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

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

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Amendment 3_Final v4.0 
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• 
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) 

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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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Amendment 3_Final v4.0 
15 March 2012 
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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Amendment 3_Final v4.0 
15 March 2012 
• 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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Amendment 3_Final v4.0 
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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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Amendment 3_Final v4.0 
15 March 2012 
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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Amendment 3_Final v4.0 
15 March 2012 
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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Amendment 3_Final v4.0 
15 March 2012 
  
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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Amendment 3_Final v4.0 
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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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Amendment 3_Final v4.0 
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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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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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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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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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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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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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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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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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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. 
 

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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.