were updated to align 
with Shire standards. to 
align with Shire 
template.
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 enternotify the sponsor. The
SAE information into InForm and fax supplementalwill 
include 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. 
The sponsor or designee will provide a FAX cover sheet for 
the investigators in the Study Reference Manual. Autopsy 
reports, if applicable, will be forwarded as they become 
available.  All pertinent laboratory results should be entered 
on the sponsor’s SAE form.
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.
SAE reporting details 
were updated to reflect 
Shire procedures.
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 an SAE 
supplementalthe Shire Investigational and Marketed Products 
Pregnancy Report form will be completed to capture potential 
drug exposure during pregnancy and will be 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, an additional SAE formthe 
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. 
An SAE supplemental formThe Shire Investigational and 
Marketed Products Pregnancy Report Form should be 
completed in the event that a female partner of a male subject 
Language was updated 
to reflect Shire 
procedures.


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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
Table 6-2 Changes are as follows:
Changes to row fields:
Adverse event monitoring (new) including pen-related 
events/complaints
Dispense/administration/accountability of study drug and pen 
injectors/ancillary suppliesn
Changes to columns:
The following columns were removed as end of study 
procedures are now included in Table 6.3: End of Treatment,  
Poststudy Int., F/up, and F/up Phone
Changes to footnotes:
**Following Month 24, the every 2-month visit schedule will 
repeat (ie, visits procedures will repeat starting withfor 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 (at 
least until October 2013)..
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. Interim total serum calcium (local) for all 
subjects 3 to 5 days (±2 days) after last dose of study drug.  Subjects 
who terminate or complete the study and opt to continue treatment 
on commercial drug (Natpara), will not require follow up serum 
calcium checks.
c A follow-up safety visit (local) will be conducted 1 week after the 
last dose of study drug. Subjects who continue treatment on 
commercial drug (Natpara), will not require a follow up serum 
calcium and phosphorus checks, but will be contacted via phone or 
email for a wellness check.
d Follow up phone contact 30 days 4 weeks after the last dose of 
study medication to check on any ongoing or new drug related AEs 
or SAEs
Footnote letters were adjusted to account for deletions.
Table 6-3 Changes are as follows:
The previous Table 6-3 is now listed as table 6-4. See Table 
All Schedule of 
Evaluations and 
Procedures tables were 
updated to reflect new 
study procedures and 
the extension past 
Month 36.


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PAR-C10-008 Protocol Amendment 5
3 May 2016
6-3 in the body of the document. This table is new to this 
Amendment text and was added to provide the Schedule of 
Evaluations and Procedures for the Long-term extension after 
Month 36. 
Table 6-4 Changes are as follows:
In the previous Amendment this was Table 6-3. The Month 2 
Follow-up column has been removed.
a Follow-up visits will be conducted for only those subjects 
who are determined to have PTH-specific antibodies at the 
end of the End of Study visit (or at the time of 
discontinuation).) and are NOT continuing treatment on 
commercial Natpara. See Section 6.4.10.
b Blood samples forSubjects who have negative antibody
determination may be collected locally.  Occurrence of any 
AEs duringresults at Month 3 do not need the Month 6
follow-up period may be determined via phone visit.
6.4.6 End of 
Treatment Visit or 
Early Termination

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.
End of study treatment 
options for patients 
clarified for patients 
that will continue to 
take commercial 
Natpara under the care 
of a physician under 
approved labeling 
instructions. 
6.4.7 Post-
treatment 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 phone call, further 
management of hypoparathyroidism will occur 
as part of the subject’s long-term non-study 
medical care.
Subjects who return to treatment with oral calcium and active 
vitamin D will have a total serum calcium level drawn locally 
between 3 to 5 days (± 2 days) following the last dose of 
study drug.  Poststudy adjustments of supplemental calcium 
and calcitriolactive vitamin D will be made (see Appendix 2 , 
NPSP558 (rhPTH[1 84]) and Supplement Titration 
Guideline) based on this value.  Subjects who continue 
treatment with commercial Natpara will not have a total 
Clarified that subjects 
who return to treatment 
with oral calcium and 
active vitamin D will 
have total serum 
calcium levels drawn 3-
5 days following the last 
dose of study drug to 
determine if dose 
adjustments need to be 
made. Subjects who 
transition to commercial 
Natpara will not need 
this poststudy safety 
check but will be 
monitored under the 
care of a physician 
under approved labeling 
instructions. 


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serum calcium level drawn (as they will continue to be 
monitored under the care of a physician under approved 
labeling instructions), but will be contacted by phone or email 
for a wellness check.
6.4.8 Follow-up 
Safety Visit
One week following the last dose of study drug, 
subjects who return to treatment with oral 
calcium and active vitamin D will have blood 
drawn for total serum calcium, and phosphorus 
levels which will be done locally.  Further 
adjustment of subjects’ supplementaloral
calcium and calcitriolactive vitamin D doses 
will be made based on these values (see 
Appendix 2 , NPSP558 (rhPTH[1 84]) and 
Supplement Titration Guideline).  Subjects will 
also be monitored for 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. Subjects who continue treatment with 
commercial Natpara will not have a total serum 
calcium level drawn (as they will continue to be 
monitored under the care of a physician under 
approved labeling instructions), but will be 
contacted by phone or email for a wellness 
check.
Clarified that subjects 
who return to treatment 
with oral calcium and 
active vitamin D will 
have total serum 
calcium levels drawn 
one week past the last 
dose of study drug to 
determine if dose 
adjustments need to be 
made. Subjects who 
transition to commercial 
Natpara will not need 
this poststudy safety 
check but will be 
monitored under the 
care of a physician 
under approved labeling 
instructions.
6.4.8 Follow-up 
Telephone 
Contact
Subjects will be contacted approximately 30 days 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.
Post-study SAE 
monitoring process was 
clarified.
6.4.9 Follow-up 
assessment for 
PTH antibodies
If anyAny 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 the final visit, they will have follow-up 
blood draws for PTH antibodies at Months 2, 3 and 6 
poststudy.  If a subject’s results are negative at 2 successive 
visits within this timeframeMonth 3, follow-up may be 
terminated.  If at the end of 6 months the subject is still 
determined to have PTH specific antibodies, the PI and the 
sponsor will determine if additional follow up may be 
required.  During this time, subjects also will be evaluated for 
AEs or SAEs related to immunogenicity, which will be 
collected in the Pharmacovigilance database (see Section 6.2).
Antibody follow-up was 
clarified. Patients will 
not be followed for 
PTH-specific antibodies 
beyond 6 months 
poststudy in order to 
eliminate the possibility 
for open-ended follow-
up without a pre-
determined endpoint. 
The Month 2 follow-up 
visit was removed Two 
consecutive visits in 
which a positive PTH-
antibodies are identified 
will confirm a persistent 
presence of antibodies 
before determining if 


Shire
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3 May 2016
follow-up is necessary. 
The Month 2 and Month 
3 visits did not offer a 
duration long enough to 
establish persistent 
antibody presence.
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.
Pen-related events or 
complaints added.
8.3 Efficacy 
Variables

Proportion of subjects that maintain a calcium-phosphate 
product in the range of 35 to< 55 mg2/dL2 (4.4 mmol2/L2)   
The lower limit for 
range was removed as it 
has no known clinical 
significance for this 
patient population and 
is not an endpoint for 
this product. Calcium 
and phosphate are 
assessed as individual 
endpoints for this study.
8.4 Other 
Variables
Other variables to be analyzed will include the following: 

calcium and active vitamin D intake (based on diary 
entries)
This change was made 
to clarify what is being 
analyzed as “subject 
accounting” was 
unclear.
8.6.3 Interim 
Analyses and Data 
Monitoring
AnNo interim study report will be completed to look 
atanalyses are planned other than as required for safety and 
efficacy compiled through 31 May 2012reporting to 
regulatory authorities. An interim analyses was performed in 
2013, no additional interim analyses are planned. 
Updated to reflect that 
no interim study report 
is planned.
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.
Error correction.


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PAR-C10-008 Protocol Amendment 5
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Amendment 4 to Amendment 5 Summary of Changes
Additions from the previous version are marked by underline. Deletions from the previous 
amendment are marked by strikethrough.
The following changes were made but are not displayed in the table below:

Sponsor information, key contacts (including SAE reporting contact information), and 
signature page contacts were updated to reflect changes related to Shire’s acquisition of NPS 
Pharmaceuticals.

Changes to the protocol summary are not displayed as they are captured within the changes 
to the body of the protocol.

Minor editorial changes are not displayed. 

Amendment number indicating the current version (Amendment 5)

Many references to NPSP558 were removed and replaced with the compound name, 
rhPTH[1-84].

“Supplemental calcitrol” has been replaced with “active Vitamin D” 
Section
Change
Rationale
1.2 Rationale for 
Clinical Study
Hypoparathyroidism is one of the few hormonal deficiency 
syndromes in which replacement therapy using the native 
hormone is not clinically available.  
The purpose of the present study is to assess the long-term 
safety and efficacy of rhPTH[1-84] to treat 
hypoparathyroidism.
Editorial updates to 
clarify rationale and 
purpose of the study, 
and to acknowledge that 
commercial Natpara has 
been approved and 
treatment for 
hypoparathyroidism is 
clinically available.
1.3 Rationale for 
Study Design
In a phase 2 study of NPSP558 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. The pivotal 
safety and efficacy study, REPLACE, 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.  Both of 
these studies are 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 NPSP558 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. 
Updated to reflect 
RELAY patients may 
elect to continue on 
NPSP558 through the 
RACE study.
2.3.1 Safety 
Endpoints

Immunogenicity analysis (AEs and SAEs related to PTH 
antibodies)

Injection pen-related events and/or complaints
New safety endpoints 
were added. This data 
was collected through 
the duration of the study 


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PAR-C10-008 Protocol Amendment 5
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but had not been 
specified in previous 
versions of the protocol.
2.3.3 Other 
efficacy endpoints

Proportion of subjects that maintain a calcium-phosphate 
product in the range of 35 to< 55 mg2/dL2 (4.4 mmol2/L2).   
The lower limit for 
range was removed as it 
has no known clinical 
significance for this 
patient population and 
is not an endpoint for 
this product. Calcium 
and phosphate are 
assessed as individual 
endpoints for this study.
3.1 Overall 
Design and 
Control Methods

At the end of Week 52, subjects will be invited to extend 
their study participation.  Continuing subjects now will 
receive NPSP558 (rhPTH[1-84]) until at least December 
2014 December 2016.  During this time, subjects will 
return to the clinic for interim visits every 2 months 
(Months 14, 16, 18, etc). A decision to extend the study 
beyond this date will be made on or before December 
2014.

During the week following the last visit (End of 
Treatment or early termination visit), subjects will have 
their total serum calcium levelswho are discontinuing 
NPSP558 (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.

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 with a physician under approved
labeling instructions.  These subjects will be contacted 
one week after end of treatment for a wellness check.

Study extension date 
was updated to 
formalize the previous 
extensions that were 
initiated by NPS 
through administrative 
letters to investigators..
Follow-up procedures 
were clarified. Patients 
that do not continue on 
commercial Natpara 
will have oral 
calcium/active vitamin 
D adjusted to 
compensate for the 
cessation of NPSP558. 
Patients that continue 
on commercial Natpara 
will not require serum 
calcium/phosphate
checks following 
treatment as a 
component of this study 
but will continue to be 
monitored under the 
care of a physician 
under approved labeling 
instructions.
Figure 3-2
* 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.
Footnotes were added to 
clarify follow-up 
procedures.
3.2Study Duration
The duration of treatment, which was initially 12 months, is 
being extended until at least December 2014 December 2016. 
The study extension 
date was formalized. It 


Shire
CONFIDENTIAL
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PAR-C10-008 Protocol Amendment 5
3 May 2016
The sponsor will re evaluate the study status at that time in 
anticipation of additional extension. Regardless of when the 
last visit occurs, However, at the conclusion of the study, 
subjects will have a follow-up visit or phone/email wellness 
check one week after the last dose of study drug and will be 
contacted by telephone 3 weeks later, approximately 4 Weeks
(30 days) after the final dose of study drug, in order to follow 
up on any SAE or study drug-related AE.  See Table 6-34 for 
additional follow-up for subjects who develop antibodies 
specific to PTH.
was clarified that the 
follow-up visit may 
occur through phone or 
email.
4.4 Subject 
Withdrawal  
Criteria

Treatment with commercial drug (Natpara)
Procedure updated due 
to commercial Natpara 
approval in the United 
States. Subjects will be 
withdrawn for use of 
commercial Natpara as 
this could lead to drug 
accountability issues.
5.1.3 Storage, 
Accountability, 
and Stability
Prior to reconstitution, cartridges have a maximum shelf life 
of 36 months and 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 with 
infrequent exposure to room temperature for up to 30 minutes 
per day.Additional data on the reconstituted solution 
demonstrates that it is stable for up to 7 days when stored at 
25°C., which provides assurance of product quality during 
any unexpected excursions.  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 NPSP558 (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

quantity removed from stock but not dispensed (eg, 
damaged, dropped, spilled)

quantity remaining at the end of the study and retained or 
returned, or destroyed, 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 or disposed of according to the sponsor’s 
instructions.
This section was 
updated to reflect the 
most current Storage 
and Stability 
information. Patients 
are required to 
refrigerate study drug 
during the course of this 
study
Unused study drug must 
now be returned 
according to the 
sponsor’s instructions.


Shire
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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 the 
monitoring visits at the end of the study and submitted to the 
sponsor. 
Study procedures have 
changed. Diaries will 
not be collected at 
monitoring visits.
5.4.1
Exclusionary 
Prior/Concomitant 
Medications
In addition, concomitant active vitamin D supplements 
from outside sources are prohibited.
Sponsor is no longer 
providing active vitamin 
D supplements.
5.4.2 Active 
Vitamin D, 
Calcium, Native 
Vitamin D, and 
Magnesium 
Supplementation
6.4.5 Long-term 
Extension Visits
Calcium
Oral calcium supplements (either calcium carbonate or 
calcium citrate) will be provided throughout this study, 
including through approximately May 2014. Calcium citrate 
will continue to be supplied through the long-term extension; 
nocalcium 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 entered on the appropriate eCRF.  
6.2 Safety 
Evaluation

Laboratory test results
o
PTH and ECP antibodies (If any(Any subject 
who tests positive for PTH-specific antibodies at 
the final visit, theylast 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 2,3 and 6 poststudy. If a subject’s 
results are negative at 2 successive visits within 
this timeframeMonth 3, follow-up may be 
terminated. If at the end of 6 months the subject 
is still determined to have PTH specific 
antibodies, the PI and the sponsor will determine 
if additional follow up may be required.  During 
this time, subjects also will be evaluated for AEs 
or SAEs related to immunogenicity, which will 
be collected in the Pharmacovigilance database.)  
Subjects may remain on study if they develop 
PTH-specific antibodies during the study, 
providing that there are no concurrent AEs 
related to immunogenicity.)

Pen-related events and/or complaints
Antibody follow-up was 
clarified. Patients will 
not be followed for 
PTH-specific antibodies 
beyond 6 months 
poststudy in order to 
eliminate the possibility 
for open-ended follow-
up without a pre-
determined endpoint. 
The Month 2 follow-up 
visit was removed Two 
consecutive visits in 
which a positive PTH-
antibodies are identified 
will confirm a persistent 
presence of antibodies 
before determining if 
follow-up is necessary. 
The Month 2 and Month 
3 visits did not offer a 
duration long enough to 
establish persistent 
antibody presence.
Pen-related events were 
added as a correction. 
Data has been collected 


Shire
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PAR-C10-008 Protocol Amendment 5
3 May 2016
through the duration of 
the study.
6.2.1.2 Abuse, 
Misuse,
Overdose, and 
Medication Error
Defined as an accidental or intentional administration of an 
excessive dose of a product, an overdose should be reported to 
the sponsor using the SAE form.  This information will be 
shared with the Safety Management Team (SMT) and medical 
monitor.
Abuse, misuse, overdose, or medication error (as defined 
below) must be reported to the sponsor according to the SAE 
reporting procedure whether or not they result in an AE/SAE 
as described in Section 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.
Language was updated 
to reflect the Shire 
protocol template.
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 completion of the last
study AE/ visit or the last study required procedure (including 
the follow-up telephone call 4 weeks after end of treatment).
SAEs will be monitored by the site with a telephone call by 
the investigator, as necessary, for approximately 30 days 
following4 weeks after the last dose of study drug or until 
resolution or the SAE is judged by the investigator to have 
stabilized.
It was clarified that the 
4 week follow-up will 
be conducted by 
telephone. Post-study 
SAE monitoring process 
was clarified.
6.2.2 Serious 
Adverse Events
AAll serious eventevents 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 
SAE reporting details 
were updated to align 
with Shire standards. to 
align with Shire 


Shire
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PAR-C10-008 Protocol Amendment 5
3 May 2016
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 CRO/Shire Medical Monitor within 24 hours after the 
investigator is made aware of the event.
template.
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 enternotify the sponsor. The
SAE information into InForm and fax supplementalwill 
include 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. 
The sponsor or designee will provide a FAX cover sheet for 
the investigators in the Study Reference Manual. Autopsy 
reports, if applicable, will be forwarded as they become 
available.  All pertinent laboratory results should be entered 
on the sponsor’s SAE form.
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.
SAE reporting details 
were updated to reflect 
Shire procedures.
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 an SAE 
supplementalthe Shire Investigational and Marketed Products 
Pregnancy Report form will be completed to capture potential 
drug exposure during pregnancy and will be 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, an additional SAE formthe 
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. 
An SAE supplemental formThe 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.
Language was updated 
to reflect Shire 
procedures.


Shire
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PAR-C10-008 Protocol Amendment 5
3 May 2016
6.3 Schedule of 
Evaluations and 
Procedures
Table 6-2 Changes are as follows:
Changes to row fields:
Serum calcium, phosphorus phosphate
Adverse event monitoring (new) including pen-related 
events/complaints
Dispense/administration/accountability of study drug and pen 
injectors/ancillary suppliesn
Changes to columns:
The following columns were removed as end of study 
procedures are now included in Table 6.3: End of Treatment,  
Poststudy Int., F/up, and F/up Phone
Changes to footnotes:
**Following Month 24, the every 2-month visit schedule will 
repeat (ie, visits procedures will repeat starting withfor 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.
currently extended at least until December 2014).  At that time, 
and periodically following the December 2014 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. Interim total serum calcium (local) for all 
subjects 3 to 5 days (±2 days) after last dose of study drug.  Subjects 
who terminate or complete the study and opt to continue treatment 
on commercial drug (Natpara), will not require follow up serum 
calcium checks.
c A follow-up safety visit (local) will be conducted 1 week after the 
last dose of study drug. Subjects who continue treatment on 
commercial drug (Natpara), will not require a follow up serum 
calcium and phosphorus checks, but will be contacted via phone or 
email for a wellness check.
d Follow up phone contact 30 days 4 weeks after the last dose of 
study medication to check on any ongoing or new drug related AEs 
or SAEs
Table 6-3 Changes are as follows:
All Schedule of 
Evaluations and 
Procedures tables were 
updated to reflect new 
study procedures and 
the extension past 
Month 36.


Shire
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PAR-C10-008 Protocol Amendment 5
3 May 2016
The previous Table 6-3 is now listed as table 6-4. See Table 
6-3 in the body of the document. This table is new to this 
Amendment text and was added to provide the Schedule of 
Evaluations and Procedures for the Long-term extension after 
Month 36. 
Table 6-4 Changes are as follows:
In the previous Amendment this was Table 6-3. The Month 2 
Follow-up column has been removed.
a Follow-up visits will be conducted for only those subjects 
who are determined to have PTH-specific antibodies at the 
end of the End of Study visit (or at the time of 
discontinuation).) and are NOT continuing treatment on 
commercial Natpara. See Section 6.4.10.
b Blood samples forSubjects who have negative antibody 
determination may be collected locally.  Occurrence of any 
AEs duringresults at Month 3 do not need the Month 6
follow-up period may be determined via phone visit.
6.4.6 End of 
Treatment Visit or 
Early Termination

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.
End of study treatment 
options for patients 
clarified for patients 
that will continue to 
take commercial 
Natpara under the care 
of a physician under 
approved labeling 
instructions. 
6.4.7 Post-
treatment 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 phone call, further management of 
hypoparathyroidism will occur as part of the subject’s long-
term non-study medical care.
Subjects who return to treatment with oral calcium and active 
vitamin D will have a total serum calcium level drawn locally 
between 3 to 5 days (± 2 days) following the last dose of 
study drug.  Poststudy adjustments of supplemental calcium 
and calcitriolactive vitamin D will be made (see Appendix 2 , 
NPSP558 (rhPTH[1 84]) and Supplement Titration 
Guideline) based on this value.  Subjects who continue 
treatment with commercial Natpara will not have a total 
serum calcium level drawn (as they will continue to be 
monitored under the care of a physician under approved 
labeling instructions), but will be contacted by phone or email 
for a wellness check.
Clarified that subjects 
who return to treatment 
with oral calcium and 
active vitamin D will 
have total serum 
calcium levels drawn 3-
5 days following the last 
dose of study drug to 
determine if dose 
adjustments need to be 
made. Subjects who 
transition to commercial 
Natpara will not need 
this poststudy safety 
check but will be 
monitored under the 
care of a physician 
under approved labeling 
instructions. 


Shire
CONFIDENTIAL
Page 94
PAR-C10-008 Protocol Amendment 5
3 May 2016
6.4.8 Follow-up 
Safety Visit
One week following the last dose of study drug, subjects who 
return to treatment with oral calcium and active vitamin D
will have blood drawn for total serum calcium, and 
phosphorus levels which will be done locally.  Further 
adjustment of subjects’ supplementaloral calcium and 
calcitriolactive vitamin D doses will be made based on these 
values (see Appendix 2 , NPSP558 (rhPTH[1 84]) and 
Supplement Titration Guideline).  Subjects will also be 
monitored for 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. Subjects who continue treatment with commercial 
Natpara will not have a total serum calcium level drawn (as 
they will continue to be monitored under the care of a 
physician under approved labeling instructions), but will be 
contacted by phone or email for a wellness check.
Clarified that subjects 
who return to treatment 
with oral calcium and 
active vitamin D will 
have total serum 
calcium levels drawn 
one week past the last 
dose of study drug to 
determine if dose 
adjustments need to be 
made. Subjects who 
transition to commercial 
Natpara will not need 
this poststudy safety 
check but will be 
monitored under the 
care of a physician 
under approved labeling 
instructions.
6.4.8 Follow-up 
Telephone 
Contact
Subjects will be contacted approximately 30 days 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.
Post-study SAE 
monitoring process was 
clarified.
6.4.9 Follow-up 
assessment for 
PTH antibodies
If anyAny 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 the final visit, they will have follow-up 
blood draws for PTH antibodies at Months 2, 3 and 6 
poststudy.  If a subject’s results are negative at 2 successive 
visits within this timeframeMonth 3, follow-up may be 
terminated.  If at the end of 6 months the subject is still 
determined to have PTH specific antibodies, the PI and the 
sponsor will determine if additional follow up may be 
required.  During this time, subjects also will be evaluated for 
AEs or SAEs related to immunogenicity, which will be 
collected in the Pharmacovigilance database (see Section 6.2).
Antibody follow-up was 
clarified. Patients will 
not be followed for 
PTH-specific antibodies
beyond 6 months 
poststudy in order to 
eliminate the possibility 
for open-ended follow-
up without a pre-
determined endpoint. 
The Month 2 follow-up 
visit was removed Two 
consecutive visits in 
which a positive PTH-
antibodies are identified 
will confirm a persistent 
presence of antibodies 
before determining if 
follow-up is necessary. 
The Month 2 and Month 
3 visits did not offer a 
duration long enough to 
establish persistent 
antibody presence.
8.2 Safety 
Variables
Safety data including vital signs assessments, physical 
examinations, AEs, SAEs, pen-related events or complaints, 
Pen-related events or 
complaints added.


Shire
CONFIDENTIAL
Page 95
PAR-C10-008 Protocol Amendment 5
3 May 2016
concomitant medications, clinical laboratory tests, ECG 
monitoring, and termination from study will be summarized 
by treatment group and point of time of collection.
8.3 Efficacy 
Variables

Proportion of subjects that maintain a calcium-phosphate 
product in the range of 35 to< 55 mg2/dL2 (4.4 mmol2/L2)    
The lower limit for 
range was removed as it 
has no known clinical 
significance for this 
patient population and 
is not an endpoint for 
this product. Calcium 
and phosphate are 
assessed as individual 
endpoints for this study.
8.4 Other 
Variables
Other variables to be analyzed will include the following: 

calcium and active vitamin D intake (based on diary 
entries)
This change was made 
to clarify what is being 
analyzed as “subject 
accounting” was 
unclear.
8.6.3 Interim 
Analyses and 
Data Monitoring
AnNo interim study report will be completed to look 
atanalyses are planned other than as required for safety and 
efficacy compiled through 25 March 2013reporting to 
regulatory authorities. An interim analyses was performed in 
2013, no additional interim analyses are planned. 
Updated to reflect that 
no interim study report 
is planned.
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.
Error correction.

Prot_001.pdf: 
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 1 
 
Protocol Version Date: 29 June 2011 


 
 
CONFIDENTIAL 
 
 
 
 
NPSP558 
 
A 12-Month 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) 
 
 
 
Clinical Protocol PAR-C10-008 
US IND Number: 76,514 
 
 
 
NPS Pharmaceuticals, Inc.  
550 Hills Drive, 3rd Floor 
Bedminster, NJ 07921 
 
ISSUED:   
Original Protocol Version 1.0: 
30 December 2010  
Amendment 1 Version 2.0:  
29 June 2011 
 


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CLINICAL PROTOCOL PAR-C10-008 AMENDMENT 1 
Page 3 of 76 
Confidential 
 
 
 
Final v2.0 
29 June 2011 
 
SUMMARY 
Title:  A 12-Month 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 
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 as hormone replacement therapy for the treatment of adult 
subjects with hypoparathyroidism. 
Secondary Objectives: 
 To evaluate the impact of different preparations of calcium and calcitriol on the 
response to NPSP558 replacement therapy 
 To demonstrate that dosing with NPSP558 across a dose range of 25 to 100 μg SC 
can be implemented in a safe and effective manner and can be maintained 
throughout 12 months (52 weeks) of treatment 
 To evaluate the impact of calcium-sparing diuretics on serum and urinary calcium 
Study Rationale 
This study is designed to evaluate 12-month treatment with NPSP558.  
Study Design 
This study is a 12-month, open-label study using NPSP558 for the treatment of adults 
with hypoparathyroidism. Subjects can enroll if they either previously completed the 
NPSP558 RELAY study (8 weeks of active therapy) and/or completed the REPLACE 
study (Visit 18). 
The goal of this study is to optimize NPSP558 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 NPSP558 and to the 
calcium/calcitriol supplements and safety monitoring of calcium levels are explained in 
Appendix 2, NPSP558 and Supplement Titration Guideline.   
 
The starting dose of NPSP558 for this study will be 25 or 50 g SC once daily  


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 
Subjects may have their NPSP558 dose adjusted by the investigator at any time 
through Week 48 of 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 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 NPSP558, 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 will be conducted at Weeks 1 (baseline), 4, 8, and then every 
8 weeks thereafter up to Week 48 (Visit 8).  The End of Treatment Visit 
(Week 52, Visit 9) is scheduled 4 weeks later followed by a safety visit at Week 
53 (Visit 10) and a follow-up telephone contact at Week 56 (Visit 11).    
 
At the Week 16 (Visit 4), subjects who are on a stable dose of NPSP558 and 
have a 24-hour urine calcium > 300 mg may be treated for hypercalciuria with 
calcium-sparing diuretics. 
 
During Week 53, subjects will have their total serum calcium levels 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 Week 53 (Visit 10) in order to have serum calcium, phosphorus, and 
albumin checked.   
Number of Subjects Planned:  Approximately 40 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 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 injection pen 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 levels (> 40 IU/L); (2) surgically 


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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.  Female 
partners (who are of childbearing potential) of male study subjects must also use 
acceptable forms of contraception during their partner’s participation.   
6. Serum creatinine <1.5 mg/dL at 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 total duration of treatment will be 12 months (52 weeks).   Subjects will have a 
follow-up visit at Week 53 and will also be contacted by telephone at Week 56.      
Test Product, Dose, and Mode of Administration:  
At the beginning of the study, subjects will receive NPSP558 25 or 50 µg SC QD in an 
open-label fashion as defined earlier.  Subjects may have their NPSP558 dose adjusted 
upwards in increments of 25 µg to a maximum of 100 µg SC QD.  NPSP558 is to be 
administered into alternating thighs each morning via a multidose injection pen device.  
Supplements:  
Calcium citrate, calcium carbonate, and calcitriol will be supplied by the sponsor.  
Criteria for Evaluation:  
Safety:  
Safety variables will be assessed by the following evaluations:  
 Adverse events and serious adverse events 


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 Incidence of adverse events 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 
o Hematology (hematocrit, hemoglobin, white blood cells, red blood cells, 
platelets, differential) 
o Serum chemistries (standard Chem-20 panel) 
o Serum 25-hydroxyvitamin D levels 
o Creatinine clearance 
o Serum bone turnover markers 
o Urinalysis 
o 24-hour urine calcium, phosphate, sodium, and creatinine excretion 
o PTH 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 
Efficacy:   
Efficacy variables will be assessed by one or more of the following evaluations: 
 Laboratory test results 
o Total serum calcium  
o 24-hour urinary calcium excretion 
o Serum phosphate (calcium-phosphate ratio)  
 Supplement usage 
o Concomitant supplemental oral calcium dosage 
o 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. 


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Analysis of Demographic and Baseline Variables 
Demographic variables (such as sex, age, race, birthdate, etc.) will be obtained from the 
REPLACE or RELAY study, if available.   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 condition.  
Efficacy Variables Summary 
Primary Efficacy Endpoint: 
The proportion of subjects in whom the following three conditions are fulfilled at 
Week 52 (Visit 9) 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 (≥7.5 mg/dL) and does not exceed the 
ULN for the central laboratory 
Secondary Efficacy Endpoints:  
 Mean percentage changes from baseline in supplemental oral calcium and 
supplemental calcitriol dosages at each visit 
 Proportion of subjects achieving the primary endpoint 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        
 Distribution of subjects by NPSP558 doses at the End of Treatment Visit 


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 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 adverse events 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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PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE 
Protocol PAR-C10-008 Amendment 1 
I agree: 
To assume responsibility for the proper conduct of this clinical study at this center and to 
conduct the study in compliance with this protocol, any future amendments, and with any 
other study conduct procedures provided by the sponsor, 
That I am aware of, and will comply with, the internationally recognized code of Good 
Clinical Practice and all other applicable regulatory requirements to obtain written and 
dated approval from the Institutional or Central Review Board (IRB) or Independent 
Ethics Committee (IEC) for the study protocol and any amendments thereof, written 
informed consent or updates thereof, subject recruitment procedures (eg, advertisements), 
and any other written information to be provided to the subjects, before initiating this 
clinical study, 
Not to implement any changes to, or deviations from the protocol without prior 
agreement from the sponsor and review and documented approval from the IRB/IEC, 
except to eliminate an immediate hazard to the study subjects, or when change(s) 
involves only logistical or administrative aspects of the clinical study, 
To permit direct monitoring and auditing by the sponsor or sponsor’s representatives and 
inspection by the appropriate regulatory authority(ies), 
That I am thoroughly familiar with the appropriate use of the investigational product(s), 
as described in this protocol, and any other information provided by the sponsor or 
designee, including, but not limited to, the current Investigator’s Brochure or equivalent 
document and approved product label (if applicable), 
To provide sufficient time and an adequate number of qualified staff and facilities for the 
foreseen duration of the clinical study in order to conduct the study properly, ethically, 
and safely, 
To ensure that all persons assisting in this study are adequately informed about the 
protocol, investigational product(s), and their clinical study-related duties and functions, 
To 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.   
 
 
Principal Investigator (Print Name) 
 
 
 
 
Principal Investigator (Signature) 
 
Date (DD MMM YYYY) 


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TABLE OF CONTENTS 
TITLE PAGE .....................................................................................................................1 
SPONSOR KEY CONTACTS..........................................................................................2 
SUMMARY ........................................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.................................15 
1 INTRODUCTION......................................................................................................17 
1.1 Background.........................................................................................................17 
1.2 Rationale for the Clinical Study..........................................................................20 
1.3 Rationale for Study Design.................................................................................24 
2 OBJECTIVES ............................................................................................................24 
2.1 Primary Objective...............................................................................................24 
2.2 Secondary Objectives..........................................................................................24 
2.3 Endpoints ............................................................................................................24 
2.3.1 
Safety Endpoints..................................................................................24 
2.3.2 
Efficacy Endpoints...............................................................................25 
2.3.2.1 Primary Efficacy Endpoint ...................................................25 
2.3.2.2 Secondary Efficacy Endpoints..............................................26 
3 STUDY DESIGN........................................................................................................26 
3.1 Overall Design and Control Methods .................................................................26 
3.2 Study Duration....................................................................................................29 
4 SUBJECT SELECTION AND PARTICIPATION................................................29 
4.1 Number of Subjects.............................................................................................29 
4.2 Inclusion Criteria ................................................................................................29 
4.3 Exclusion Criteria ...............................................................................................30 
4.4 Subject Withdrawal Criteria ...............................................................................30 
5 TREATMENTS AND TREATMENT PLAN .........................................................31 
5.1 Treatments Administered....................................................................................31 
5.1.1 
Identification of Investigational Product(s) .........................................31 
5.1.2 
Packaging and Labeling.......................................................................31 
5.1.3 
Storage, Accountability, and Stability .................................................32 


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5.2 Methods of Assigning Subjects to Treatment Groups........................................33 
5.3 Dose Regimens ...................................................................................................33 
5.3.1 
Selection of Doses in Study.................................................................33 
5.3.2 
Selection and Timing of Dose for Each Subject..................................34 
5.3.3 
Compliance With Dosing Regimens....................................................34 
5.4 Prior and Concomitant Medications ...................................................................34 
5.4.1 
Exclusionary Prior/Concomitant Medications.....................................34 
5.4.2 
Active Calcitriol, Calcium, Native Vitamin D, and Magnesium 
Supplementation ..................................................................................36 
6 STUDY EVALUATIONS AND PROCEDURES ...................................................36 
6.1 Efficacy Evaluations...........................................................................................36 
6.2 Safety Evaluations ..............................................................................................37 
6.2.1 
Adverse Events ....................................................................................37 
6.2.1.1 Adverse Event Definition .....................................................38 
6.2.1.2 Procedures for Reporting Adverse Events............................38 
6.2.2 
Serious Adverse Events .......................................................................39 
6.2.2.1 Serious Adverse Event Definition ........................................40 
6.2.2.2 Procedures for Reporting Serious Adverse Events...............40 
6.2.3 
Laboratory Evaluations........................................................................43 
6.2.4 
Vital Signs and Body Weight ..............................................................44 
6.2.5 
Electrocardiograms ..............................................................................44 
6.2.6 
Physical Examinations.........................................................................45 
6.2.7 
Dual-energy X-ray Absorptiometry.....................................................45 
6.2.8 
Women of Childbearing Potential .......................................................45 
6.2.9 
Pregnancy Reporting............................................................................46 
6.3 Schedule of Evaluations and Procedures............................................................46 
6.4 Description of Study Procedures ........................................................................49 
6.4.1 
Visit 1 Baseline Procedures .................................................................49 
6.4.2 
Week 1 Interim Safety Check..............................................................50 
6.4.3 
Weeks 4, 8, 16, 24, 32, 40, and 48 (Visits 2 through 8) Study 
Clinic Visits .........................................................................................50 
6.4.4 
Week 52 (Visit 9) End of Study Visit..................................................51 
6.4.5 
Week 53 Interim Safety Check............................................................52 


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6.4.6 
End of Week 53 (Visit 10) Follow-up Safety Visit .............................52 
6.4.7 
Week 56 (Visit 11) Follow-up Telephone Contact..............................52 
7 DATA MANAGEMENT...........................................................................................52 
7.1 Data Collection ...................................................................................................52 
7.2 Record Retention ................................................................................................53 
8 STATISTICAL METHODOLOGY AND SAMPLE SIZE...................................53 
8.1 Demographic and Baseline Variables.................................................................53 
8.2 Safety Variables..................................................................................................54 
8.2.1 
Efficacy Variables................................................................................54 
8.3 Other Variables...................................................................................................55 
8.4 Analysis Populations, Data Sets, and Time Points .............................................55 
8.4.1 
Analysis Populations............................................................................55 
8.5 Statistical/Analytical Issues ................................................................................56 
8.5.1 
Adjustments for Covariates..................................................................56 
8.5.2 
Handling of Dropouts or Missing Data................................................56 
8.5.3 
Interim Analyses and Data Monitoring................................................56 
8.5.4 
Multiple Comparisons/Multiplicity .....................................................56 
8.5.5 
Use of a Pharmacokinetic Subset of Subjects......................................56 
8.5.6 
Examination of Subgroups...................................................................56 
8.6 Determination of Sample Size ............................................................................56 
8.7 Changes to Planned Statistical Analyses ............................................................56 
9 ADMINISTRATIVE AND ETHICAL REQUIREMENTS...................................56 
9.1 Declaration of Helsinki and Ethical Review.......................................................56 
9.2 Subject Information and Consent........................................................................57 
9.3 Subject Data Protection.......................................................................................57 
9.4 Financial Disclosure............................................................................................58 
9.5 Changes to the Protocol ......................................................................................59 
9.6 Investigator Obligations......................................................................................59 
9.7 Confidentiality/Publication of the Study ............................................................60 
9.8 Selection of a Primary Principal Investigator.....................................................60 


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9.9 Study Termination ..............................................................................................60 
10 REFERENCES...........................................................................................................61 
APPENDIX 1 
INSTRUCTIONS FOR USE FOR THE PTH YPSOMED 
INJECTION PEN ......................................................................................................63 
APPENDIX 2 
NPSP558 AND SUPPLEMENT TITRATION GUIDELINE........72 
APPENDIX 3   METHOD OF BIRTH CONTROL.....................................................76 
 
 
LIST OF FIGURES AND TABLES  
Figure 3-1 
Study Design..............................................................................................29 
 
Table 5-1 
Prohibited Medications or Therapies.........................................................35 
Table 6-1 
Schedule of Evaluations and Procedures...................................................47 
 


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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 
ECG 
Electrocardiogram 
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 
IRB 
Institutional Review Board 
ITT 
Intention to treat 
IV 
Intravenous 
mm Hg 
Millimeters of mercury 
NPS 
NPS Pharmaceuticals 
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 
RELAY 
NPSP558 Study PAR-C10-007 
REPLACE 
NPSP558 Study C1-11-040 
rhPTH 
Recombinant human parathyroid hormone 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
s-CTx 
Serum carboxy-terminal telopeptide of type I collagen 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
SMT 
Safety Management Team  
SOC 
System organ class  
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 as hormone replacement therapy for the treatment of adult 
subjects with hypoparathyroidism. 
1.1 
Background 
Compound 
NPSP558 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).  hPTH 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 
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 


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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, 
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 


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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, 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 


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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).  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  
Hypoparathyroidism is one of the few hormonal deficiency syndromes in which 
replacement therapy using the native hormone is not clinically available.  Treatment of 
hypoparathyroidism is also 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 


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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 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 


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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 et al, 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 NPSP558 is not identical to the full 
84 amino acid sequence. 
One prospective, open-label clinical trial of PTH in the treatment of hypoparathyroidism 
is ongoing (Bilezikian et al, 2008).  In that study, patients with hypoparathyroidism were 
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.  
An investigator-initiated open-label study evaluating the utility of PTH(1-84) 100 g 
QOD for 24 months as hormone-replacement therapy in 30 patients with 


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hypoparathyroidism is also ongoing (Rubin et al, 2010).  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, 2008c, 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 patients with 
hypoparathyroidism is currently ongoing (CL1-11-040, REPLACE).  This study is 
investigating 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 phase 1 pharmacokinetic/ 
pharmacodynamic study is also being conducted to assess these aspects of NPSP558 
administered as single SC doses of 50 and 100 μg in patients with hypoparathyroidism. 
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 NPSP558 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 hypoparathyroidism provide a 
framework of information that supports the safety and potential clinical utility of PTH 
replacement therapy in hypoparathyroidism.   


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1.3 
Rationale for Study Design  
Dose 
In a phase 2 study of NPSP558 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 ongoing 
REPLACE study is evaluating these same doses in hypoparathyroid patients.  An 8-week 
study of fixed doses of 25 and 50 µg (RELAY) is currently being undertaken to explore a 
broader range of treatment dose options.  The purpose of this study is to assess the 
12-month safety and tolerability of varying doses of NPSP558 in reducing requirements 
for supplemental oral calcium and calcitriol, while 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.  
NPSP558 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.   
2 
OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to demonstrate the long-term safety and tolerability 
of SC NPSP558 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 and calcitriol on the 
response to NPSP558 replacement therapy 
 To demonstrate that dosing with NPSP558 across a dose range of 25 to 100 μg SC 
can be implemented in a safe and effective manner and can be maintained 
throughout 12 months (52 weeks) of 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 


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 Incidence of adverse events 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 
o Hematology (hematocrit, hemoglobin, white blood cells, red blood cells, 
platelets, differential) 
o Serum chemistries (standard Chem-20 panel, including calcium, 
phosphorus, and albumin) 
o Serum 25-hydroxyvitamin D levels 
o Creatinine clearance 
o Serum bone turnover markers 
o Urinalysis 
o 24-hour urine calcium, phosphate, sodium, and creatinine excretion 
o PTH antibodies 
 Bone mineral density by dual-energy x-ray absorptiometry (DXA) 
Electrocardiogram (ECG) parameters 
 Physical examinations (including vital signs) 
 Reason for termination from the study 
2.3.2 
Efficacy Endpoints 
2.3.2.1 
Primary Efficacy Endpoint 
The proportion of subjects in whom the following three conditions are fulfilled at 
Week 52 (Visit 9) 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 (≥7.5 mg/dL) and does not exceed 
the ULN for the central laboratory 


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2.3.2.2 
Secondary Efficacy Endpoints  
 Mean percentage changes from baseline in supplemental oral calcium and 
supplemental calcitriol dosages at each visit. 
 Proportion of subjects achieving the primary endpoint 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        
 Distribution of subjects by NPSP558 doses at the End of Treatment Visit 
 Change from baseline in bone turnover markers (bone-specific alkaline 
phosphatase [BSAP], serum carboxy-terminal telopeptide of type I collagen 
[P1NP], serum procollagen type 1 amino-terminal propeptide [s-CTx], and 
osteocalcin), PTH antibodies, and BMD by DXA  
 Additional subgroup analyses that are specified in the Statistical Analysis Plan 
(SAP) 
3 
STUDY DESIGN 
3.1 
Overall Design and Control Methods 
This study is a 12-month, open-label study using NPSP558 for the treatment of adult 
male and female subjects with hypoparathyroidism. Either subjects must have previously 
completed the NPSP558 RELAY study (8 weeks of active therapy) and/or previously 
completed the NPSP558 REPLACE study (Visit 18). 
The goal of this study is to optimize NPSP558 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, NPSP558 and Supplement 
Titration Guideline).   
 
The starting dose of NPSP558 for this study will be 25 or 50 g SC once daily.  
o Subjects with a total serum calcium value of ≤ 9.5 mg/dL will have a 
starting dose of 50 μg.   
o Subjects with a total serum calcium value of > 9.5 mg/dL will have a 
starting dose as follows: 


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o 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.  
o 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 will be conducted at Weeks 1 (baseline), 4, 8, and then every 
8 weeks thereafter up to Week 48 (Visit 8).  The End of Treatment Visit 
(Week 52, Visit 9) is scheduled 4 weeks later followed by a safety visit at 
Week 53 (Visit 10) and a follow-up telephone contact at Week 56 (Visit 11).   
 
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 NPSP558 dose increased by the investigator at any time 
through Week 48 of 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 NPSP558 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 NPSP558, after 
any significant change in doses of calcium and/or and calcitriol supplements, or 
at any other time at the discretion of the investigator.   
 
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 NPSP558.      
 
If ANY predose total serum calcium is > 11.9 mg/dL study drug will be 
stopped.  Once total serum calcium returns to the normal range, NPSP558 can 
be reintroduced.  The NPSP558 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 NPSP558 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. 


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 
 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 NPSP558 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 NPS medical monitor.   
 
At the Week 16 (Visit 4), subjects who are on a stable dose of NPSP558 and 
have a 24-hour urine calcium > 300 mg 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. 
o 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 visit.   
o Monitoring of urine calcium will be performed at Weeks 16, 32, and 52 
(Visits 4, 6, and 9) 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 Week 53, subjects will have their total serum calcium levels 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 Week 53 (Visit 10) in order to have serum calcium, phosphorus, and 
albumin checked.   
 
At Week 56 (Visit 11), approximately 4 weeks (30 days) following the End of 
Treatment visit (Week 52), subjects will be contacted by telephone in order to 
assess adverse events (AEs)/serious AEs (SAEs).  
  
A schematic representation of the study design is displayed in Figure 3-1. 




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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.  
Female partners (who are of childbearing potential) of male study subjects must 
also use acceptable forms of contraception during their partner’s participation.   
6. Serum creatinine <1.5 mg/dL at 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 that 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 (IRB/IEC), Health Authority and/or NPS, 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  


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 
Hypersensitivity determined by the investigator to be possibly related to study 
drug 
 
Pregnancy or lactation  
 
Administrative reasons 
In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) and 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 
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 NPSP558 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)  
NPSP558  is manufactured using a strain of E. coli modified by DNA technology and is 
identical to native human PTH.  NPSP558 is a single-chain polypeptide containing 
84 amino acid residues.  The drug substance is clear and colorless to light straw-colored. 
NPSP558 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).  The dual-chamber cartridge is installed by the user into a reusable injection 
pen device, in which reconstitution occurs in a total volume of 1.15 mL.  
(See Appendix 1, Instructions for Use)    
The injection pen serves as a holder for the cartridge and does not come in contact with 
rhPTH product.  Using the injection pen 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 


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and sufficient cartridges to provide daily doses for 52 weeks.  Drug cartridges will be 
provided 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.   
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 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 have a maximum shelf-life of 36 months and should be 
stored at 2ºC to 8ºC (36ºF to 46ºF).  After study drug reconstitution in the injection pen 
device, 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. 
 Additional data on the reconstituted solution demonstrates that it is stable for up to 
7 days when stored at 25°C, which provides assurance of product quality during any 
unexpected excursions.  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.  In this study, subjects will be supplied with cartridges 
in sufficient quantity to maintain daily self-administration of varying dose of NPSP558.  
Subjects should be reminded to return all cartridges, even if empty, at the final study 
visit. 
Pharmacy records will be maintained to capture the following information by lot number 
for each drug: 


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 
quantity received 
 
current quantity on site 
 
quantity administered to each subject 
 
quantity removed from stock but not dispensed (eg, damaged, dropped, spilled) 
 
quantity remaining at the end of the study and retained, returned, or destroyed, 
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 or disposed of 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 NPSP558 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 NPSP558 SC injections will be self-administered into alternating thighs each 
morning using a multidose pen injection device (see Appendix 1, Instructions for Use).    
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 NPSP558.    
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).  The phase 3, randomized, double-blind placebo-controlled 
REPLACE study in subjects with hypoparathyroidism is ongoing.  This registrational 


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study is exploring the biologic activity of NPSP558 at doses of 50, 75, or 100 g 
administered as SC injections to the thigh.  An ongoing pharmacokinetic study (C09-002) 
utilizes two single doses of 50 and 100 g each, also as SC injections to the thigh.  The 
phase 3 fixed-dose study (RELAY) utilized dose of 25 and 50 g SC daily.  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 NPSP558 in the morning, using the multidose injection pen 
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.  Calcium and/or vitamin D should be taken in the morning as normal after the 
NPSP558 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 the end of the study 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. 


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Table 5-1 
Prohibited Medications or Therapies  
Medication/Therapy 
Regimen 
Raloxifene hydrochloride 
Any  
Bisphosphonates, intravenous 
Any 
Bisphosphonates, oral 
≥ 1 month of chronic use 
Systemic corticosteriods, oral or depot form (chronic use) 
≥ 1 month of chronic use 
Calcitonin, cinacalcet or other drugs that influence calcium or 
bone metabolism 
≥ 1 month of chronic use 
Fluoride tablets 
≥ 1 month of chronic use 
 
In addition, concomitant active vitamin D supplements from outside sources are 
prohibited. 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 
 
nasal and inhaled corticosteroids for the management of allergic rhinitis and 
asthma  
 
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 signing the ICF through study exit), including administration 
dates and dosage, are to be recorded on the appropriate eCRF.  Any medication 
which contains either calcium or vitamin D must be recorded on the eCRF 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 entered on the appropriate eCRF. 
 
 


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5.4.2 
Active Calcitriol, Calcium, Native Vitamin D, and Magnesium 
Supplementation 
Calcitriol 
Subjects enrolled in this study will be taking calcitriol to control serum calcium levels.  
Oral calcitriol supplements will be provided for this study by the sponsor or designee; no 
other sources of calcitriol should be used during the study.  Prescribed doses of calcitriol 
will be entered on the appropriate eCRF. 
Calcium 
Oral calcium supplements (either calcium carbonate or calcium citrate) will be provided 
for 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 entered on the appropriate eCRF. 
In the case that extra calcium supplementation is taken by the subject due to symptoms of 
hypocalcemia, the dose/time and associated symptoms should be recorded by the subject 
in 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 Week 52 (End of Treatment).  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 on the concomitant medication eCRF. 
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 on the 
concomitant medication eCRF. 
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 
o Total serum calcium  
o 24-hour urinary calcium excretion 


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o Serum phosphate (calcium-phosphate ratio)  
 
Supplement usage 
o Concomitant supplemental oral calcium dosage 
o 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 adverse events 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 
o Hematology (hematocrit, hemoglobin, white blood cells, red blood cells, 
platelets, differential) 
o Serum chemistries (standard Chem-20 panel, including calcium, 
phosphorus, and albumin) 
o Serum 25-hydroxyvitamin D levels 
o Creatinine clearance 
o Serum bone turnover markers 
o Urinalysis 
o 24-hour urine calcium, phosphate, sodium, and creatinine excretion 
o PTH antibodies 
 Bone mineral density by DXA  
 Electrocardiogram parameters 
 Physical examinations (including vital signs) 
 Reason for termination from the study 
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.  


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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 
Overdose 
Defined as an accidental or intentional administration of an excessive dose of a product, 
an overdose should be reported to the sponsor using the SAE form.  This information will 
be shared with the Safety Management Team (SMT) and medical monitor. 
6.2.1.2 
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 completion of the study.  
AE/SAEs will be monitored by the site with a telephone call at Week 56, approximately 
30 days following the last dose of study drug.     


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At each visit, new AEs will be recorded sequentially on the AE page of the eCRF.  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) 
o Mild:  usually transient, requiring no special treatment and generally not 
interfering with usual daily activities 
o Moderate:  usually ameliorated by simple therapeutic maneuvers and 
impairs usual activities 
o Severe:  requires vigorous therapeutic intervention and interrupts usual 
activities.  Hospitalization may or may not be required. 
 
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 
A serious event must be recorded on the sponsor’s Serious Adverse Event Report Form.  
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 


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drug will be captured in the SAE database and must be reported 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 
 
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 complete the sponsor’s SAE form (even if all information regarding the 


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SAE is unknown or incomplete) and forward the SAE form via FAX to the sponsor or 
designee.  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 sponsor or designee will provide a FAX cover sheet for the investigators in the Study 
Reference Manual. 
Autopsy reports, if applicable, will be forwarded as they become available.  All pertinent 
laboratory results should be entered on the sponsor’s SAE form. 
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 6.2.1.2).  A causality assessment should always be included on 
the sponsor’s 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) 


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 
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 determined that there is an unanticipated signal, the NPS 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).   
NPS Pharmaceuticals (sponsor) 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  the 
sponsor 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.   


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6.2.3 
Laboratory Evaluations  
The following laboratory tests will be performed with subjects in a fasted state (6 to 
8 hours) at baseline and Week 52 (End of Treatment), unless otherwise noted.  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 will be analyzed by a central laboratory, 
with the exception of all urine pregnancy tests and total serum calcium levels obtained at 
baseline, Week 53, 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: 
 
Hematology: hemoglobin concentration, hematocrit, erythrocyte count, platelet 
count, and leukocyte counts with differential 
 
Serum Chem-20 panel: alanine transaminase, aspartate transaminase, alkaline 
phosphatase, lactate dehydrogenase, inorganic phosphorus, 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  
 
Urinalysis: specific gravity, pH, protein, glucose, ketones, bilirubin, 
urobilinogen, blood, and microscopic analysis of sediment 
 
Creatinine clearance will be done at baseline and Weeks 16, 32, and 52. 
 
Total serum calcium (local) will be drawn at baseline and at the Week 53 (Visit 
10) follow-up visit. 
 
Total serum calcium, albumin, and phosphorus will be drawn at baseline and at 
each subsequent scheduled study visit through Week 52.   
 
All subjects will have local blood draws to assess  total serum calcium levels 
during Week 1, 3 to 5 days (± 2 days) after baseline and again during Week 53, 
3 to 5 days (± 2 days) after the last dose of study drug.  Following any 
adjustment of NPSP558 or a significant change in calcium/calcitriol 
supplements, a local total serum calcium level will also be drawn after 
3 to 5 days. 
 
Serum 25-hydroxyvitamin D additional levels will be drawn at baseline and at 
each subsequent scheduled study visit through Week 52.  
 
24-hour urine calcium, phosphate, sodium, and creatinine will be done at 
baseline and Weeks 16, 32, and 52. 
 
Serum bone turnover markers (BSAP, s-CTx, P1NP, and osteocalcin) will be 
done at baseline and Weeks 8, 16, 24, 40, and 52. 


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 
Serum beta human chorionic gonadotropin (-HCG) pregnancy test will be 
done at  baseline and Weeks 16, 24, 32, 40, 48, and 52 (women of child-bearing 
potential [WOCBP] only) 
 
An FSH test to confirm postmenopausal status, if subjects have met the 
definition of postmenopausal after the beginning of the RELAY or REPLACE 
study (newly postmenopausal females only) will be done at baseline only, if 
necessary. 
 
Urine pregnancy test (WOCBP only) will also be collected at baseline and 
Weeks 4 and 8. 
 
PTH  antibodies will be done at  baseline and Weeks 24,  40, and 52  
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 at baseline and each clinic study visit through Week 52 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 and Week 52, at the study center on the same 
model unit.  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 AE.  All ECGs 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 and the eCRF.  Two copies of the 
ECG tracings should be retained in the subject source record. 


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6.2.6 
Physical Examinations 
Physical examinations will be performed at baseline and Week 52 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.  
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 and Week 52 and 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.  
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, and 52.  Pregnancy occurring during the trial will necessitate 
immediately withdrawal from study.  A WOCBP must be willing to use two medically 
acceptable methods of contraception for the duration of the study (see Appendix 3).  
Female partners of male subjects should also use medically acceptable means to avoid 
pregnancy during their partner’s participation in the study.  


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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 an 
SAE supplemental form will be completed to capture potential drug exposure during 
pregnancy and will be 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, an additional SAE form will be 
completed and submitted to the sponsor or designee within 24 hours as discussed above.  
An SAE supplemental 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.  Details of the 
exact date and time of medical assessments (day/month/year) will be documented in the 
eCRF.  Any deviations from protocol requirements will be documented in the eCRF. 


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Table 6-1 
Schedule of Evaluations and Procedures 
Visit Number 
1 
Int. 
2 
3 
4 
5 
6 
7 
8 
9 
Int. 
10 
11 
Study Procedures / Proposed Study Weeka 
BLb 
1c 
4 
8 
16 
24 
32 
40 
48 
52 
(EoT) 
53c, d 
53 d 
(F/up) 
56 
(F/up) 
Phone 
 
 
Visit Windows 
± 3 
days 
± 2 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7  
days 
± 2 
days 
± 3 
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 
 
X 
X 
Adverse event monitoring (new) 
X 
 
X 
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 signse and weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Electrocardiogram (12-lead)  
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Bone mineral density by DXAf      
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Hematology  
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Serum chemistry (20-panel)g 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Serum calcium (local)* 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Serum calcium, phosphorus, and albumin 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Serum 25-hydroxyvitamin D 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Serum bone turnover markers 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
 
 
Serum thyroid function testh 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine clearance (estimated GFR) 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
 
PTH antibodiesi 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
FSH (newly menopausal women only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test  
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Urine pregnancy test 
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 injection pens  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Dispense/accountability of calcium/calcitriol supplements (see 
guideline)  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Collect used/unused study drug, supplements, and injection pensk 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 


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Visit Number 
1 
Int. 
2 
3 
4 
5 
6 
7 
8 
9 
Int. 
10 
11 
Study Procedures / Proposed Study Weeka 
BLb 
1c 
4 
8 
16 
24 
32 
40 
48 
52 
(EoT) 
53c, d 
53 d 
(F/up) 
56 
(F/up) 
Phone 
 
 
Visit Windows 
± 3 
days 
± 2 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7  
days 
± 2 
days 
± 3 
days 
± 7 
days 
BL = baseline; DXA = dual-energy x-ray absorptiometry; EoT = end of treatment; FSH = follicle stimulating hormone; F/up = follow up; GFR = glomerular filtration rate; Int.= interim visit;  
PTH = parathyroid hormone 
*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 and 53.  Week 56 is telephone contact only.  
b Week 8 from the RELAY Study; subjects will return all used/unused drug, supplements, and pens from RELAY/REPLACE. 
c Interim total serum calcium for all subjects 3 to 5 days (±2 days) after baseline and after last dose of study drug 
d Week 53 will be comprised of 2 visits:  one interim safety check and one end of week study visit. 
e Vital signs should be done prior to blood draws 
f 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 (all 
subjects will have a DXA performed at the end of the study Visit 9) 
g Fasting for at least 6 to 8 hours prior to test 
h Thyroid function tests done for final visit of the RELAY/REPLACE studies only 
 i Blood draw for PTH 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.  Pens will be collected at the final visit. 
 


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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, phosphorus, and 
albumin), hematology, serum 25(OH) vitamin D, creatinine clearance, and bone 
turnover markers.  The blood sample for serum chemistries will be split and a 
local total serum calcium will also be performed. 
 
Blood sample for PTH 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). 


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 
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: 
o Study medication cartridges in sufficient number to supply daily doses until 
the next scheduled clinic visit  
o Two injection pens 
o Ancillary injection supplies (ie, alcohol swabs, needles, etc.) 
o Paper diaries  
o 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, NPSP558 and Supplement Titration Guideline) 
based on this value.  If further adjustments are made to the NPSP558 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) 
 
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 calcium, phosphorus, and albumin (all visits) 
 
Serum bone turnover markers (Weeks 8, 16, 24, and 40) 
 
Serum -HCG pregnancy test (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)  


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 
Blood sample for PTH antibodies (predose on Weeks 24 and 40) 
 
Subjects will be provided with the following study supplies: 
o Study medication cartridges in sufficient number to supply daily doses until 
the next scheduled clinic visit  
o Ancillary injection supplies (ie, alcohol swabs, needles, etc.) 
o Calcium (carbonate or citrate) and calcitriol supplements in sufficient 
quantity to supply daily doses until the next scheduled clinic visit 
o Collection container for 24-hour urine (Weeks 16 and 32) 
6.4.4 
Week 52 (Visit 9) End of Study Visit  
Subjects will be instructed to come into the study center after having fasted for 
approximately 6 to 8 hours and prior to taking their last dose of 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 
 
Physical examination 
 
12-lead electrocardiogram 
 
Blood samples for serum chemistries (including calcium, phosphorus, and 
albumin), hematology, serum 25(OH) vitamin D, creatinine clearance, and bone 
turnover markers  
 
Blood sample for PTH antibodies (predose) 
 
Administration of the last dose of study medication following the predose PTH 
samples 
 
Urinalysis  
 
24-hour urine calcium, phosphate, sodium, and creatinine 
 
A BMD test by DXA  
 
Serum -HCG pregnancy test (females only) 
 
Review the subject’s diary to assess compliance to protocol procedures and 
dosing/supplement regimens. 
 
Collect used and unused drug cartridges, supplements (calcium and calcitriol), 
and injection pens for assessment of accountability and subject diaries. 


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6.4.5 
Week 53 Interim Safety Check 
Subjects will have a total serum calcium level drawn locally between 3 to 5 days 
(± 2 days) following the last dose of study drug.  Poststudy adjustments of supplemental 
calcium and calcitriol will be made (see Appendix 2, NPSP558 and Supplement Titration 
Guideline) based on this value.   
6.4.6 
End of Week 53 (Visit 10) Follow-up Safety Visit  
Subjects will have blood drawn for total serum calcium, phosphorus, and albumin levels.  
This sample will be split in order to provide blood for a local total serum calcium to be 
done at the investigator’s local laboratory.  Further adjustment of subjects’ supplemental 
calcium and calcitriol doses will be made based on these values (see Appendix 2, 
NPSP558 and Supplement Titration Guideline).  Subjects will also be monitored for 
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. 
6.4.7 
Week 56 (Visit 11) Follow-up Telephone Contact  
Subjects will be contacted approximately 30 days 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. 
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 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. 


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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 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  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   
Statistical analyses 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).  
8.1 
Demographic and Baseline Variables 
Demographic variables (such as sex, age, race, birthdate, etc.) will be obtained from the 
REPLACE or RELAY study, if available.   Medical history from the RELAY study will 


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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 and surgical 
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, 
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.  
8.2.1 
Efficacy Variables 
Primary Efficacy Endpoint: 
The proportion of subjects in whom the following three conditions are fulfilled at 
Week 52 (Visit 9) 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 (≥7.5 mg/dL) and does not exceed the 
ULN of the central laboratory 


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In addition, the following efficacy variables will be summarized:  
 Mean percentage changes from baseline in supplemental oral calcium and 
supplemental calcitriol dosages at each visit 
 Proportion of subjects achieving the primary endpoint 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        
 Distribution of subjects by NPSP558 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. 
8.3 
Other Variables  
Other variables to be analyzed will include the following:  
 
Subject accounting 
 
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. 
8.4 
Analysis Populations, Data Sets, and Time Points 
8.4.1 
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.  


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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. 
8.5 
Statistical/Analytical Issues  
8.5.1 
Adjustments for Covariates 
No preselected covariates are selected for adjustments. 
8.5.2 
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. 
8.5.3 
Interim Analyses and Data Monitoring 
An interim study report will be completed to look at safety and efficacy at a date to be 
determined.    
8.5.4 
Multiple Comparisons/Multiplicity 
No adjustment for multiplicity in treatment is planned. 
8.5.5 
Use of a Pharmacokinetic Subset of Subjects 
No pharmacokinetic subset of subjects was selected for analysis. 
8.5.6 
Examination of Subgroups 
Subgroup analyses (if any), in addition to the possible ones by gender, will be discussed 
in the SAP.  
8.6 
Determination of Sample Size 
Approximately 40 subjects are anticipated to be enrolled.  Sample sizes were not 
estimated for this extension study.  
8.7 
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 


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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). 
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 NPS 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 
partner of male subjects who is a WOCBP) 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 
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. 


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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 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 


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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 revised protocol.  Changes to the protocol may require notification 
to or approval by the IRB/IEC 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 
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 


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 
IRB/IEC 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 “Principal Investigator Protocol Agreement 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. 
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 
Aug 4;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. 
Rubin MR, Sliney J Jr, McMahon DJ, Silverberg SJ, Bilezikian JP.  Therapy of 
hypoparathyroid with intact parathyroid hormone.  Osteoporos Int. 2010;21(11):1927-34. 
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 
Sep;88(9):4214-20. 


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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 
YPSOMED INJECTION PEN  
 


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APPENDIX 2 
NPSP558 AND SUPPLEMENT TITRATION 
GUIDELINE 
In this study the goal is to continue NPSP558 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 NPSP558.  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 in a fasting state prior to administration of 
study drug, NPSP558. 
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 NPSP558 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 


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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 NPSP558 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, NPSP558 
can be reintroduced with clinically appropriate doses of calcitriol and oral calcium, with 
the aim to avoid further episodes of abnormal serum calcium.   
 
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 
NPSP558 reviewed with the subject to ensure proper administration.  At planned study 
visits (Week 4, 8 etc until Week 48) the NPSP558 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  
 
Subjects who are sexually active, or considering sexual activity, will be instructed to use 
two 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) .  
Female partners (who are of childbearing potential) of male study subjects must also use 
acceptable forms of contraception during their partner’s participation.   
True sexual abstinence is defined as not having any type of intercourse or sex play with a 
partner. 
 

Prot_000.pdf: 
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  
 
Protocol Version Date: 30 Dec 2010 


 
 
 
NPSP558 
 
A 12-Month 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) 
 
 
 
Clinical Protocol PAR-C10-008 
US IND Number: 76,514 
 
 
 
 
NPS Pharmaceuticals, Inc.  
550 Hills Drive, 3rd Floor 
Bedminster, NJ 07921 
 
 
 
ISSUED:  30 December 2010 Version 2.0
 
CONFIDENTIAL 
 


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SPONSOR:   
NPS Pharmaceuticals, Inc.  
550 Hills Drive, 3rd Floor 
Bedminster, NJ 07921 
             
 
KEY SPONSOR CONTACTS: 
 
Medical Director: 
 
Title:  
, MD  
 
, Clinical Development  
 
 
 
 
 
& Medical Affairs  
Phone:   
 
 
 
 
Mobile: 
                                    
 
Fax Number:    
 
 
 
 
Clinical Operations:  
 
Title:  
, RN, BSN  
 
, Clinical Operations 
Phone:                                 
 
 
Mobile:                                               
 
Fax Number:    
 
 
 
 
To Report an SAE: 
 
Title:  
 
 
 
, RPh, PhD 
, Pharmacovigilance  
Phone:   
 
 
 
 
 
Fax Number:    
 
 
 
30 December 2010 
 
PPD
PPD
PPD
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Version 2.0 
SUMMARY 
Title:  A 12-Month 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 
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 as hormone replacement therapy for the treatment of adult 
patients with hypoparathyroidism. 
Secondary Objectives: 
 To evaluate the impact of different preparations of calcium and calcitriol on the 
response to NPSP558 replacement therapy 
 To demonstrate that dosing with NPSP558 across a dose range of 25 to 100 μg SC 
can be implemented in a safe and effective manner and can be maintained 
throughout 12 months (52 weeks) of treatment 
 To evaluate the impact of calcium-sparing diuretics on serum and urinary calcium 
Study Rationale 
This study is designed to evaluate 12-month treatment with NPSP558.  
Study Design 
This study is a 12-month, open-label study using NPSP558 for the treatment of adults 
with hypoparathyroidism.  Patients must have previously completed the NPSP558 
RELAY study (8 weeks of active therapy) to enroll in this study.   
The goal of this study is to optimize NPSP558 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 NPSP558 and to the 
calcium/calcitriol supplements and safety monitoring of calcium levels are explained in 
Appendix 2, NPSP558 and Supplement Titration Guideline.   
 The starting dose of NPSP558 for this study will be 25 or 50 g SC once daily  
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 Patients may have their NPSP558 dose adjusted by the investigator at any time 
through Week 48 of 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 total serum calcium is > 11.9 mg/dL study drug will be 
stopped. 
 Patients will have blood draws to assess total serum calcium levels (which may 
be performed locally) 3 to 5 days after ANY dose adjustment of NPSP558, 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 will be conducted at Weeks 1 (baseline), 4, 8, and then every 
8 weeks thereafter up to Week 48 (Visit 8).  The End of Treatment Visit 
(Week 52, Visit 9) is scheduled 4 weeks later followed by a safety visit at Week 
53 (Visit 10) and a follow-up telephone contact at Week 56 (Visit 11).    
 At the Week 16 (Visit 4), patients who are on a stable dose of NPSP558 and 
have a 24-hour urine calcium > 300 mg may be treated for hypercalciuria with 
calcium-sparing diuretics. 
 During Week 53, patients will have their total serum calcium levels checked 
locally at an interim visit scheduled 3 to 5 days after the last dose of study 
medication.  Patients will also be scheduled for a follow-up clinic visit at the 
end of Week 53 (Visit 10) in order to have serum calcium, phosphorus, and 
albumin checked.   
Number of Patients Planned:  Approximately 40 patients will be enrolled.  
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria 
Patients 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 NPSP558 RELAY study (8 weeks of active therapy) 
3. Able to perform daily SC self-injections of study medication (or have designee 
perform injection) via a multidose injection pen 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 levels (> 40 IU/L); (2) surgically 
sterilized; OR (3) of childbearing potential with a negative pregnancy test at 
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screening and who consent to use two acceptable methods of contraception for the 
duration of the study, with pregnancy testing at every scheduled visit.  Female 
partners (who are of childbearing potential) of male study patients must also use 
acceptable forms of contraception during their partner’s participation.   
Exclusion Criteria 
Patients 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 patient from completing the study or where the 
patient cannot or will not appropriately comply with study requirements 
3. Pregnant or lactating women  
All patients are free to withdraw from participation in this study at any time, for any 
reason, specified or unspecified, without prejudice to subsequent care.  Withdrawn 
patients will not be replaced.   
Duration of Study/Treatment: 
The total duration of treatment will be 12 months (52 weeks).   Patients will have a 
follow-up visit at Week 53 and will also be contacted by telephone at Week 56.      
Test Product, Dose, and Mode of Administration:  
At the beginning of the study, patients will receive NPSP558 25 or 50 µg SC QD in an 
open-label fashion as defined earlier.  Patients may have their NPSP558 dose adjusted 
upwards in increments of 25 µg to a maximum of 100 µg SC QD.  NPSP558 is to be 
administered into alternating thighs each morning via a multidose injection pen device.  
Supplements:  
Calcium citrate, calcium carbonate, and calcitriol will be supplied by the sponsor.  
Criteria for Evaluation:  
Safety:  
Safety variables will be assessed by the following evaluations:  
 Adverse events and serious adverse events 
 Incidence of adverse events of hypocalcemia (eg, paresthesia, numbness, tetany) 
and hypercalcemia (eg, constipation, nausea, poor appetite or vomiting, frequent 
urination, thirst, and kidney stones) 
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 Incidence of hypercalciuria  
 Laboratory test results 
o Hematology (hematocrit, hemoglobin, white blood cells, red blood cells, 
platelets, differential) 
o Serum chemistries (standard Chem-20 panel) 
o Serum 25-hydroxyvitamin D levels 
o Creatinine clearance 
o Serum bone turnover markers 
o Urinalysis 
o 24-hour urine calcium, phosphate, sodium, and creatinine excretion 
o PTH 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 
Efficacy:   
Efficacy variables will be assessed by one or more of the following evaluations: 
 Laboratory test results 
o Total serum calcium  
o 24-hour urinary calcium excretion 
o Serum phosphate (calcium-phosphate ratio)  
 Supplement usage 
o Concomitant supplemental oral calcium dosage 
o 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. 
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Analysis of Demographic and Baseline Variables 
Demographic variables (such as sex, age, race, birthdate, etc.) will be obtained from the 
REPLACE or RELAY study, if available.   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 patients with specific prior medications will be 
summarized.  The number and percentage of patients will be summarized by system 
organ class and by high-level term and preferred term for each condition.  
Efficacy Variables Summary 
Primary Efficacy Endpoint: 
The proportion of patients in whom the following three conditions are fulfilled at 
Week 52 (Visit 9) 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 (≥7.5 mg/dL) and does not exceed 
the ULN for the central laboratory 
Secondary Efficacy Endpoints:  
 Mean percentage changes from baseline in supplemental oral calcium and 
supplemental calcitriol dosages at each visit 
 Proportion of patients achieving the primary endpoint 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 patients that maintain a calcium phosphate product in the range of 
35 to 55 mg2/dL2        
 Distribution of patients by NPSP558 doses at the End of Treatment Visit 
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 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 adverse events 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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PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE 
Protocol PAR-C10-008  
I agree: 
To assume responsibility for the proper conduct of this clinical study at this center and to 
conduct the study in compliance with this protocol, any future amendments, and with any 
other study conduct procedures provided by the sponsor, 
That I am aware of, and will comply with, the internationally recognized code of Good 
Clinical Practice and all other applicable regulatory requirements to obtain written and 
dated approval from the Institutional or Central Review Board (IRB) or Independent 
Ethics Committee (IEC) for the study protocol and any amendments thereof, written 
informed consent or updates thereof, patient recruitment procedures (eg, advertisements), 
and any other written information to be provided to the patients, before initiating this 
clinical study, 
Not to implement any changes to, or deviations from the protocol without prior 
agreement from the sponsor and review and documented approval from the IRB/IEC, 
except to eliminate an immediate hazard to the study patients, or when change(s) involves 
only logistical or administrative aspects of the clinical study, 
To permit direct monitoring and auditing by the sponsor or sponsor’s representatives and 
inspection by the appropriate regulatory authority(ies), 
That I am thoroughly familiar with the appropriate use of the investigational product(s), 
as described in this protocol, and any other information provided by the sponsor or 
designee, including, but not limited to, the current Investigator’s Brochure or equivalent 
document and approved product label (if applicable), 
To provide sufficient time and an adequate number of qualified staff and facilities for the 
foreseen duration of the clinical study in order to conduct the study properly, ethically, 
and safely, 
To ensure that all persons assisting in this study are adequately informed about the 
protocol, investigational product(s), and their clinical study-related duties and functions, 
To maintain drug records, copies of eCRFs, laboratory records, data sheets, 
correspondence records, and signed patient 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.   
 
 
Principal Investigator (Print Name) 
 
 
 
 
Principal Investigator (Signature) 
 
Date (DD MMM YYYY) 
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TABLE OF CONTENTS 
TITLE PAGE .....................................................................................................................1 
SPONSOR KEY CONTACTS..........................................................................................2 
SUMMARY ........................................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.................................15 
1 INTRODUCTION......................................................................................................17 
1.1 Background.........................................................................................................17 
1.2 Rationale for the Clinical Study..........................................................................20 
1.3 Rationale for Study Design.................................................................................24 
2 OBJECTIVES ............................................................................................................24 
2.1 Primary Objective...............................................................................................24 
2.2 Secondary Objectives..........................................................................................24 
2.3 Endpoints ............................................................................................................24 
2.3.1 
Safety Endpoints..................................................................................24 
2.3.2 
Efficacy Endpoints...............................................................................25 
2.3.2.1 Primary Efficacy Endpoint ...................................................25 
2.3.2.2 Secondary Efficacy Endpoints..............................................26 
3 STUDY DESIGN........................................................................................................26 
3.1 Overall Design and Control Methods .................................................................26 
3.2 Study Duration....................................................................................................29 
4 PATIENT SELECTION AND PARTICIPATION ................................................29 
4.1 Number of Patients .............................................................................................29 
4.2 Inclusion Criteria ................................................................................................29 
4.3 Exclusion Criteria ...............................................................................................30 
4.4 Patient Withdrawal Criteria ................................................................................30 
5 TREATMENTS AND TREATMENT PLAN .........................................................31 
5.1 Treatments Administered....................................................................................31 
5.1.1 
Identification of Investigational Product(s) .........................................31 
5.1.2 
Packaging and Labeling.......................................................................31 
5.1.3 
Storage, Accountability, and Stability .................................................32 
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5.2 Methods of Assigning Patients to Treatment Groups.........................................33 
5.3 Dose Regimens ...................................................................................................33 
5.3.1 
Selection of Doses in Study.................................................................33 
5.3.2 
Selection and Timing of Dose for Each Patient...................................34 
5.3.3 
Compliance With Dosing Regimens....................................................34 
5.4 Prior and Concomitant Medications ...................................................................34 
5.4.1 
Exclusionary Prior/Concomitant Medications.....................................34 
5.4.2 
Active Calcitriol, Calcium, Native Vitamin D, and Magnesium 
Supplementation ..................................................................................35 
6 STUDY EVALUATIONS AND PROCEDURES ...................................................36 
6.1 Efficacy Evaluations...........................................................................................36 
6.2 Safety Evaluations ..............................................................................................36 
6.2.1 
Adverse Events ....................................................................................37 
6.2.1.1 Adverse Event Definition .....................................................37 
6.2.1.2 Procedures for Reporting Adverse Events............................38 
6.2.2 
Serious Adverse Events .......................................................................39 
6.2.2.1 Serious Adverse Event Definition ........................................39 
6.2.2.2 Procedures for Reporting Serious Adverse Events...............40 
6.2.3 
Laboratory Evaluations........................................................................42 
6.2.4 
Vital Signs and Body Weight ..............................................................43 
6.2.5 
Electrocardiograms ..............................................................................44 
6.2.6 
Physical Examinations.........................................................................44 
6.2.7 
Dual-energy X-ray Absorptiometry.....................................................44 
6.2.8 
Women of Childbearing Potential .......................................................44 
6.2.9 
Pregnancy Reporting............................................................................45 
6.3 Schedule of Evaluations and Procedures............................................................45 
6.4 Description of Study Procedures ........................................................................48 
6.4.1 
Visit 1 Baseline Procedures .................................................................48 
6.4.2 
Week 1 Interim Safety Check..............................................................49 
6.4.3 
Weeks 4, 8, 16, 24, 32, 40, and 48 (Visits 2 through 8) Study 
Clinic Visits .........................................................................................49 
6.4.4 
Week 52 (Visit 9) End of Study Visit..................................................50 
6.4.5 
Week 53 Interim Safety Check............................................................51 
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6.4.6 
End of Week 53 (Visit 10) Follow-up Safety Visit .............................51 
6.4.7 
Week 56 (Visit 11) Follow-up Telephone Contact..............................51 
7 DATA MANAGEMENT...........................................................................................51 
7.1 Data Collection ...................................................................................................51 
7.2 Record Retention ................................................................................................52 
8 STATISTICAL METHODOLOGY AND SAMPLE SIZE...................................52 
8.1 Demographic and Baseline Variables.................................................................53 
8.2 Safety Variables..................................................................................................53 
8.2.1 
Efficacy Variables................................................................................53 
8.3 Other Variables...................................................................................................54 
8.4 Analysis Populations, Data Sets, and Time Points .............................................54 
8.4.1 
Analysis Populations............................................................................54 
8.5 Statistical/Analytical Issues ................................................................................55 
8.5.1 
Adjustments for Covariates..................................................................55 
8.5.2 
Handling of Dropouts or Missing Data................................................55 
8.5.3 
Interim Analyses and Data Monitoring................................................55 
8.5.4 
Multiple Comparisons/Multiplicity .....................................................55 
8.5.5 
Use of a Pharmacokinetic Subset of Patients.......................................55 
8.5.6 
Examination of Subgroups...................................................................55 
8.6 Determination of Sample Size ............................................................................55 
8.7 Changes to Planned Statistical Analyses ............................................................55 
9 ADMINISTRATIVE AND ETHICAL REQUIREMENTS...................................55 
9.1 Declaration of Helsinki and Ethical Review.......................................................55 
9.2 Patient Information and Consent ........................................................................56 
9.3 Patient Data Protection .......................................................................................56 
9.4 Financial Disclosure............................................................................................57 
9.5 Changes to the Protocol ......................................................................................58 
9.6 Investigator Obligations......................................................................................58 
9.7 Confidentiality/Publication of the Study ............................................................59 
9.8 Selection of a Primary Principal Investigator.....................................................59 
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9.9 Study Termination ..............................................................................................59 
10 REFERENCES...........................................................................................................60 
APPENDIX 1 
INSTRUCTIONS FOR USE FOR THE PTH YPSOMED 
INJECTION PEN ......................................................................................................62 
APPENDIX 2 
NPSP558 AND SUPPLEMENT TITRATION GUIDELINE........71 
APPENDIX 3   METHOD OF BIRTH CONTROL.....................................................75 
 
 
LIST OF FIGURES AND TABLES  
Figure 3-1 
Study Design..............................................................................................29 
 
Table 5-1 
Prohibited Medications or Therapies.........................................................34 
Table 6-1 
...................................................46 
Schedule of Evaluations and Procedures
 
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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 
ECG 
Electrocardiogram 
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 
IRB 
Institutional Review Board 
ITT 
Intention to treat 
IV 
Intravenous 
mm Hg 
Millimeters of mercury 
NPS 
NPS Pharmaceuticals 
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 
RELAY 
NPSP558 Study PAR-C10-007 
REPLACE 
NPSP558 Study C1-11-040 
rhPTH 
Recombinant human parathyroid hormone 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
s-CTx 
Serum carboxy-terminal telopeptide of type I collagen 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
SMT 
Safety Management Team  
SOC 
System organ class  
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 as hormone replacement therapy for the treatment of adult 
patients with hypoparathyroidism. 
1.1 
Background 
Compound 
NPSP558 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).  hPTH 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 
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 
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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, 
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 
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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, 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 
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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).  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  
Hypoparathyroidism is one of the few hormonal deficiency syndromes in which 
replacement therapy using the native hormone is not clinically available.  Treatment of 
hypoparathyroidism is also 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 
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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 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 
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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 et al, 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 NPSP558 is not identical to the full 
84 amino acid sequence. 
One prospective, open-label clinical trial of PTH in the treatment of hypoparathyroidism 
is ongoing (Bilezikian et al, 2008).  In that study, patients with hypoparathyroidism were 
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.  
An investigator-initiated open-label study evaluating the utility of PTH(1-84) 100 g 
QOD for 24 months as hormone-replacement therapy in 30 patients with 
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hypoparathyroidism is also ongoing (Rubin et al, 2010).  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, 2008c, 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 patients with 
hypoparathyroidism is currently ongoing (CL1-11-040, REPLACE).  This study is 
investigating 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 phase 1 pharmacokinetic/ 
pharmacodynamic study is also being conducted to assess these aspects of NPSP558 
administered as single SC doses of 50 and 100 μg in patients with hypoparathyroidism. 
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 NPSP558 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 hypoparathyroidism provide a 
framework of information that supports the safety and potential clinical utility of PTH 
replacement therapy in hypoparathyroidism.   
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1.3 
Rationale for Study Design  
Dose 
In a phase 2 study of NPSP558 in osteoporosis, SC daily doses of 50, 75, and 100 µg 
were well tolerated.  In these patients with osteoporosis and intact parathyroid function, a 
dose-dependent increased incidence of hypercalcemia was observed.  The ongoing 
REPLACE study is evaluating these same doses in hypoparathyroid patients.  An 8-week 
study of fixed doses of 25 and 50 µg (RELAY) is currently being undertaken to explore a 
broader range of treatment dose options.  The purpose of this study is to assess the 
12-month safety and tolerability of varying doses of NPSP558 in reducing requirements 
for supplemental oral calcium and calcitriol, while maintaining stable total serum calcium 
levels and controlling hypercalciuria in adult patients with hypoparathyroidism.  
Route of administration 
A single daily SC injection of PTH (versus infusion) increases PTH levels transiently.  
NPSP558 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.   
2 
OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to demonstrate the long-term safety and tolerability 
of SC NPSP558 as hormone replacement therapy for the treatment of adult patients with 
hypoparathyroidism. 
2.2 
Secondary Objectives 
The secondary objectives of this study are: 
 To evaluate the impact of different preparations of calcium and calcitriol on the 
response to NPSP558 replacement therapy 
 To demonstrate that dosing with NPSP558 across a dose range of 25 to 100 μg SC 
can be implemented in a safe and effective manner and can be maintained 
throughout 12 months (52 weeks) of 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 
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 Incidence of adverse events 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 
o Hematology (hematocrit, hemoglobin, white blood cells, red blood cells, 
platelets, differential) 
o Serum chemistries (standard Chem-20 panel, including calcium, 
phosphorus, and albumin) 
o Serum 25-hydroxyvitamin D levels 
o Creatinine clearance 
o Serum bone turnover markers 
o Urinalysis 
o 24-hour urine calcium, phosphate, sodium, and creatinine excretion 
o PTH antibodies 
 Bone mineral density by dual-energy x-ray absorptiometry (DXA) 
 Electrocardiogram (ECG) parameters 
 Physical examinations (including vital signs) 
 Reason for termination from the study 
2.3.2 
Efficacy Endpoints 
2.3.2.1 
Primary Efficacy Endpoint 
The proportion of patients in whom the following three conditions are fulfilled at 
Week 52 (Visit 9) 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 (≥7.5 mg/dL) and does not exceed 
the ULN for the central laboratory 
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2.3.2.2 
Secondary Efficacy Endpoints  
 Mean percentage changes from baseline in supplemental oral calcium and 
supplemental calcitriol dosages at each visit. 
 Proportion of patients achieving the primary endpoint 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 patients that maintain a calcium phosphate product in the range of 
35 to 55 mg2/dL2        
 Distribution of patients by NPSP558 doses at the End of Treatment Visit 
 Change from baseline in bone turnover markers (bone-specific alkaline 
phosphatase [BSAP], serum carboxy-terminal telopeptide of type I collagen 
[P1NP], serum procollagen type 1 amino-terminal propeptide [s-CTx], and 
osteocalcin), PTH antibodies, and BMD by DXA 
 Additional subgroup analyses that are specified in the Statistical Analysis Plan 
(SAP) 
3 
STUDY DESIGN 
3.1 
Overall Design and Control Methods 
This study is a 12-month, open-label study using NPSP558 for the treatment of adult 
male and female patients with hypoparathyroidism.  Patients must have previously 
completed the NPSP558 RELAY study (8 weeks of active therapy) to enroll in this study.   
The goal of this study is to optimize NPSP558 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, NPSP558 and Supplement 
Titration Guideline).   
 The starting dose of NPSP558 for this study will be 25 or 50 g SC once daily.  
o Patients with a total serum calcium value of ≤ 9.5 mg/dL will have a 
starting dose of 50 μg.   
o Patients with a total serum calcium value of > 9.5 mg/dL will have a 
starting dose as follows: 
 Patients 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.  
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 Patients 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 will be conducted at Weeks 1 (baseline), 4, 8, and then every 
8 weeks thereafter up to Week 48 (Visit 8).  The End of Treatment Visit 
(Week 52, Visit 9) is scheduled 4 weeks later followed by a safety visit at 
Week 53 (Visit 10) and a follow-up telephone contact at Week 56 (Visit 11).   
 All patients will have their total serum calcium checked by a local laboratory 
3 to 5 days (± 2 days) following the baseline visit.  
 Patients may have their NPSP558 dose increased by the investigator at any time 
through Week 48 of 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 NPSP558 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.   
 Patients will have blood draws to assess total serum calcium levels (which may 
be performed locally) 3 to 5 days after ANY dose adjustment of NPSP558, after 
any significant change in doses of calcium and/or and calcitriol supplements, or 
at any other time at the discretion of the investigator.   
 Once a patient 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 NPSP558.      
 If ANY predose total serum calcium is > 11.9 mg/dL study drug will be 
stopped.  Once total serum calcium returns to the normal range, NPSP558 can 
be reintroduced.  The NPSP558 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 NPSP558 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 NPSP558 dose may be reduced to the next lowest dose level and 
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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 NPS medical monitor.   
 At the Week 16 (Visit 4), patients who are on a stable dose of NPSP558 and 
have a 24-hour urine calcium > 300 mg 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. 
o 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 visit.   
o Monitoring of urine calcium will be performed at Weeks 16, 32, and 52 
(Visits 4, 6, and 9) for patients 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 Week 53, patients will have their total serum calcium levels checked 
locally at an interim visit scheduled 3 to 5 days after the last dose of study 
medication.  Patients will also be scheduled for a follow-up clinic visit at the 
end of Week 53 (Visit 10) in order to have serum calcium, phosphorus, and 
albumin checked.   
 At Week 56 (Visit 11), approximately 4 weeks (30 days) following the End of 
Treatment visit (Week 52), patients will be contacted by telephone in order to 
assess adverse events (AEs)/serious AEs (SAEs).  
  
A schematic representation of the study design is displayed in Figure 3-1. 
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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.  
Female partners (who are of childbearing potential) of male study patients must 
also use acceptable forms of contraception during their partner’s participation.   
4.3 
Exclusion Criteria 
Patients 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 that has a high 
probability of precluding the patient from completing the study or where the 
patient cannot or will not appropriately comply with study requirements 
3. Pregnant or lactating woman  
4.4 
Patient Withdrawal Criteria 
All patients 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 
patients will not be replaced.  A patient 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 (IRB/IEC), Health Authority and/or NPS, it is no longer in 
the patient’s best interest to continue in the study 
 Patient 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 
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In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) and in the patient’s medical records.  If the reason is not known, the patient 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 
As far as possible, all examinations scheduled for the end-of-study evaluations must be 
performed on all patients who participate but do not complete the study according to 
protocol. 
5 
TREATMENTS AND TREATMENT PLAN 
5.1 
Treatments Administered  
Patients will self-administer an SC injection of NPSP558 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)  
NPSP558  is manufactured using a strain of E. coli modified by DNA technology and is 
identical to native human PTH.  NPSP558 is a single-chain polypeptide containing 
84 amino acid residues.  The drug substance is clear and colorless to light straw-colored. 
NPSP558 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).  The dual-chamber cartridge is installed by the user into a reusable injection 
pen device, in which reconstitution occurs in a total volume of 1.15 mL.  
(See Appendix 1, Instructions for Use)    
The injection pen serves as a holder for the cartridge and does not come in contact with 
rhPTH product.  Using the injection pen 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 patient will receive two pens for use during the study period 
and sufficient cartridges to provide daily doses for 52 weeks.  Drug cartridges will be 
provided 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 
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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.   
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 patient numbers.  The 
label on the kit will be a tear-off label, which the center can affix to the patient’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 patient 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 have a maximum shelf-life of 36 months and should be 
stored at 2ºC to 8ºC (36ºF to 46ºF).  After study drug reconstitution in the injection pen 
device, 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. 
 Additional data on the reconstituted solution demonstrates that it is stable for up to 
7 days when stored at 25°C, which provides assurance of product quality during any 
unexpected excursions.  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.  In this study, patients will be supplied with cartridges 
in sufficient quantity to maintain daily self-administration of varying dose of NPSP558.  
Patients should be reminded to return all cartridges, even if empty, at the final 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 patient 
 quantity removed from stock but not dispensed (eg, damaged, dropped, spilled) 
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 quantity remaining at the end of the study and retained, returned, or destroyed, 
as per the sponsor’s instructions 
For each patient, 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 or disposed of according to the sponsor’s instructions. 
5.2 
Methods of Assigning Patients to Treatment Groups 
Patients will utilize the same 8-digit patient number that they had been assigned during 
the RELAY study.  The first 4 digits consist of the center number and the last 4 digits are 
the sequential patient number.  An additional suffix of “E” will be added to this number 
to distinguish this study data from the RELAY study.  This number will be utilized to 
identify the patient throughout the study period.   
Patients will receive study treatment in an open-label fashion at starting doses of 
NPSP558 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 patient will be recorded on the appropriate 
eCRF.  All subsequent kit numbers will be similarly recorded.  All doses of study 
medication for each patient must be taken from the kit(s) designated for that patient and 
cartridges from an assigned kit will not be dispensed to any other patient. 
5.3 
Dose Regimens 
Daily NPSP558 SC injections will be self-administered into alternating thighs each 
morning using a multidose pen injection device (see Appendix 1, Instructions for Use).    
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 patients with PMO at doses ranging 
between 0.02 to 5.0 g/kg.  The phase 2 and 3 studies alone exposed 2891 patients with 
PMO to doses ranging between 50 to 100 µg of NPSP558.    
In patients 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).  The phase 3, randomized, double-blind placebo-controlled 
REPLACE study in patients with hypoparathyroidism is ongoing.  This registrational 
study is exploring the biologic activity of NPSP558 at doses of 50, 75, or 100 g 
administered as SC injections to the thigh.  An ongoing pharmacokinetic study (C09-002) 
utilizes two single doses of 50 and 100 g each, also as SC injections to the thigh.  The 
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phase 3 fixed-dose study (RELAY) utilized dose of 25 and 50 g SC daily.  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 patients.  
5.3.2 
Selection and Timing of Dose for Each Patient 
Patients will self-administer NPSP558 in the morning, using the multidose injection pen 
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.  Calcium and/or vitamin D should be taken in the morning as normal after the 
NPSP558 injection.  
5.3.3 
Compliance With Dosing Regimens 
Paper diaries will be provided for the patients to record study drug administration and 
supplement regimens.  Patients should be requested to bring the diaries to each clinic 
study visit for review.  Patients with ≥ 80%  to ≤ 120% compliance level will be 
considered to be compliant with regard to study drug administration.  Diaries will be 
collected at the end of the study and submitted to the sponsor. 
5.4 
Prior and Concomitant Medications 
5.4.1 
Exclusionary Prior/Concomitant Medications 
Patients 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 patient’s entry into this study. 
Exclusionary concomitant medications are shown in Table 5-1. 
Table 5-1 
Prohibited Medications or Therapies  
Medication/Therapy 
Regimen 
Raloxifene hydrochloride 
Any  
Bisphosphonates, intravenous 
Any 
Bisphosphonates, oral 
≥ 1 month of chronic use 
Systemic corticosteriods, oral or depot form (chronic use) 
≥ 1 month of chronic use 
Calcitonin, cinacalcet or other drugs that influence calcium or 
bone metabolism 
≥ 1 month of chronic use 
Fluoride tablets 
≥ 1 month of chronic use 
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In addition, concomitant active vitamin D supplements from outside sources are 
prohibited. 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 
 nasal and inhaled corticosteroids for the management of allergic rhinitis and 
asthma  
 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 signing the ICF through study exit), including administration 
dates and dosage, are to be recorded on the appropriate eCRF.  Any medication 
which contains either calcium or vitamin D must be recorded on the eCRF 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 entered on the appropriate eCRF. 
5.4.2 
Active Calcitriol, Calcium, Native Vitamin D, and Magnesium 
Supplementation 
Calcitriol 
Patients enrolled in this study will be taking calcitriol to control serum calcium levels.  
Oral calcitriol supplements will be provided for this study by the sponsor or designee; no 
other sources of calcitriol should be used during the study.  Prescribed doses of calcitriol 
will be entered on the appropriate eCRF. 
Calcium 
Oral calcium supplements (either calcium carbonate or calcium citrate) will be provided 
for 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 entered on the appropriate eCRF. 
In the case that extra calcium supplementation is taken by the patient due to symptoms of 
hypocalcemia, the dose/time and associated symptoms should be recorded by the patient 
in the diary.  
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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 Week 52 (End of Treatment).  During the study, 
sufficient supplemental native vitamin D should be administered in order to maintain the 
patient’s serum 25(OH) vitamin D level in the normal range.  Any dose taken by the 
patient must be recorded on the concomitant medication eCRF. 
Magnesium   
Magnesium is required for normal parathyroid function and disordered magnesium levels 
can exacerbate hypoparathyroidism.  Patients 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 patient must be recorded on the 
concomitant medication eCRF. 
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 
o Total serum calcium  
o 24-hour urinary calcium excretion 
o Serum phosphate (calcium-phosphate ratio)  
 Supplement usage 
o Concomitant supplemental oral calcium dosage 
o 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 adverse events 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 
o Hematology (hematocrit, hemoglobin, white blood cells, red blood cells, 
platelets, differential) 
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o Serum chemistries (standard Chem-20 panel, including calcium, 
phosphorus, and albumin) 
o Serum 25-hydroxyvitamin D levels 
o Creatinine clearance 
o Serum bone turnover markers 
o Urinalysis 
o 24-hour urine calcium, phosphate, sodium, and creatinine excretion 
o PTH antibodies 
 Bone mineral density by DXA 
 Electrocardiogram parameters 
 Physical examinations (including vital signs) 
 Reason for termination from the study 
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 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 
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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 
Overdose 
Defined as an accidental or intentional administration of an excessive dose of a product, 
an overdose should be reported to the sponsor using the SAE form.  This information will 
be shared with the Safety Management Team (SMT) and medical monitor. 
6.2.1.2 
Procedures for Reporting Adverse Events 
Adverse events may be spontaneously reported by the patient, obtained through 
nonleading questioning, or noted during examination of a patient.  All AEs and SAEs will 
be recorded from the signing of the ICF through the completion of the study.  AE/SAEs 
will be monitored by the site with a telephone call at Week 56, approximately 30 days 
following the last dose of study drug.     
At each visit, new AEs will be recorded sequentially on the AE page of the eCRF.  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) 
o Mild:  usually transient, requiring no special treatment and generally not 
interfering with usual daily activities 
o Moderate:  usually ameliorated by simple therapeutic maneuvers and 
impairs usual activities 
o Severe:  requires vigorous therapeutic intervention and interrupts usual 
activities.  Hospitalization may or may not be required. 
 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. 
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 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 patient discontinuation from the study. 
6.2.2 
Serious Adverse Events 
A serious event must be recorded on the sponsor’s Serious Adverse Event Report Form.  
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 in the SAE database and must be reported 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 
 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 
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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 patient signs the ICF through 30 days after the study drug is completed, the 
investigator must complete the sponsor’s SAE form (even if all information regarding the 
SAE is unknown or incomplete) and forward the SAE form via FAX to the sponsor or 
designee.  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 
patient to have surgery is the SAE term.  Death is not an SAE, but an outcome. 
The sponsor or designee will provide a FAX cover sheet for the investigators in the Study 
Reference Manual. 
Autopsy reports, if applicable, will be forwarded as they become available.  All pertinent 
laboratory results should be entered on the sponsor’s SAE form. 
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 6.2.1.2).  A causality assessment should always be included on 
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the sponsor’s 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 
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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 determined that there is an unanticipated signal, the NPS 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).   
NPS Pharmaceuticals (sponsor) 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  the 
sponsor 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 with patients in a fasted state (6 to 
8 hours) at baseline and Week 52 (End of Treatment), unless otherwise noted.  Final 
RELAY study parameters may be used as baseline parameters for this study.  All 
laboratory tests will be analyzed by a central laboratory, with the exception of all urine 
pregnancy tests and total serum calcium levels obtained at baseline, Week 53, and interim 
time points for safety checks, which will be done at the investigators’ or patients’ local 
laboratories.  The following laboratory parameters will be collected: 
 Hematology: hemoglobin concentration, hematocrit, erythrocyte count, platelet 
count, and leukocyte counts with differential 
 Serum Chem-20 panel: alanine transaminase, aspartate transaminase, alkaline 
phosphatase, lactate dehydrogenase, inorganic phosphorus, 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  
 Urinalysis: specific gravity, pH, protein, glucose, ketones, bilirubin, 
urobilinogen, blood, and microscopic analysis of sediment 
 Creatinine clearance will be done at baseline and Weeks 16, 32, and 52. 
 Total serum calcium (local) will be drawn at baseline and at the Week 53 (Visit 
10) follow-up visit. 
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 Total serum calcium, albumin, and phosphorus will be drawn at baseline and at 
each subsequent scheduled study visit through Week 52.   
 All patients will have local blood draws to assess  total serum calcium levels 
during Week 1, 3 to 5 days (± 2 days) after baseline and again during Week 53, 
3 to 5 days (± 2 days) after the last dose of study drug.  Following any 
adjustment of NPSP558 or a significant change in calcium/calcitriol 
supplements, a local total serum calcium level will also be drawn after 
3 to 5 days. 
 Serum 25-hydroxyvitamin D additional levels will be drawn at baseline and at 
each subsequent scheduled study visit through Week 52.  
 24-hour urine calcium, phosphate, sodium, and creatinine will be done at 
baseline and Weeks 16, 32, and 52. 
 Serum bone turnover markers (BSAP, s-CTx, P1NP, and osteocalcin) will be 
done at baseline and Weeks 8, 16, 24, 40, and 52. 
 Serum beta human chorionic gonadotropin (-HCG) pregnancy test will be 
done at  baseline and Weeks 16, 24, 32, 40, 48, and 52 (women of child-bearing 
potential [WOCBP] only) 
 An FSH test to confirm postmenopausal status, if patients have met the 
definition of postmenopausal after the beginning of the RELAY study (newly 
postmenopausal females only) will be done at baseline only, if necessary. 
 Urine pregnancy test (WOCBP only) will also be collected at baseline and 
Weeks 4 and 8. 
 PTH  antibodies will be done at  baseline and Weeks 24,  40, and 52  
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 at baseline and each clinic study visit through Week 52 and 
will include systolic and diastolic blood pressure (mm Hg), pulse (beats per minute or 
bpm), and body temperature (ºC) after the patient has been sitting for 5 minutes.  Body 
weight will also be recorded. 
If any of the patient’s measurements are outside of the normal range at screening (prior to 
receiving the first dose) the investigator will determine, based on medical history, 
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whether the patient 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 and Week 52, at the study center on the same 
model unit.  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 AE.  All ECGs 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 and the eCRF.  Two copies of the 
ECG tracings should be retained in the patient source record. 
6.2.6 
Physical Examinations 
Physical examinations will be performed at baseline and Week 52 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.  
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 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 and Week 52 and 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 patient cannot withhold the calcium 
supplements due to safety concern, the DXA should be performed 2 hours after the last 
calcium tablet has been ingested. 
6.2.8 
Women of Childbearing Potential 
Any patient that has become postmenopausal since entering the RELAY 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).   
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If the result is not in the postmenopausal range and the patient is not surgically sterile, 
then the patient 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, and 52.  Pregnancy occurring during the trial will necessitate 
immediately withdrawal from study.  A WOCBP must be willing to use two medically 
acceptable methods of contraception for the duration of the study (see Appendix 3).  
Female partners of male patients should also use medically acceptable means to avoid 
pregnancy during their partner’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 patient becomes pregnant during the study, study drug will be discontinued, and an 
SAE supplemental form will be completed to capture potential drug exposure during 
pregnancy and will be reported to the sponsor or designee within 24 hours of becoming 
aware of the pregnancy.  The pregnant patient will be followed until an outcome is 
known (ie, normal delivery, abnormal delivery, spontaneous/voluntary/therapeutic 
abortion).  If a pregnant patient also experiences an SAE, an additional SAE form will be 
completed and submitted to the sponsor or designee within 24 hours as discussed above.  
An SAE supplemental form should be completed in the event that a female partner of a 
male patient 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.  Details of the 
exact date and time of medical assessments (day/month/year) will be documented in the 
eCRF.  Any deviations from protocol requirements will be documented in the eCRF. 


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Table 6-1 
Schedule of Evaluations and Procedures 
Visit Number 
1 
Int. 
2 
3 
4 
5 
6 
7 
8 
9 
Int. 
10 
11 
Study Procedures / Proposed Study Weeka 
BLb 
1c 
4 
8 
16 
24 
32 
40 
48 
52 
(EoT) 
53c, d 
53 d 
(F/up) 
56 
(F/up) 
Phone 
 
 
Visit Windows 
± 3 
days 
± 2 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7  
days 
± 2 
days 
± 3 
days 
± 7 
days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History (updated from RELAY) 
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 
 
X 
X 
Adverse event monitoring (new) 
X 
 
X 
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 signse and weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Electrocardiogram (12-lead)  
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Bone mineral density by DXAf      
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Hematology  
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Serum chemistry (20-panel)g 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Serum calcium (local)* 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Serum calcium, phosphorus, and albumin 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Serum 25-hydroxyvitamin D 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Serum bone turnover markers 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
 
 
Serum thyroid function testh 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine clearance (estimated GFR) 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
 
PTH antibodiesi 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
FSH (newly menopausal women only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test  
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Urine pregnancy test 
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 injection pens  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Dispense/accountability of calcium/calcitriol supplements (see 
guideline)  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Collect used/unused study drug, supplements, and injection pensk 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
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30 December 2010 
 
Visit Number 
1 
Int. 
2 
3 
4 
5 
6 
7 
8 
9 
Int. 
10 
11 
Study Procedures / Proposed Study Weeka 
BLb 
1c 
4 
8 
16 
24 
32 
40 
48 
52 
(EoT) 
53c, d 
53 d 
(F/up) 
56 
(F/up) 
Phone 
 
 
Visit Windows 
± 3 
days 
± 2 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7  
days 
± 2 
days 
± 3 
days 
± 7 
days 
BL = baseline; DXA = dual-energy x-ray absorptiometry; EoT = end of treatment; FSH = follicle stimulating hormone; F/up = follow up; GFR = glomerular filtration rate; Int.= interim visit;  
PTH = parathyroid hormone 
*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 and 53.  Week 56 is telephone contact only.  
b Week 8 from the RELAY Study; patients will return all used/unused drug, supplements, and pens from RELAY. 
c Interim total serum calcium for all patients 3 to 5 days (±2 days) after baseline and after last dose of study drug 
d Week 53 will be comprised of 2 visits:  one interim safety check and one end of week study visit. 
e Vital signs should be done prior to blood draws 
f Calcium supplements should be withheld for 24 hours prior to the DXA scan.  If a patient cannot withhold the calcium supplements due to safety concern, the DXA should be 
performed 2 hours after the last calcium tablet has been ingested. 
g Fasting for at least 6 to 8 hours prior to test 
h Thyroid function tests done for final visit of the RELAY study only 
 i Blood draw for PTH antibodies will be done predose. 
 j A paper diary will be dispensed at baseline for the investigator’s use to assess patient’s compliance and adherence to the protocol procedures. 
 k Patient is to return unused and used cartridges and supplements at each visit.  Pens will be collected at the final visit. 
 


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6.4 
Description of Study Procedures 
6.4.1 
Visit 1 Baseline Procedures  
Patients must sign an ICF for this study prior to having any study-related procedures 
performed.  Baseline procedures may be performed at the same time as the RELAY study 
Week 8 procedures.   
Patients 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 patient’s medical history, demographic information, ongoing 
concomitant medications, and ongoing AEs from the RELAY 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, phosphorus, and 
albumin), hematology, serum 25(OH) vitamin D, creatinine clearance, and bone 
turnover markers.  The blood sample for serum chemistries will be split and a 
local total serum calcium will also be performed. 
 Blood sample for PTH antibodies  
 Urinalysis and 24-hour urine calcium, phosphate, sodium, and creatinine 
 Serum -HCG pregnancy test (WOCBP only) 
 Urine pregnancy test for immediate confirmation of nonpregnant status 
(WOCBP only) 
 A BMD test by DXA  
 An FSH test to confirm postmenopausal status, EXCEPT if patients have met 
the definition of postmenopausal after the beginning the RELAY study (for 
newly postmenopausal females only). 
 The first dose of study medication will be administered after appropriate fasting 
laboratory evaluations have been taken. 
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 Patients will be provided with the following study supplies: 
o Study medication cartridges in sufficient number to supply daily doses until 
the next scheduled clinic visit  
o Two injection pens 
o Ancillary injection supplies (ie, alcohol swabs, needles, etc.) 
o Paper diaries  
o 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   
Patients 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, NPSP558 and Supplement Titration Guideline) 
based on this value.  If further adjustments are made to the NPSP558 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 patient’s diary for compliance with protocol procedures and 
dosing/supplement regimens (all visits) 
 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 calcium, phosphorus, and albumin (all visits) 
 Serum bone turnover markers (Weeks 8, 16, 24, and 40) 
 Serum -HCG pregnancy test (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 antibodies (predose on Weeks 24 and 40) 
 Patients will be provided with the following study supplies: 
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o Study medication cartridges in sufficient number to supply daily doses until 
the next scheduled clinic visit  
o Ancillary injection supplies (ie, alcohol swabs, needles, etc.) 
o Calcium (carbonate or citrate) and calcitriol supplements in sufficient 
quantity to supply daily doses until the next scheduled clinic visit 
o Collection container for 24-hour urine (Weeks 16 and 32) 
6.4.4 
Week 52 (Visit 9) End of Study Visit  
Patients will be instructed to come into the study center after having fasted for 
approximately 6 to 8 hours and prior to taking their last dose of 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 
 Physical examination 
 12-lead electrocardiogram 
 Blood samples for serum chemistries (including calcium, phosphorus, and 
albumin), hematology, serum 25(OH) vitamin D, creatinine clearance, and bone 
turnover markers  
 Blood sample for PTH antibodies (predose) 
 Administration of the last dose of study medication following the predose PTH 
samples 
 Urinalysis  
 24-hour urine calcium, phosphate, sodium, and creatinine 
 A BMD test by DXA  
 Serum -HCG pregnancy test (females only) 
 Review the patient’s diary to assess compliance to protocol procedures and 
dosing/supplement regimens. 
 Collect used and unused drug cartridges, supplements (calcium and calcitriol), 
and injection pens for assessment of accountability and patient diaries. 
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6.4.5 
Week 53 Interim Safety Check 
Patients will have a total serum calcium level drawn locally between 3 to 5 days 
(± 2 days) following the last dose of study drug.  Poststudy adjustments of supplemental 
calcium and calcitriol will be made (see Appendix 2, NPSP558 and Supplement Titration 
Guideline) based on this value.   
6.4.6 
End of Week 53 (Visit 10) Follow-up Safety Visit  
Patients will have blood drawn for total serum calcium, phosphorus, and albumin levels.  
This sample will be split in order to provide blood for a local total serum calcium to be 
done at the investigator’s local laboratory.  Further adjustment of patients’ supplemental 
calcium and calcitriol doses will be made based on these values (see Appendix 2, 
NPSP558 and Supplement Titration Guideline).  Patients will also be monitored for 
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. 
6.4.7 
Week 56 (Visit 11) Follow-up Telephone Contact  
Patients will be contacted approximately 30 days 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. 
7 
DATA MANAGEMENT 
7.1 
Data Collection  
Data collected during the study will be recorded in the patient’s eCRF by the study 
center’s research team.  The research team will keep records of the patient’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 patient data. 
The investigator will review all eCRFs (including the termination page after the patient’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 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. 
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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 patients’ 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 review, and regulatory inspections by providing direct access to source 
data/documents. 
Patients will retain the patient number utilized in the RELAY study.  The first four digits 
consist of the center number.  An additional suffix of “E” will be added to this number to 
distinguish this study data from that in the RELAY study.  This number is the main 
identifier for patients. 
7.2 
Record Retention 
The clinical investigators will maintain drug records, copies of eCRFs, laboratory 
records, data sheets, correspondence records, and signed patient 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   
Statistical analyses 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, if available.   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 
patients with specific prior medications will be summarized.  Medical and surgical 
history will be coded using the Medical Dictionary for Regulatory Activities.  The 
number and percentage of patients 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, 
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.  
8.2.1 
Efficacy Variables 
Primary Efficacy Endpoint: 
The proportion of patients in whom the following three conditions are fulfilled at 
Week 52 (Visit 9) 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 (≥7.5 mg/dL) and does not exceed the 
ULN of the central laboratory 
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In addition, the following efficacy variables will be summarized:  
 Mean percentage changes from baseline in supplemental oral calcium and 
supplemental calcitriol dosages at each visit 
 Proportion of patients achieving the primary endpoint 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 patients that maintain a calcium phosphate product in the range of 
35 to 55 mg2/dL2        
 Distribution of patients by NPSP558 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 study.  The visits will be 
defined in the SAP.  No between-group comparisons with p-values are planned. 
8.3 
Other Variables  
Other variables to be analyzed will include the following:  
 Patient accounting 
 Duration of study medication exposure  
 Patient compliance  
 The number and percentage of patients who complete the study, are lost to 
follow-up, and who are discontinued from the study (including reason for study 
withdrawal) will be summarized.  
Patients will be considered compliant if study drug was taken according to protocol for 
≥ 80% to ≤ 120% of doses.  The number and percentage of patients who were compliant 
will be summarized. 
8.4 
Analysis Populations, Data Sets, and Time Points 
8.4.1 
Analysis Populations  
The primary and secondary efficacy analyses will be based on the intention-to-treat (ITT) 
population.  This population includes all patients who received at least one dose of study 
drug and had at least one efficacy measurement.  
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The safety analyses will be based on the Safety population.  This population includes all 
patients who received at least one dose of study drug with any follow-up information. 
8.5 
Statistical/Analytical Issues  
8.5.1 
Adjustments for Covariates 
No preselected covariates are selected for adjustments. 
8.5.2 
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. 
8.5.3 
Interim Analyses and Data Monitoring 
No interim analyses are planned. 
8.5.4 
Multiple Comparisons/Multiplicity 
No adjustment for multiplicity in treatment is planned. 
8.5.5 
Use of a Pharmacokinetic Subset of Patients 
No pharmacokinetic subset of patients was selected for analysis. 
8.5.6 
Examination of Subgroups 
Subgroup analyses (if any), in addition to the possible ones by gender, will be discussed 
in the SAP.  
8.6 
Determination of Sample Size 
Approximately 40 patients are anticipated to be enrolled.  Sample sizes were not 
estimated for this extension study.  
8.7 
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 
Patients', Helsinki 1964, amended in Tokyo 1975, Venice 1983, Hong Kong 1989, 
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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). 
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 NPS 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 
Patient 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 patient 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 patient the nature of the study, the 
action of the test product, and any risks and benefits.  The patient 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 
partner of male patients who is a WOCBP) and lactating females should be provided in 
the ICF regarding unintended pregnancy and methods of contraception. 
The patient will be given a copy of the fully executed consent form and the original will 
be maintained with the patient’s records. 
9.3 
Patient Data Protection 
All data provided to the sponsor or designee will be identified only by patient number 
and initials, thereby ensuring that the patient’s identity remains unknown.  Patients 
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. 
Patients 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 
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hospital/clinic records which are relevant to the study, including medical history, for data 
verification purposes. 
The principal investigator is responsible for keeping a patient identification list of all 
patients screened and enrolled which includes the following information: patient number, 
full name, and a secondary unique identifier (ie, hospital/clinic number).  A list of 
patients 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 patients.  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. 
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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 revised protocol.  Changes to the protocol may require notification 
to or approval by the IRB/IEC 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 
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 membership list or Department of Health and Human Services General 
Assurance Number, which must be maintained current during the trial 
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 Laboratory certification and normal ranges, unless a central laboratory is being 
used exclusively 
The “Principal Investigator Protocol Agreement 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. 
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 patient 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 
Aug 4;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. 
Rubin MR, Sliney J Jr, McMahon DJ, Silverberg SJ, Bilezikian JP.  Therapy of 
hypoparathyroid with intact parathyroid hormone.  Osteoporos Int. 2010;21(11):1927-34. 
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 
Sep;88(9):4214-20. 
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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 
YPSOMED INJECTION PEN  
 
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APPENDIX 2 
NPSP558 AND SUPPLEMENT TITRATION 
GUIDELINE 
In this study the goal is to continue NPSP558 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 patients will receive NPSP558.  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 patient’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 in a fasting state prior to administration of 
study drug, NPSP558. 
The order and magnitude of subsequent reductions in either calcitriol or oral calcium 
supplementation is left to the investigator’s discretion, based on individual patient 
response.  After any change in the NPSP558 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 patient that terminates early) patients 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 
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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 NPSP558 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 patient’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 patient safety.  Thereafter, NPSP558 
can be reintroduced with clinically appropriate doses of calcitriol and oral calcium, with 
the aim to avoid further episodes of abnormal serum calcium.   
 
Hypocalcemia  
If the total serum calcium level falls below 8.0 mg/dL (or below the baseline values, if 
the patient entered the study with a total serum calcium < 8.0 mg/dL), then the patient’s 
calcitriol and oral calcium doses should be checked and the injection technique of 
NPSP558 reviewed with the patient to ensure proper administration.  At planned study 
visits (Week 4, 8 etc until Week 48) the NPSP558 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 
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APPENDIX 3   METHOD OF BIRTH CONTROL  
 
Patients who are sexually active, or considering sexual activity, will be instructed to use 
two 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) .  
Female partners (who are of childbearing potential) of male study patients must also use 
acceptable forms of contraception during their partner’s participation.   
True sexual abstinence is defined as not having any type of intercourse or sex play with a 
partner. 
 
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