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  
 
Protocol Version Date: 30 Dec 2010 

 
 
 
NPSP558 
 
A 12-Month Open-label Study Investigating the Safety 
and Tolerability of NPSP558, a Recombinant Human 
Parathyroid Hormone (rhPTH [1-84]), for the 
Treatment of Adults with Hypoparathyroidism –  
A Clinical Extension Study (RACE) 
 
 
 
Clinical Protocol PAR-C10-008 
US IND Number: 76,514 
 
 
 
 
NPS Pharmaceuticals, Inc.  
550 Hills Drive, 3rd Floor 
Bedminster, NJ 07921 
 
 
 
ISSUED:  30 December 2010 Version 2.0
 
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SPONSOR:   
NPS Pharmaceuticals, Inc.  
550 Hills Drive, 3rd Floor 
Bedminster, NJ 07921 
             
 
KEY SPONSOR CONTACTS: 
 
Medical Director: 
 
Title:  
, MD  
 
, Clinical Development  
 
 
 
 
 
& Medical Affairs  
Phone:   
 
 
 
 
Mobile: 
                                    
 
Fax Number:    
 
 
 
 
Clinical Operations:  
 
Title:  
, RN, BSN  
 
, Clinical Operations 
Phone:                                 
 
 
Mobile:                                               
 
Fax Number:    
 
 
 
 
To Report an SAE: 
 
Title:  
 
 
 
, RPh, PhD 
, Pharmacovigilance  
Phone:   
 
 
 
 
 
Fax Number:    
 
 
 
30 December 2010 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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CLINICAL PROTOCOL PAR-C10-008 
 
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SUMMARY 
Title:  A 12-Month Open-label Study Investigating the Safety and Tolerability of 
NPSP558, a Recombinant Human Parathyroid Hormone (rhPTH [1-84]), for the 
Treatment of Adults with Hypoparathyroidism – A Clinical Extension Study (RACE) 
Protocol No:  PAR-C10-008 
Phase of Development: Phase 3 
Objectives:  
Primary Objective: 
The objective of this study is to demonstrate the long-term safety and tolerability of 
subcutaneous (SC) NPSP558 as hormone replacement therapy for the treatment of adult 
patients with hypoparathyroidism. 
Secondary Objectives: 
 To evaluate the impact of different preparations of calcium and calcitriol on the 
response to NPSP558 replacement therapy 
 To demonstrate that dosing with NPSP558 across a dose range of 25 to 100 μg SC 
can be implemented in a safe and effective manner and can be maintained 
throughout 12 months (52 weeks) of treatment 
 To evaluate the impact of calcium-sparing diuretics on serum and urinary calcium 
Study Rationale 
This study is designed to evaluate 12-month treatment with NPSP558.  
Study Design 
This study is a 12-month, open-label study using NPSP558 for the treatment of adults 
with hypoparathyroidism.  Patients must have previously completed the NPSP558 
RELAY study (8 weeks of active therapy) to enroll in this study.   
The goal of this study is to optimize NPSP558 dosing while reducing calcitriol and oral 
calcium (carbonate or citrate) supplementation to as low as safely possible and 
maintaining total serum calcium levels.  Dose adjustments to NPSP558 and to the 
calcium/calcitriol supplements and safety monitoring of calcium levels are explained in 
Appendix 2, NPSP558 and Supplement Titration Guideline.   
 The starting dose of NPSP558 for this study will be 25 or 50 g SC once daily  
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 Patients may have their NPSP558 dose adjusted by the investigator at any time 
through Week 48 of the study, with the goal of achieving or maintaining total 
serum calcium levels in the range of 8.0 to 9.0 mg/dL.   
 If ANY predose total serum calcium is > 11.9 mg/dL study drug will be 
stopped. 
 Patients will have blood draws to assess total serum calcium levels (which may 
be performed locally) 3 to 5 days after ANY dose adjustment of NPSP558, after 
any significant change in doses of calcium and/or calcitriol supplements, or at 
any other time at the discretion of the investigator.   
 Study visits will be conducted at Weeks 1 (baseline), 4, 8, and then every 
8 weeks thereafter up to Week 48 (Visit 8).  The End of Treatment Visit 
(Week 52, Visit 9) is scheduled 4 weeks later followed by a safety visit at Week 
53 (Visit 10) and a follow-up telephone contact at Week 56 (Visit 11).    
 At the Week 16 (Visit 4), patients who are on a stable dose of NPSP558 and 
have a 24-hour urine calcium > 300 mg may be treated for hypercalciuria with 
calcium-sparing diuretics. 
 During Week 53, patients will have their total serum calcium levels checked 
locally at an interim visit scheduled 3 to 5 days after the last dose of study 
medication.  Patients will also be scheduled for a follow-up clinic visit at the 
end of Week 53 (Visit 10) in order to have serum calcium, phosphorus, and 
albumin checked.   
Number of Patients Planned:  Approximately 40 patients will be enrolled.  
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria 
Patients who meet all of the following inclusion criteria may be enrolled in this study:  
1. Signed and dated informed consent form before any study-related procedures are 
performed 
2. Previously completed the NPSP558 RELAY study (8 weeks of active therapy) 
3. Able to perform daily SC self-injections of study medication (or have designee 
perform injection) via a multidose injection pen into the thigh 
4. Willingness and ability to understand and comply with the protocol 
5. Women who are: (1) postmenopausal defined as 12 months amenorrhea with 
appropriate serum follicle stimulating hormone levels (> 40 IU/L); (2) surgically 
sterilized; OR (3) of childbearing potential with a negative pregnancy test at 
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screening and who consent to use two acceptable methods of contraception for the 
duration of the study, with pregnancy testing at every scheduled visit.  Female 
partners (who are of childbearing potential) of male study patients must also use 
acceptable forms of contraception during their partner’s participation.   
Exclusion Criteria 
Patients who meet any of the following exclusion criteria at baseline (Visit 1) are not 
eligible for enrollment in this study:  
1. Any condition that, in the investigator’s opinion after consultation with the 
sponsor, would preclude the safe use of parathyroid hormone (PTH) 
2. Any disease or condition, in the opinion of the investigator, which has a high 
probability of precluding the patient from completing the study or where the 
patient cannot or will not appropriately comply with study requirements 
3. Pregnant or lactating women  
All patients are free to withdraw from participation in this study at any time, for any 
reason, specified or unspecified, without prejudice to subsequent care.  Withdrawn 
patients will not be replaced.   
Duration of Study/Treatment: 
The total duration of treatment will be 12 months (52 weeks).   Patients will have a 
follow-up visit at Week 53 and will also be contacted by telephone at Week 56.      
Test Product, Dose, and Mode of Administration:  
At the beginning of the study, patients will receive NPSP558 25 or 50 µg SC QD in an 
open-label fashion as defined earlier.  Patients may have their NPSP558 dose adjusted 
upwards in increments of 25 µg to a maximum of 100 µg SC QD.  NPSP558 is to be 
administered into alternating thighs each morning via a multidose injection pen device.  
Supplements:  
Calcium citrate, calcium carbonate, and calcitriol will be supplied by the sponsor.  
Criteria for Evaluation:  
Safety:  
Safety variables will be assessed by the following evaluations:  
 Adverse events and serious adverse events 
 Incidence of adverse events of hypocalcemia (eg, paresthesia, numbness, tetany) 
and hypercalcemia (eg, constipation, nausea, poor appetite or vomiting, frequent 
urination, thirst, and kidney stones) 
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 Incidence of hypercalciuria  
 Laboratory test results 
o Hematology (hematocrit, hemoglobin, white blood cells, red blood cells, 
platelets, differential) 
o Serum chemistries (standard Chem-20 panel) 
o Serum 25-hydroxyvitamin D levels 
o Creatinine clearance 
o Serum bone turnover markers 
o Urinalysis 
o 24-hour urine calcium, phosphate, sodium, and creatinine excretion 
o PTH antibodies 
 Bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) 
 Electrocardiogram (ECG) parameters 
 Physical examinations (including vital signs) 
 Reason for termination from the study 
Efficacy:   
Efficacy variables will be assessed by one or more of the following evaluations: 
 Laboratory test results 
o Total serum calcium  
o 24-hour urinary calcium excretion 
o Serum phosphate (calcium-phosphate ratio)  
 Supplement usage 
o Concomitant supplemental oral calcium dosage 
o Concomitant supplemental oral calcitriol dosage  
Statistical Methods:  
Detailed statistical analyses will be conducted as described in the Statistical Analysis 
Plan (SAP) for this study.  Deviations from the SAP (if any) will be described and 
justified in the Clinical Study Report. 
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Analysis of Demographic and Baseline Variables 
Demographic variables (such as sex, age, race, birthdate, etc.) will be obtained from the 
REPLACE or RELAY study, if available.   Demographic and/or other variables at 
baseline will be summarized for medical history, demography, physical examination, 
vital signs, prior medications, ECG, and laboratory test results. 
The number and percentage of patients with specific prior medications will be 
summarized.  The number and percentage of patients will be summarized by system 
organ class and by high-level term and preferred term for each condition.  
Efficacy Variables Summary 
Primary Efficacy Endpoint: 
The proportion of patients in whom the following three conditions are fulfilled at 
Week 52 (Visit 9) will be summarized: 
 A ≥ 50% reduction from baseline in dose of oral calcium supplementation or an 
oral calcium dose of ≤ 500 mg 
AND 
 A ≥ 50% reduction from baseline in dose of oral calcitriol supplementation or 
an oral calcitriol dose of ≤ 0.25 μg 
AND 
 An albumin-corrected total serum calcium concentration that is normalized or 
maintained compared to the baseline value (≥7.5 mg/dL) and does not exceed 
the ULN for the central laboratory 
Secondary Efficacy Endpoints:  
 Mean percentage changes from baseline in supplemental oral calcium and 
supplemental calcitriol dosages at each visit 
 Proportion of patients achieving the primary endpoint at each visit 
 Mean change from baseline in 24-hour urine calcium excretion 
 Impact of calcium source (carbonate vs. citrate) on response 
 Impact of calcium-sparing diuretics on serum and urinary calcium 
 Proportion of patients that maintain a calcium phosphate product in the range of 
35 to 55 mg2/dL2        
 Distribution of patients by NPSP558 doses at the End of Treatment Visit 
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 Change from baseline in bone turnover markers, bone-specific alkaline 
phosphatase, serum carboxy-terminal telopeptide of type I collagen, serum 
procollagen type 1 amino-terminal propeptide, osteocalcin, PTH antibodies, and 
BMD by DXA 
 Additional subgroup analyses that are specified in the SAP 
 
Safety Analysis: 
Safety data including vital signs assessments, physical examinations, AEs, SAEs, the 
frequency of adverse events of hypocalcemia or hypercalcemia, concomitant 
medications, clinical laboratory tests, ECG monitoring, and termination from study will 
be summarized by point of time of collection. 
Descriptive statistics (arithmetic mean, standard deviation, median, minimum and 
maximum) will be calculated for quantitative safety data as well as for the difference 
from baseline, if applicable.  Frequency counts will be compiled for classification of 
qualitative safety data. 
 
 
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PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE 
Protocol PAR-C10-008  
I agree: 
To assume responsibility for the proper conduct of this clinical study at this center and to 
conduct the study in compliance with this protocol, any future amendments, and with any 
other study conduct procedures provided by the sponsor, 
That I am aware of, and will comply with, the internationally recognized code of Good 
Clinical Practice and all other applicable regulatory requirements to obtain written and 
dated approval from the Institutional or Central Review Board (IRB) or Independent 
Ethics Committee (IEC) for the study protocol and any amendments thereof, written 
informed consent or updates thereof, patient recruitment procedures (eg, advertisements), 
and any other written information to be provided to the patients, before initiating this 
clinical study, 
Not to implement any changes to, or deviations from the protocol without prior 
agreement from the sponsor and review and documented approval from the IRB/IEC, 
except to eliminate an immediate hazard to the study patients, or when change(s) involves 
only logistical or administrative aspects of the clinical study, 
To permit direct monitoring and auditing by the sponsor or sponsor’s representatives and 
inspection by the appropriate regulatory authority(ies), 
That I am thoroughly familiar with the appropriate use of the investigational product(s), 
as described in this protocol, and any other information provided by the sponsor or 
designee, including, but not limited to, the current Investigator’s Brochure or equivalent 
document and approved product label (if applicable), 
To provide sufficient time and an adequate number of qualified staff and facilities for the 
foreseen duration of the clinical study in order to conduct the study properly, ethically, 
and safely, 
To ensure that all persons assisting in this study are adequately informed about the 
protocol, investigational product(s), and their clinical study-related duties and functions, 
To maintain drug records, copies of eCRFs, laboratory records, data sheets, 
correspondence records, and signed patient consent documents for at least 5 years or until 
instructed in writing by the sponsor that records may be destroyed or forwarded to the 
sponsor.   
 
 
Principal Investigator (Print Name) 
 
 
 
 
Principal Investigator (Signature) 
 
Date (DD MMM YYYY) 
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TABLE OF CONTENTS 
TITLE PAGE .....................................................................................................................1 
SPONSOR KEY CONTACTS..........................................................................................2 
SUMMARY ........................................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.................................15 
1 INTRODUCTION......................................................................................................17 
1.1 Background.........................................................................................................17 
1.2 Rationale for the Clinical Study..........................................................................20 
1.3 Rationale for Study Design.................................................................................24 
2 OBJECTIVES ............................................................................................................24 
2.1 Primary Objective...............................................................................................24 
2.2 Secondary Objectives..........................................................................................24 
2.3 Endpoints ............................................................................................................24 
2.3.1 
Safety Endpoints..................................................................................24 
2.3.2 
Efficacy Endpoints...............................................................................25 
2.3.2.1 Primary Efficacy Endpoint ...................................................25 
2.3.2.2 Secondary Efficacy Endpoints..............................................26 
3 STUDY DESIGN........................................................................................................26 
3.1 Overall Design and Control Methods .................................................................26 
3.2 Study Duration....................................................................................................29 
4 PATIENT SELECTION AND PARTICIPATION ................................................29 
4.1 Number of Patients .............................................................................................29 
4.2 Inclusion Criteria ................................................................................................29 
4.3 Exclusion Criteria ...............................................................................................30 
4.4 Patient Withdrawal Criteria ................................................................................30 
5 TREATMENTS AND TREATMENT PLAN .........................................................31 
5.1 Treatments Administered....................................................................................31 
5.1.1 
Identification of Investigational Product(s) .........................................31 
5.1.2 
Packaging and Labeling.......................................................................31 
5.1.3 
Storage, Accountability, and Stability .................................................32 
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5.2 Methods of Assigning Patients to Treatment Groups.........................................33 
5.3 Dose Regimens ...................................................................................................33 
5.3.1 
Selection of Doses in Study.................................................................33 
5.3.2 
Selection and Timing of Dose for Each Patient...................................34 
5.3.3 
Compliance With Dosing Regimens....................................................34 
5.4 Prior and Concomitant Medications ...................................................................34 
5.4.1 
Exclusionary Prior/Concomitant Medications.....................................34 
5.4.2 
Active Calcitriol, Calcium, Native Vitamin D, and Magnesium 
Supplementation ..................................................................................35 
6 STUDY EVALUATIONS AND PROCEDURES ...................................................36 
6.1 Efficacy Evaluations...........................................................................................36 
6.2 Safety Evaluations ..............................................................................................36 
6.2.1 
Adverse Events ....................................................................................37 
6.2.1.1 Adverse Event Definition .....................................................37 
6.2.1.2 Procedures for Reporting Adverse Events............................38 
6.2.2 
Serious Adverse Events .......................................................................39 
6.2.2.1 Serious Adverse Event Definition ........................................39 
6.2.2.2 Procedures for Reporting Serious Adverse Events...............40 
6.2.3 
Laboratory Evaluations........................................................................42 
6.2.4 
Vital Signs and Body Weight ..............................................................43 
6.2.5 
Electrocardiograms ..............................................................................44 
6.2.6 
Physical Examinations.........................................................................44 
6.2.7 
Dual-energy X-ray Absorptiometry.....................................................44 
6.2.8 
Women of Childbearing Potential .......................................................44 
6.2.9 
Pregnancy Reporting............................................................................45 
6.3 Schedule of Evaluations and Procedures............................................................45 
6.4 Description of Study Procedures ........................................................................48 
6.4.1 
Visit 1 Baseline Procedures .................................................................48 
6.4.2 
Week 1 Interim Safety Check..............................................................49 
6.4.3 
Weeks 4, 8, 16, 24, 32, 40, and 48 (Visits 2 through 8) Study 
Clinic Visits .........................................................................................49 
6.4.4 
Week 52 (Visit 9) End of Study Visit..................................................50 
6.4.5 
Week 53 Interim Safety Check............................................................51 
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6.4.6 
End of Week 53 (Visit 10) Follow-up Safety Visit .............................51 
6.4.7 
Week 56 (Visit 11) Follow-up Telephone Contact..............................51 
7 DATA MANAGEMENT...........................................................................................51 
7.1 Data Collection ...................................................................................................51 
7.2 Record Retention ................................................................................................52 
8 STATISTICAL METHODOLOGY AND SAMPLE SIZE...................................52 
8.1 Demographic and Baseline Variables.................................................................53 
8.2 Safety Variables..................................................................................................53 
8.2.1 
Efficacy Variables................................................................................53 
8.3 Other Variables...................................................................................................54 
8.4 Analysis Populations, Data Sets, and Time Points .............................................54 
8.4.1 
Analysis Populations............................................................................54 
8.5 Statistical/Analytical Issues ................................................................................55 
8.5.1 
Adjustments for Covariates..................................................................55 
8.5.2 
Handling of Dropouts or Missing Data................................................55 
8.5.3 
Interim Analyses and Data Monitoring................................................55 
8.5.4 
Multiple Comparisons/Multiplicity .....................................................55 
8.5.5 
Use of a Pharmacokinetic Subset of Patients.......................................55 
8.5.6 
Examination of Subgroups...................................................................55 
8.6 Determination of Sample Size ............................................................................55 
8.7 Changes to Planned Statistical Analyses ............................................................55 
9 ADMINISTRATIVE AND ETHICAL REQUIREMENTS...................................55 
9.1 Declaration of Helsinki and Ethical Review.......................................................55 
9.2 Patient Information and Consent ........................................................................56 
9.3 Patient Data Protection .......................................................................................56 
9.4 Financial Disclosure............................................................................................57 
9.5 Changes to the Protocol ......................................................................................58 
9.6 Investigator Obligations......................................................................................58 
9.7 Confidentiality/Publication of the Study ............................................................59 
9.8 Selection of a Primary Principal Investigator.....................................................59 
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9.9 Study Termination ..............................................................................................59 
10 REFERENCES...........................................................................................................60 
APPENDIX 1 
INSTRUCTIONS FOR USE FOR THE PTH YPSOMED 
INJECTION PEN ......................................................................................................62 
APPENDIX 2 
NPSP558 AND SUPPLEMENT TITRATION GUIDELINE........71 
APPENDIX 3   METHOD OF BIRTH CONTROL.....................................................75 
 
 
LIST OF FIGURES AND TABLES  
Figure 3-1 
Study Design..............................................................................................29 
 
Table 5-1 
Prohibited Medications or Therapies.........................................................34 
Table 6-1 
...................................................46 
Schedule of Evaluations and Procedures
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
25(OH) vitamin D 
25-hydroxyvitamin D 
1,25(OH)2 vitamin D 
1,25-dihydroxyvitamin D 
-HCG 
Beta human chorionic gonadotropin 
AE 
Adverse event 
BMD 
Bone mineral density 
bpm 
Beats per minute 
BSAP 
Bone-specific alkaline phosphatase 
CaSR 
Calcium-sensing receptor 
CSR 
Clinical study report 
DNA 
Deoxyribonucleic acid 
DXA 
Dual-energy x-ray absorptiometry 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GI 
Gastrointestinal 
hPTH 
Human parathyroid hormone 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intention to treat 
IV 
Intravenous 
mm Hg 
Millimeters of mercury 
NPS 
NPS Pharmaceuticals 
NPSP558 
Recombinant human parathyroid hormone (1-84) 
P1NP 
Serum procollagen type 1 amino-terminal propeptide 
PMO 
Postmenopausal osteoporosis 
PTH 
Parathyroid hormone 
QD 
Once daily 
QOD 
Every other day 
RACE 
NPSP558 Study PAR-C10-008 
RELAY 
NPSP558 Study PAR-C10-007 
REPLACE 
NPSP558 Study C1-11-040 
rhPTH 
Recombinant human parathyroid hormone 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
s-CTx 
Serum carboxy-terminal telopeptide of type I collagen 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
SMT 
Safety Management Team  
SOC 
System organ class  
SUSAR 
Suspected, unexpected, serious, adverse reaction 
ULN 
Upper limit of normal 
WMA 
World Medical Association 
WOCBP 
Woman of childbearing potential 
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1 
INTRODUCTION 
The purpose of this study is to demonstrate the long-term safety and tolerability of 
subcutaneous (SC) NPSP558 as hormone replacement therapy for the treatment of adult 
patients with hypoparathyroidism. 
1.1 
Background 
Compound 
NPSP558 is the sponsor’s designation for recombinant human parathyroid hormone 
(rhPTH), a single-chain polypeptide consisting of 84 amino acid residues (rhPTH[1-84]).  
It is identical in structure to endogenous human parathyroid hormone (hPTH).  hPTH is 
the principal regulator of plasma calcium homeostasis through concerted actions on the 
kidneys and bone.  rhPTH(1-84) is manufactured using a strain of Escherichia coli 
modified by recombinant deoxyribonucleic acid (DNA) technology.  
Calcium and Phosphate Absorption, Storage, and Excretion 
Dietary calcium is absorbed primarily in the small intestine with an efficiency of 
30% to 40%. Up to half of absorbed dietary calcium is returned to the gastrointestinal 
(GI) tract and is excreted in the stool.  Most of the remainder is excreted by the kidneys.  
The efficiency of absorption of dietary phosphate is greater than that of calcium (about 
70%) and most is excreted by the kidneys.  Approximately 99% of body calcium (the 
most abundant body cation) and 85% of phosphorus are found in bone, where they serve 
not only a structural role, but also as a reservoir for tissue and plasma calcium and 
phosphate. Most of the remaining phosphorus is intracellular.  The majority of the 1% of 
calcium not found within the skeleton is located in the extracellular fluid.  About half of 
this plasma calcium is ionized and capable of capillary diffusion into the intercellular 
space; the rest is bound to plasma proteins such as albumin or other substances (citrate, 
sulfate, and phosphates).  Ionized calcium, the physiologically active moiety, plays a vital 
role in many physiological processes including bone formation, blood coagulation 
(prothrombin to thrombin conversion), skeletal and smooth muscle function, cardiac 
automaticity and inotropy, nerve impulse initiation, and a host of other key physiological 
functions (Bilezikian et al, 2001).  
Calcium and Phosphate Regulation 
Serum calcium and phosphate levels are regulated principally by parathyroid hormone 
(PTH), the active vitamin D metabolite 1,25-dihydroxyvitamin D (1,25[OH]2 vitamin D; 
calcitriol), and calcitonin.  PTH maintains an inverse relationship with serum calcium.  
Normal total serum calcium levels (generally 8.4 to 10.2 mg/dL) and serum phosphate 
levels (2.5 to 4.5 mg/dL) are regulated to yield a calcium phosphate product of 
approximately 35 mg2/dL2.  This product is important because of the potential for 
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calcium phosphate salts to be deposited in soft tissues.  Levels of the calcium phosphate 
product that exceed 50 mg2/dL2 are believed to place patients at risk for ectopic soft 
tissue calcification.  PTH is synthesized and secreted by the parathyroid glands primarily 
in response to a fall in serum calcium levels.  Through concerted actions on the kidney 
and bone, PTH is the principal regulator of plasma calcium homeostasis.  In the kidney, 
PTH increases renal tubular reabsorption of calcium (while inversely inhibiting 
phosphate reabsorption) and increases the synthesis of 1,25(OH)2 vitamin D from its 
precursor 25-hydroxyvitamin D (25[OH] vitamin D).  Although 1,25(OH)2 vitamin D has 
a short in vivo half-life (approximately 6 hours), it directly increases intestinal calcium 
and phosphate absorption.  In bone, PTH increases the efflux of calcium from bone, both 
from the rapidly exchangeable pool of calcium within bone, and by increasing the 
number and activity of osteoblasts and osteoclasts, thereby increasing bone turnover.  As 
PTH also acts to inhibit the reabsorption of phosphate in the proximal nephron, it 
prevents an increase in plasma phosphate levels that could result from increased intestinal 
phosphate absorption and efflux of phosphate from bone. Calcitonin, secreted by C-cells 
of the thyroid gland, decreases serum calcium by inhibiting bone resorption and 
promoting renal tubular calcium excretion, but its effects are relatively minor in 
comparison to those of PTH and 1,25(OH)2 vitamin D (Bilezikian et al, 2001).  
Disorders of Calcium Homeostasis 
Situations Associated With Hypocalcemia 
Hypocalcemia (low serum ionized calcium) may result from abnormally increased 
calcium binding (rapid blood transfusion due to citrate binding or increased serum free 
fatty acids due to stress, medications, alcohol, or acute pancreatitis), abnormal calcium 
losses (impaired phosphate excretion leading to hyperphosphatemia in renal failure), 
vitamin D deficiency (impaired GI calcium absorption and renal or liver disease with 
associated vitamin D activation impairment), inadequate calcium intake, or 
hypoparathyroidism (Shoback, 2008).  Hypocalcemia due to deficient protein-bound 
(non-ionized) calcium may result from decreased serum albumin, but this condition is 
usually asymptomatic because serum ionized calcium levels are typically normal. 
Hypoparathyroidism and Hypocalcemia 
The most common cause of chronic hypocalcemia is hypoparathyroidism, a condition in 
which there is deficient production of PTH from the parathyroid glands.  
Hypoparathyroidism results in decreased calcium reabsorption from renal tubules, 
malabsorption of calcium from the GI tract and reduced calcium mobilization from bone.  
Hypoparathyroidism may result from permanent injury to the parathyroid gland(s) during 
thyroid or parathyroid surgery or other surgical procedures in the neck, radiation to the 
neck region, autoimmune destruction of the parathyroid glands, or their congenital 
absence.  Although rare, hypoparathyroidism can also result from genetic mutations, such 
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as activating mutations in the calcium-sensing receptor (CaSR) gene that encodes CaSRs 
present on parathyroid and kidney tubule cells.  Activating mutations of the CaSR gene 
result in an inappropriately low PTH secretion for the prevailing serum calcium level and 
increased fractional clearance of calcium by the kidney. 
Since free ionized serum calcium stabilizes neural and muscle cell membranes, 
hypocalcemia can lead to neuromuscular irritability and contribute to the chief signs and 
symptoms of hypoparathyroidism, which are tetany, twitching, paresthesia, tremor, and 
spasm.  Seizures and laryngospasm are severe symptomatic manifestations.  
Hypocalcemia may also influence cardiac function by inducing arrhythmias, hypotension, 
or heart failure.  Psychiatric symptoms (anxiety, irritability, depression, or delirium) may 
also be present in patients with hypocalcemia.  Latent tetany may be demonstrated by 
eliciting a positive Chvostek sign (hyperirritability of the facial nerve when tapped) or 
Trousseau sign (carpal spasm induced by brachial nerve ischemia produced by inflating 
an arm blood pressure cuff above systolic for about 3 minutes).  The manifestations of 
hypocalcemia, when present, vary greatly in severity among patients with 
hypoparathyroidism. 
In hypoparathyroidism, concomitant hyperphosphatemia is a frequent occurrence.  A 
resulting high calcium phosphate product may lead to the deposition of calcium 
phosphate salts in soft tissues.  Such soft tissue calcification can result in important 
morbidities that include renal parenchymal damage and premature cataracts.  Imaging 
studies in patients with hypoparathyroidism may reveal calcification of the basal ganglia 
and the grey-white matter interface in the brain. 
Clinical effects of hypoparathyroidism can be ameliorated using oral calcium and 
calcitriol.  Supplementation with an analog of vitamin D, 1-alpha-(OH) vitamin D3 
(alphacalcidol) is used in the place of calcitriol in some countries.  The goal is to raise the 
serum calcium to a point where symptoms are no longer present.  This generally means 
that the serum calcium should be maintained just below or at the low-normal range 
(8.0 to 8.5 mg/dL) (Shoback, 2008).  It is also desirable to avoid hypercalciuria 
(Shoback, 2008).  Acute or life-threatening tetany may be treated with an 
intravenous (IV) calcium infusion (eg, calcium gluconate) preferably under cardiac 
monitoring (Bilezikian et al, 2001). 
Hypercalciuria 
Parathyroid hormone promotes calcium reabsorption in the distal renal tubules, with 
decreasing nephrogenous cyclic adenosine monophosphate excretion and elevated tubular 
reabsorption of phosphate.  Hypercalciuria is due to the lack of PTH effect on the renal 
tubules resulting in the inappropriate loss of calcium in the presence of normo- or 
hypocalcemia.    Under normal conditions any decrease in serum calcium would result in 
increased PTH production.  Parathyroid hormone  then causes the kidney to limit calcium 
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excretion, but without the presence of sufficient PTH the kidneys continue to excrete 
calcium into the urine, causing the hypercalciuria.  Elevated vitamin D levels and oral 
supplementation of calcium to maintain the serum calcium level also contribute to 
hypercalciuria  by increasing small bowel absorption of calcium and phosphate, 
enhancing renal filtration, further decreasing any residual PTH levels, and, therefore, 
additionally reducing renal tubular calcium absorption.  Thiazide diuretics can be used to 
reduce (or prevent) hypercalciuria caused by calcium and vitamin D therapy.  Once the 
24-hour urinary calcium level approaches 250 mg, a thiazide diuretic combined with a 
low-salt diet can be added (Shoback, 2008). 
Hypercalcemia 
Hypercalcemia occurs when calcium entry into the circulation exceeds renal and other 
routes of calcium excretion.  This may occur due to excessive dietary calcium absorption, 
hypervitaminosis D, increased bone resorption due to immobility, malignancy, and 
thiazide diuretics that decrease urinary calcium excretion, or increased PTH levels 
(hyperparathyroidism).  Symptoms of hypercalcemia are generally due to alterations in 
central and peripheral nervous system function (altered mental status, fatigue, weakness, 
muscle flaccidity) and other organ involvement such as the heart (ventricular 
arrhythmias).  Bone resorption occurs over time.  The kidneys are threatened by exposure 
to high serum calcium concentrations leading at times to renal calculi due to calcium 
phosphate precipitation in the renal pelvis and parenchyma.  Frank renal dysfunction is 
not uncommon during an acute period of hypercalcemia with polyuria being a cardinal 
manifestation (due to antidiuretic hormone interference).  When the albumin-corrected 
total serum calcium exceeds 14 mg/dL, the hypercalcemia needs attention on an urgent 
basis.  Such emergencies can lead to many complications, particularly cardiac ones 
(Bilezikian et al, 2001).  
1.2 
Rationale for the Clinical Study  
Hypoparathyroidism is one of the few hormonal deficiency syndromes in which 
replacement therapy using the native hormone is not clinically available.  Treatment of 
hypoparathyroidism is also complicated by the lack of national or international consensus 
management guidelines (Shoback, 2008).  Patients with hypoparathyroidism are unable to 
regulate normal albumin-corrected total serum calcium and phosphate handling 
physiologically.  Current therapy is limited to calcium supplementation and parental or 
metabolic forms of vitamin D.  These therapies, which are suboptimal, present specific 
challenges for adequate clinical care. 
Challenges Associated With Vitamin D Therapy 
Patients with hypoparathyroidism are unable to efficiently convert precursor 25(OH) 
vitamin D to fully active 1,25(OH)2 vitamin D in the kidney because they lack PTH and 
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are hyperphosphatemic, both of which reduce the activity of 1α-hydroxylase, the enzyme 
that drives production of calcitriol.  Therefore, standard therapy for hypoparathyroidism 
usually relies on the administration of active vitamin D metabolites such as calcitriol 
(Rocaltrol®) or analogs such as alphacalcidol, which do not require PTH-dependent 
1α-hydroxylation.  To demonstrate any appreciable clinical effect with less active forms 
of vitamin D (eg, cholecalciferol), these must be used at very high dosages.  Such high 
doses of less active, precursor forms of vitamin D are more lipophilic than calcitriol and 
thus have a propensity to accumulate in fat, posing a real threat of vitamin D toxicity.  
Furthermore, active vitamin D forms can increase both calcium and phosphate absorption 
from the gut, which can, in turn, exacerbate the risk of hyperphosphatemia and an 
abnormal calcium phosphate product with subsequent soft tissue calcification. 
Challenges Associated With Oral Calcium Therapy 
The US Institute of Medicine/National Academy of Sciences daily Dietary Reference 
Intake for calcium for individuals aged 18 to 70 years is 1000 to 1200 mg/day, while the 
daily Tolerable Upper Intake level (level at which there is no likely risk of adverse 
events [AEs]) is 2500 mg/day for adults.  Patients with hypoparathyroidism typically 
require supplemental oral calcium therapy at or higher than this recommended limit, 
typically ranging between 2000 and 3500 mg/day.  Impaired regulation of calcium and 
phosphate homeostasis due to a lack of PTH and pharmacological treatment with vitamin 
D metabolites/analogs combine with high oral calcium intake to increase the likelihood of 
soft tissue deposition of calcium salts.  These can occur in the brain (ie, basal ganglia), 
kidneys, ocular lens, and other organs leading to structural damage and a loss of function, 
as seen in premature cataracts, and even Parkinsonism.  Without PTH to help conserve 
the filtered calcium in the kidney, substantial amounts of calcium can be lost leading to 
hypercalciuria with the attendant risks of nephrocalcinosis, hematuria and renal 
dysfunction.  Thiazide diuretics such as hydrochlorothiazide may be used to stimulate the 
reabsorption of calcium in the distal nephron.  In cases of profound hypocalcemia 
patients often require treatment with IV calcium along with cardiac monitoring.  Some 
patients may require a permanent catheter placement for IV access.  
In hypoparathyroidism, chronically low bone turnover results in significant abnormalities 
in bone structure, with bone mineral density (BMD) being very high because of increased 
mineralization.  Several studies, mostly in animals and in vitro, have suggested that 
vitamin D and PTH act interdependently at the level of bone.  In patients with 
hypoparathyroidism, the actions of vitamin D alone on bone remodeling are relatively 
minor.  Langdahl et al studied bone biopsies in 12 hypoparathyroid patients treated with 
vitamin D or alphacalcidol and compared them with matched normal controls  
(Langdahl et al, 1996).  With vitamin D alone, trabecular bone volume and thickness, 
marrow space star volume, and trabecular star volume were no different from controls, 
but bone turnover remained low.  In the absence of PTH, therefore, vitamin D therapy 
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alone is not able to normalize bone resorption and bone turnover.  A recent study reported 
the abnormal structural/dynamic properties of bone in 33 patients with 
hypoparathyroidism treated with conventional oral calcium and vitamin D-based therapy 
as compared with matched controls (Rubin et al, 2008a).  Histomorphometric assessment 
of iliac crest bone biopsies showed that hypoparathyroid patients had significantly greater 
cancellous bone volume and cortical bone width than healthy controls.  In parallel, 
measures such as mineralizing surface and bone formation rate were profoundly 
decreased below normal in the hypoparathyroid group.  The pathological effects of PTH 
deficiency on bone are largely asymptomatic, but can potentially include accumulation of 
microcracks in an environment of adynamic, dense bone tissue.  
How this situation relates to rhPTH(1-84) and its potential therapeutic use in 
hypoparathyroidism differs fundamentally from its use in osteoporosis.  In osteoporosis, 
PTH is used to increase BMD and improve bone structure, while in hypoparathyroidism, 
evidence from one recent study (Bilezikian et al, 2008) indicates that PTH replacement 
appears to increase bone turnover from its low baseline level, potentially leading to 
improvements in bone structure.  
Clinical Experience With PTH Peptides in the Treatment of Hypoparathyroidism 
Few studies of PTH use have been performed in the setting of hypoparathyroidism.  
Winer and colleagues have reported experience with twice-daily use of subcutaneously 
injected rhPTH(1-34) in the setting of adult and pediatric patients with 
hypoparathyroidism (Winer et al, 1998; Winer et al, 2003; Winer et al, 2008).  In this 
setting, PTH(1-34) was shown to maintain eucalcemia and to reduce urinary calcium 
excretion.  In these studies, PTH(1-34) was also compared to treatment with calcitriol, 
and showed that twice-daily PTH(1-34) or twice-daily calcitriol maintained similar 
albumin-corrected total serum calcium levels although urinary excretion of calcium was 
lower in the PTH(1-34) treated patients.  PTH (1-34) is identical to the 34 N-terminal 
amino acids of the 84-amino acid hPTH, but unlike NPSP558 is not identical to the full 
84 amino acid sequence. 
One prospective, open-label clinical trial of PTH in the treatment of hypoparathyroidism 
is ongoing (Bilezikian et al, 2008).  In that study, patients with hypoparathyroidism were 
treated for 12 months with 100 g of PTH(1-84) SC every other day (QOD).  Despite the 
study having off-PTH days due to QOD dosing, there was, on average, a 30% reduction 
from baseline in supplemental calcium requirements over the course of the study.  Total 
serum calcium concentrations remained stable.   Improved renal calcium handling was 
also seen, with calcium excretion falling to 60% of baseline levels at the end of the study.  
Adverse event rates were low and PTH(1-84) was well tolerated.  
An investigator-initiated open-label study evaluating the utility of PTH(1-84) 100 g 
QOD for 24 months as hormone-replacement therapy in 30 patients with 
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hypoparathyroidism is also ongoing (Rubin et al, 2010).  Two-year data show that 100 μg 
of rhPTH(1-84) is a safe and effective replacement therapy in patients with 
hypoparathyroidism.  Dosing with 100 μg of rhPTH(1-84) QOD resulted in an 
approximate decrease of 40% in requirements for supplemental calcium and calcitriol.  
These effects were seen as soon as 1 to 3 months after the onset of rhPTH(1-84) therapy.  
PTH(1-84) maintained serum calcium within the low normal range.  Bone health was an 
outcome measure for this study and at baseline patients with hypoparathyroidism were 
reported to have increased cancellous bone volume, and increased trabecular and cortical 
bone width (Rubin et al, 2008b, 2008c, 2008d).  Bone turnover was suppressed and bone 
formation was low.  PTH(1-84) therapy QOD led to a marked increase in bone turnover 
markers, which were accompanied by histopathological changes indicating increased 
osteoblast activity and alteration in BMD at the spine and radius.  PTH(1-84) therapy was 
well tolerated throughout the 2 years of the study.   
A randomized, double-blind, placebo-controlled, phase 3 study in adult patients with 
hypoparathyroidism is currently ongoing (CL1-11-040, REPLACE).  This study is 
investigating the effects of daily SC injections of rhPTH(1-84) at doses of 50, 75, or 
100 µg administered in the thigh.  In addition, a phase 1 pharmacokinetic/ 
pharmacodynamic study is also being conducted to assess these aspects of NPSP558 
administered as single SC doses of 50 and 100 μg in patients with hypoparathyroidism. 
Summary 
Parathyroid hormone replacement therapy may improve calcium homeostasis and thus 
reduce requirements for supplemental calcium and vitamin D metabolites or analogs in 
patients with hypoparathyroidism.  rhPTH treatment can offset hypocalcemia by 
increasing bone turnover, renal tubular calcium reabsorption (while potentially inversely 
inhibiting renal phosphate reabsorption), and enhancing GI absorption of calcium via 
normalized endogenous formation of 1,25(OH)2 vitamin D.  This improved calcium 
handling may reduce risks of calcification and damage of soft tissues.  Furthermore, 
because NPSP558 is identical in structure to endogenous human PTH(1-84), the potential 
for hypersensitivity reactions would be low as compared to nonbiologically identical 
peptides.  Results from studies of rhPTH(1-34) twice daily SC and from an open-label 
study of rhPTH(1-84) 100 g QOD SC in patients with hypoparathyroidism provide a 
framework of information that supports the safety and potential clinical utility of PTH 
replacement therapy in hypoparathyroidism.   
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1.3 
Rationale for Study Design  
Dose 
In a phase 2 study of NPSP558 in osteoporosis, SC daily doses of 50, 75, and 100 µg 
were well tolerated.  In these patients with osteoporosis and intact parathyroid function, a 
dose-dependent increased incidence of hypercalcemia was observed.  The ongoing 
REPLACE study is evaluating these same doses in hypoparathyroid patients.  An 8-week 
study of fixed doses of 25 and 50 µg (RELAY) is currently being undertaken to explore a 
broader range of treatment dose options.  The purpose of this study is to assess the 
12-month safety and tolerability of varying doses of NPSP558 in reducing requirements 
for supplemental oral calcium and calcitriol, while maintaining stable total serum calcium 
levels and controlling hypercalciuria in adult patients with hypoparathyroidism.  
Route of administration 
A single daily SC injection of PTH (versus infusion) increases PTH levels transiently.  
NPSP558 will be administered by daily SC injection into alternating thighs.  The thigh 
was chosen due to the prolongation of the calcemic response when the drug is 
administered in the thigh compared to the abdomen.   
2 
OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to demonstrate the long-term safety and tolerability 
of SC NPSP558 as hormone replacement therapy for the treatment of adult patients with 
hypoparathyroidism. 
2.2 
Secondary Objectives 
The secondary objectives of this study are: 
 To evaluate the impact of different preparations of calcium and calcitriol on the 
response to NPSP558 replacement therapy 
 To demonstrate that dosing with NPSP558 across a dose range of 25 to 100 μg SC 
can be implemented in a safe and effective manner and can be maintained 
throughout 12 months (52 weeks) of treatment 
 To evaluate the impact of calcium-sparing diuretics on serum and urinary calcium 
2.3 
Endpoints 
2.3.1 
Safety Endpoints 
Safety variables will be assessed by the following evaluations:  
 Adverse events and serious adverse events 
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 Incidence of adverse events of hypocalcemia (eg, paresthesia, numbness, tetany) 
and hypercalcemia (eg, constipation, nausea, poor appetite or vomiting, frequent 
urination, thirst, and kidney stones) 
 Incidence of hypercalciuria  
 Laboratory test results 
o Hematology (hematocrit, hemoglobin, white blood cells, red blood cells, 
platelets, differential) 
o Serum chemistries (standard Chem-20 panel, including calcium, 
phosphorus, and albumin) 
o Serum 25-hydroxyvitamin D levels 
o Creatinine clearance 
o Serum bone turnover markers 
o Urinalysis 
o 24-hour urine calcium, phosphate, sodium, and creatinine excretion 
o PTH antibodies 
 Bone mineral density by dual-energy x-ray absorptiometry (DXA) 
 Electrocardiogram (ECG) parameters 
 Physical examinations (including vital signs) 
 Reason for termination from the study 
2.3.2 
Efficacy Endpoints 
2.3.2.1 
Primary Efficacy Endpoint 
The proportion of patients in whom the following three conditions are fulfilled at 
Week 52 (Visit 9) will be summarized: 
 A ≥ 50% reduction from baseline in dose of oral calcium supplementation or an 
oral calcium dose of ≤ 500 mg 
AND 
 A ≥ 50% reduction from baseline in dose of oral calcitriol supplementation or 
an oral calcitriol dose of ≤ 0.25 μg 
AND 
 An albumin-corrected total serum calcium concentration that is normalized or 
maintained compared to the baseline value (≥7.5 mg/dL) and does not exceed 
the ULN for the central laboratory 
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2.3.2.2 
Secondary Efficacy Endpoints  
 Mean percentage changes from baseline in supplemental oral calcium and 
supplemental calcitriol dosages at each visit. 
 Proportion of patients achieving the primary endpoint at each visit 
 Mean change from baseline in 24-hour urine calcium excretion 
 Impact of calcium source (carbonate vs. citrate) on response 
 Impact of calcium-sparing diuretics on serum and urinary calcium 
 Proportion of patients that maintain a calcium phosphate product in the range of 
35 to 55 mg2/dL2        
 Distribution of patients by NPSP558 doses at the End of Treatment Visit 
 Change from baseline in bone turnover markers (bone-specific alkaline 
phosphatase [BSAP], serum carboxy-terminal telopeptide of type I collagen 
[P1NP], serum procollagen type 1 amino-terminal propeptide [s-CTx], and 
osteocalcin), PTH antibodies, and BMD by DXA 
 Additional subgroup analyses that are specified in the Statistical Analysis Plan 
(SAP) 
3 
STUDY DESIGN 
3.1 
Overall Design and Control Methods 
This study is a 12-month, open-label study using NPSP558 for the treatment of adult 
male and female patients with hypoparathyroidism.  Patients must have previously 
completed the NPSP558 RELAY study (8 weeks of active therapy) to enroll in this study.   
The goal of this study is to optimize NPSP558 dosing while reducing calcitriol and oral 
calcium (carbonate or citrate) supplementation to as low as safely possible while 
maintaining total serum calcium levels (see Appendix 2, NPSP558 and Supplement 
Titration Guideline).   
 The starting dose of NPSP558 for this study will be 25 or 50 g SC once daily.  
o Patients with a total serum calcium value of ≤ 9.5 mg/dL will have a 
starting dose of 50 μg.   
o Patients with a total serum calcium value of > 9.5 mg/dL will have a 
starting dose as follows: 
 Patients who are taking supplements (≥ 500 mg calcium and/or any 
calcitriol) will have the supplements reduced or stopped and will 
start at a dose of 50 g SC QD.  
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 Patients who are taking minimal or no supplemental calcium 
(< 500 mg) and no calcitriol will have a starting dose of 
25 g SC QD.   
 Study visits will be conducted at Weeks 1 (baseline), 4, 8, and then every 
8 weeks thereafter up to Week 48 (Visit 8).  The End of Treatment Visit 
(Week 52, Visit 9) is scheduled 4 weeks later followed by a safety visit at 
Week 53 (Visit 10) and a follow-up telephone contact at Week 56 (Visit 11).   
 All patients will have their total serum calcium checked by a local laboratory 
3 to 5 days (± 2 days) following the baseline visit.  
 Patients may have their NPSP558 dose increased by the investigator at any time 
through Week 48 of the study, with the goal of achieving or maintaining total 
serum calcium levels in the range of 8.0 to 9.0 mg/dL.  The NPSP558 dose may 
be adjusted downward at any time as needed to maintain appropriate serum 
calcium levels (approximately 8.0 to 9.0 mg/dL) or due to any safety concerns. 
 Adjustment of supplemental calcium and calcitriol regimens will be based on 
serum calcium levels, with the goal to be a reduction or removal of calcitriol 
treatment to the maximum degree clinically possible and to decrease the 
prescribed oral calcium supplementation to ≤ 500 mg daily.   
 Patients will have blood draws to assess total serum calcium levels (which may 
be performed locally) 3 to 5 days after ANY dose adjustment of NPSP558, after 
any significant change in doses of calcium and/or and calcitriol supplements, or 
at any other time at the discretion of the investigator.   
 Once a patient achieves a stable serum calcium (target:  between 8.0 and 
9.0 mg/dL) with the minimum doses of supplements possible, they will be 
maintained at that dose of NPSP558.      
 If ANY predose total serum calcium is > 11.9 mg/dL study drug will be 
stopped.  Once total serum calcium returns to the normal range, NPSP558 can 
be reintroduced.  The NPSP558 dose may be maintained at the previous level if 
reductions in oral calcium supplements and/or calcitriol are possible.  If oral 
calcium supplements have been previously reduced to ≤ 500 mg daily and 
calcitriol has been eliminated, then NPSP558 should be reintroduced at the next 
lowest dose level and supplemental oral calcium and calcitriol should then be 
adjusted accordingly to obtain a predose total serum calcium level of 
approximately 8.0 to 9.0 mg/dL. 
  If the predose total serum calcium level remains above 10.0 mg/dL for two or 
more safety assessments or study visits on normal dietary intake and study drug 
alone, then the NPSP558 dose may be reduced to the next lowest dose level and 
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supplemental oral calcium and calcitriol then adjusted accordingly to obtain a 
predose total serum calcium level of approximately 8.0 to 9.0 mg/dL.  Study 
medication will be stopped if the predose total serum calcium remains above the 
upper limit of the laboratory normal range (ULN) for two or more safety 
assessments or study visits (no more than 5 days apart) at the lowest dose 
regimen, following withdrawal of all supplementary oral calcium and calcitriol 
therapy.  Further choices on adaptation of treatment regimens, reinstitution of 
previous therapy, or discontinuation from study will be made in consultation 
with the NPS medical monitor.   
 At the Week 16 (Visit 4), patients who are on a stable dose of NPSP558 and 
have a 24-hour urine calcium > 300 mg may be treated for hypercalciuria with 
calcium-sparing diuretics, if this therapy had not been introduced prior to the 
study.  Newly started calcium-sparing diuretics will be given initially at a low 
dose. 
o Monitoring for serum potassium, sodium, and calcium will be performed 
1 week and again 1 month following the institution or change in dose of 
the calcium-sparing diuretic and then at each subsequent scheduled visit.   
o Monitoring of urine calcium will be performed at Weeks 16, 32, and 52 
(Visits 4, 6, and 9) for patients on calcium-sparing diuretics. Further dose 
adjustment of the diuretic will be done at the discretion of the investigator, 
based on urinary and serum calcium values. 
 During Week 53, patients will have their total serum calcium levels checked 
locally at an interim visit scheduled 3 to 5 days after the last dose of study 
medication.  Patients will also be scheduled for a follow-up clinic visit at the 
end of Week 53 (Visit 10) in order to have serum calcium, phosphorus, and 
albumin checked.   
 At Week 56 (Visit 11), approximately 4 weeks (30 days) following the End of 
Treatment visit (Week 52), patients will be contacted by telephone in order to 
assess adverse events (AEs)/serious AEs (SAEs).  
  
A schematic representation of the study design is displayed in Figure 3-1. 
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5. Women who are: (1) postmenopausal defined as 12 months amenorrhea with 
appropriate serum follicle stimulating hormone (FSH) levels (> 40 IU/L); (2) 
surgically sterilized; OR (3) of childbearing potential with a negative pregnancy 
test at screening and who consent to use two acceptable methods of contraception 
for the duration of the study, with pregnancy testing at every scheduled visit.  
Female partners (who are of childbearing potential) of male study patients must 
also use acceptable forms of contraception during their partner’s participation.   
4.3 
Exclusion Criteria 
Patients who meet any of the following exclusion criteria at baseline (Visit 1) are not 
eligible for enrollment in this study:  
1. Any condition that, in the investigator’s opinion after consultation with the 
sponsor, would preclude the safe use of PTH 
2. Any disease or condition in the opinion of the investigator that has a high 
probability of precluding the patient from completing the study or where the 
patient cannot or will not appropriately comply with study requirements 
3. Pregnant or lactating woman  
4.4 
Patient Withdrawal Criteria 
All patients are free to withdraw from participation in this study at any time, for any 
reason, specified or unspecified without prejudice to subsequent care.  Withdrawn dosed 
patients will not be replaced.  A patient may be withdrawn from the study under any of 
the following circumstances: 
 Withdrawal of informed consent 
 If, in the opinion of the investigator, Institutional Review Board/Independent 
Ethics Committee (IRB/IEC), Health Authority and/or NPS, it is no longer in 
the patient’s best interest to continue in the study 
 Patient no longer meets all inclusion criteria or meets any criterion for exclusion 
 Lack of compliance with study procedures or study drug administration, as 
determined by the investigator 
 Occurrence of an SAE determined by the investigator to be possibly related to 
study drug and not alleviated with treatment of symptoms 
 Adverse event  
 Hypersensitivity determined by the investigator to be possibly related to study 
drug 
 Pregnancy or lactation  
 Administrative reasons 
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In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) and in the patient’s medical records.  If the reason is not known, the patient must 
be followed up to establish whether the reason was an AE and, if so, this must be 
reported in accordance with the procedures described in Section 6.2.1 
As far as possible, all examinations scheduled for the end-of-study evaluations must be 
performed on all patients who participate but do not complete the study according to 
protocol. 
5 
TREATMENTS AND TREATMENT PLAN 
5.1 
Treatments Administered  
Patients will self-administer an SC injection of NPSP558 at a starting dose of either 25 or 
50 μg daily into alternating thighs, based on their total serum calcium level at baseline as 
described in Section 3.1.   
5.1.1 
Identification of Investigational Product(s)  
NPSP558  is manufactured using a strain of E. coli modified by DNA technology and is 
identical to native human PTH.  NPSP558 is a single-chain polypeptide containing 
84 amino acid residues.  The drug substance is clear and colorless to light straw-colored. 
NPSP558 parathyroid hormone (rhPTH) product is provided in a dual-chamber cartridge.  
The front chamber (chamber 1) contains a sterile, white to off-white lyophilized powder 
containing rhPTH(1-84), sodium chloride, mannitol and citric acid.  The rear chamber 
(chamber 2) contains a sterile diluent for reconstitution (m-cresol and sterile water for 
injection).  The dual-chamber cartridge is installed by the user into a reusable injection 
pen device, in which reconstitution occurs in a total volume of 1.15 mL.  
(See Appendix 1, Instructions for Use)    
The injection pen serves as a holder for the cartridge and does not come in contact with 
rhPTH product.  Using the injection pen device, each dual-chamber cartridge is designed 
to deliver 14 doses of 71.4 μL, each dose containing either 25, 50, 75, or 100 μg of 
rhPTH.  The pen and reconstituted rhPTH product should be stored under refrigeration.   
5.1.2 
Packaging and Labeling 
Packaging 
The study drug will be packaged, labeled, and delivered to the clinical centers by the 
sponsor or designee.  Each patient will receive two pens for use during the study period 
and sufficient cartridges to provide daily doses for 52 weeks.  Drug cartridges will be 
provided in kits containing eight cartridges each and each kit will be sufficient for up to 
16 weeks of treatment.  Each cartridge will contain study drug for 14 doses.  Drug 
cartridges will be provided at each clinic visit in sufficient quantity and at appropriate 
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dose levels to ensure uninterrupted administration until the next study visit.  Ancillary 
supplies including single use needles (31-gauge) and alcohol wipes will also be provided.   
Labeling 
Study drug will be supplied in individual kits labeled with the following information: 
investigational drug warning, company name, protocol number, lot number, storage 
conditions, contents, instructions regarding general dosing, and brief SC administration 
instructions.  Label space will be provided for recording center and patient numbers.  The 
label on the kit will be a tear-off label, which the center can affix to the patient’s source 
document or study document provided for this purpose.  Boxes containing pens will be 
labeled with the following info: investigational warning, company name, protocol 
number, lot number, and patient number. 
5.1.3 
Storage, Accountability, and Stability 
The clinical center’s pharmacist or delegate is responsible for ensuring that all study drug 
received at the center is inventoried and accounted for throughout the study.  All study 
drug must be kept in a locked area with access restricted to specific study personnel.  The 
study drug and supplements are to be stored according to the manufacturers’ 
specifications.  The investigator or designee (ie, pharmacist) will conduct an inventory 
upon receipt of the clinical supplies from the sponsor, and will acknowledge receipt of 
the supplies to the sponsor or designee.  A copy of the shipping documents must be 
maintained for the investigator’s records.   
Prior to reconstitution, cartridges have a maximum shelf-life of 36 months and should be 
stored at 2ºC to 8ºC (36ºF to 46ºF).  After study drug reconstitution in the injection pen 
device, the device can be used for up to 14 days when stored refrigerated at 2°C to 8°C 
and with infrequent exposure to room temperature for up to 30 minutes per day. 
 Additional data on the reconstituted solution demonstrates that it is stable for up to 
7 days when stored at 25°C, which provides assurance of product quality during any 
unexpected excursions.  Cartridges must be replaced 14 days after reconstitution.  
Cartridges should not be exposed to temperature extremes and should not be used if they 
have been or currently are frozen.  In this study, patients will be supplied with cartridges 
in sufficient quantity to maintain daily self-administration of varying dose of NPSP558.  
Patients should be reminded to return all cartridges, even if empty, at the final study visit. 
Pharmacy records will be maintained to capture the following information by lot number 
for each drug: 
 quantity received 
 current quantity on site 
 quantity administered to each patient 
 quantity removed from stock but not dispensed (eg, damaged, dropped, spilled) 
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 quantity remaining at the end of the study and retained, returned, or destroyed, 
as per the sponsor’s instructions 
For each patient, dates that study medication was dispensed, administered, returned, or 
otherwise disposed of will be recorded.  
All original containers, whether empty or containing study drug will be returned to the 
pharmacy.  Contents of the study drug containers will not be combined.  Unused study 
drug will be returned or disposed of according to the sponsor’s instructions. 
5.2 
Methods of Assigning Patients to Treatment Groups 
Patients will utilize the same 8-digit patient number that they had been assigned during 
the RELAY study.  The first 4 digits consist of the center number and the last 4 digits are 
the sequential patient number.  An additional suffix of “E” will be added to this number 
to distinguish this study data from the RELAY study.  This number will be utilized to 
identify the patient throughout the study period.   
Patients will receive study treatment in an open-label fashion at starting doses of 
NPSP558 25 or 50 g SC QD, as described in Section 3.1.  On Day 1, the kit number 
from which cartridges are dispensed to a patient will be recorded on the appropriate 
eCRF.  All subsequent kit numbers will be similarly recorded.  All doses of study 
medication for each patient must be taken from the kit(s) designated for that patient and 
cartridges from an assigned kit will not be dispensed to any other patient. 
5.3 
Dose Regimens 
Daily NPSP558 SC injections will be self-administered into alternating thighs each 
morning using a multidose pen injection device (see Appendix 1, Instructions for Use).    
5.3.1 
Selection of Doses in Study 
rhPTH (1-84) given as a daily SC injection of 100 g was approved in 2006 in the 
European Union for the treatment of postmenopausal osteoporosis (PMO).  There is an 
extensive safety database with this product in patients with PMO at doses ranging 
between 0.02 to 5.0 g/kg.  The phase 2 and 3 studies alone exposed 2891 patients with 
PMO to doses ranging between 50 to 100 µg of NPSP558.    
In patients with hypoparathyroidism, several phase 1/2, single-center, open-label studies 
have demonstrated preliminary biologic activity of rhPTH(1-84) and PTH(1-34) given as 
daily or alternate day SC injections (Bilezikian, 2008; Winer et al, 1998; Winer et al, 
2003; Winer et al, 2008).  The phase 3, randomized, double-blind placebo-controlled 
REPLACE study in patients with hypoparathyroidism is ongoing.  This registrational 
study is exploring the biologic activity of NPSP558 at doses of 50, 75, or 100 g 
administered as SC injections to the thigh.  An ongoing pharmacokinetic study (C09-002) 
utilizes two single doses of 50 and 100 g each, also as SC injections to the thigh.  The 
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phase 3 fixed-dose study (RELAY) utilized dose of 25 and 50 g SC daily.  This current 
study will utilize varying doses starting at either 25 or 50 g SC QD with the potential for 
upward adjustments in increments of 25 g to a maximum dose of 100 g SC QD, in 
order to assess its long-term effect in hypoparathyroid patients.  
5.3.2 
Selection and Timing of Dose for Each Patient 
Patients will self-administer NPSP558 in the morning, using the multidose injection pen 
devices.  On the days of clinic visits, the injections of study drug will occur after the 
serum is taken for laboratory assessments and may be administered by the clinic study 
personnel.  Calcium and/or vitamin D should be taken in the morning as normal after the 
NPSP558 injection.  
5.3.3 
Compliance With Dosing Regimens 
Paper diaries will be provided for the patients to record study drug administration and 
supplement regimens.  Patients should be requested to bring the diaries to each clinic 
study visit for review.  Patients with ≥ 80%  to ≤ 120% compliance level will be 
considered to be compliant with regard to study drug administration.  Diaries will be 
collected at the end of the study and submitted to the sponsor. 
5.4 
Prior and Concomitant Medications 
5.4.1 
Exclusionary Prior/Concomitant Medications 
Patients may remain on baseline concomitant medications during the trial (eg, hormone 
replacement therapy, antihypertensives, calcium-sparing diuretics, etc.).  Prohibited prior 
and concomitant medications are generally those that may affect bone metabolism, 
confound efficacy or safety measurements, potentially pose a safety concern, or adversely 
potentiate or antagonize study drug therapy.  Incidental or transient use of most of these 
medications (see list below) will not preclude a patient’s entry into this study. 
Exclusionary concomitant medications are shown in Table 5-1. 
Table 5-1 
Prohibited Medications or Therapies  
Medication/Therapy 
Regimen 
Raloxifene hydrochloride 
Any  
Bisphosphonates, intravenous 
Any 
Bisphosphonates, oral 
≥ 1 month of chronic use 
Systemic corticosteriods, oral or depot form (chronic use) 
≥ 1 month of chronic use 
Calcitonin, cinacalcet or other drugs that influence calcium or 
bone metabolism 
≥ 1 month of chronic use 
Fluoride tablets 
≥ 1 month of chronic use 
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In addition, concomitant active vitamin D supplements from outside sources are 
prohibited. Over the counter medications such as TUMS® are not to be taken as calcium 
supplementation.  Please refer to Section 5.4.2 for information on calcium and vitamin D 
supplementation. 
Permissible medications are:  
 nonprescription topical medications (that are not systemically absorbed)  
 acetaminophen 
 nasal and inhaled corticosteroids for the management of allergic rhinitis and 
asthma  
 oral, implantable, vaginal rings, transdermal patch and injectable contraceptives 
and/or hormone replacement therapy  
 All prescription and over the counter medication (including vitamins, herbs, or 
dietary supplements) being taken at baseline and all medications started during 
the study (from signing the ICF through study exit), including administration 
dates and dosage, are to be recorded on the appropriate eCRF.  Any medication 
which contains either calcium or vitamin D must be recorded on the eCRF with 
the amount of calcium and/or vitamin D content.  To the extent possible, no 
changes should be made to the concomitant treatment during the study.  Any 
additions, deletions or changes in the dose of these medications during the study 
also will be entered on the appropriate eCRF. 
5.4.2 
Active Calcitriol, Calcium, Native Vitamin D, and Magnesium 
Supplementation 
Calcitriol 
Patients enrolled in this study will be taking calcitriol to control serum calcium levels.  
Oral calcitriol supplements will be provided for this study by the sponsor or designee; no 
other sources of calcitriol should be used during the study.  Prescribed doses of calcitriol 
will be entered on the appropriate eCRF. 
Calcium 
Oral calcium supplements (either calcium carbonate or calcium citrate) will be provided 
for this study; no other sources of calcium supplementation should be used during the 
study.  Calcium supplements should be taken regularly with meals, ideally morning and 
evening.  Prescribed doses of calcium will be entered on the appropriate eCRF. 
In the case that extra calcium supplementation is taken by the patient due to symptoms of 
hypocalcemia, the dose/time and associated symptoms should be recorded by the patient 
in the diary.  
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Native Vitamin D [25(OH) vitamin D] 
The serum 25(OH) vitamin D levels will be measured at the beginning of the study and at 
all scheduled study visits through Week 52 (End of Treatment).  During the study, 
sufficient supplemental native vitamin D should be administered in order to maintain the 
patient’s serum 25(OH) vitamin D level in the normal range.  Any dose taken by the 
patient must be recorded on the concomitant medication eCRF. 
Magnesium   
Magnesium is required for normal parathyroid function and disordered magnesium levels 
can exacerbate hypoparathyroidism.  Patients with low serum magnesium should undergo 
supplementation at a clinically appropriate level until the serum magnesium is within the 
normal range and normal serum magnesium should be maintained throughout the 
remainder of the study.  Any dose taken by the patient must be recorded on the 
concomitant medication eCRF. 
6 
STUDY EVALUATIONS AND PROCEDURES 
6.1 
Efficacy Evaluations 
Efficacy variables will be assessed by one or more of the following evaluations: 
 Laboratory test results 
o Total serum calcium  
o 24-hour urinary calcium excretion 
o Serum phosphate (calcium-phosphate ratio)  
 Supplement usage 
o Concomitant supplemental oral calcium dosage 
o Concomitant supplemental oral calcitriol dosage  
6.2 
Safety Evaluations 
Safety variables will be assessed by the following evaluations:  
 Adverse events and serious adverse events 
 Incidence of adverse events of hypocalcemia (eg, paresthesia, numbness, tetany) 
and hypercalcemia (eg, constipation, nausea, poor appetite or vomiting, frequent 
urination, thirst, and kidney stones) 
 Incidence of hypercalciuria  
 Laboratory test results 
o Hematology (hematocrit, hemoglobin, white blood cells, red blood cells, 
platelets, differential) 
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o Serum chemistries (standard Chem-20 panel, including calcium, 
phosphorus, and albumin) 
o Serum 25-hydroxyvitamin D levels 
o Creatinine clearance 
o Serum bone turnover markers 
o Urinalysis 
o 24-hour urine calcium, phosphate, sodium, and creatinine excretion 
o PTH antibodies 
 Bone mineral density by DXA 
 Electrocardiogram parameters 
 Physical examinations (including vital signs) 
 Reason for termination from the study 
6.2.1 
Adverse Events 
The investigator is responsible for the detection and documentation of any AE or SAE, as 
defined in this protocol, during the study.  Adverse events that were ongoing at the end of 
the RELAY study will be recorded and updated for this study.  Any newly occurring AEs 
in this study, will be recorded separately.  
6.2.1.1 
Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical/medicinal product.  An AE does not 
necessarily have to have a causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (including a clinically 
significant abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product (investigational or marketed), whether or 
not considered related to treatment with the medicinal product. 
An AE includes: 
 An exacerbation of a pre-existing illness, sign, symptom, or clinically 
significant (as determined by the investigator) laboratory test abnormality and 
clinically significant ECG abnormality 
 An illness, sign, symptom, or clinically significant laboratory abnormality that 
is detected or diagnosed after study drug administration 
 Pretreatment or post-treatment events that occur as a result of protocol-
mandated procedures 
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An AE does not include: 
 The disease or disorder being studied or signs and symptoms associated with the 
disease or disorder, unless there is worsening of the condition of the disease or 
disorder 
 A pre-existing disease or condition, present at the start of the study, that does 
not worsen 
Overdose 
Defined as an accidental or intentional administration of an excessive dose of a product, 
an overdose should be reported to the sponsor using the SAE form.  This information will 
be shared with the Safety Management Team (SMT) and medical monitor. 
6.2.1.2 
Procedures for Reporting Adverse Events 
Adverse events may be spontaneously reported by the patient, obtained through 
nonleading questioning, or noted during examination of a patient.  All AEs and SAEs will 
be recorded from the signing of the ICF through the completion of the study.  AE/SAEs 
will be monitored by the site with a telephone call at Week 56, approximately 30 days 
following the last dose of study drug.     
At each visit, new AEs will be recorded sequentially on the AE page of the eCRF.  The 
AE term should note the diagnosis whenever possible, not the individual signs or 
symptoms (eg, myocardial infarction should be recorded rather than chest pain, elevated 
cardiac enzymes, and abnormal ECG).  Also recorded are:  
 Start and stop date and time 
 Whether the event is continuing 
 Frequency (intermittent, continuous) 
 Intensity (mild, moderate, severe) 
o Mild:  usually transient, requiring no special treatment and generally not 
interfering with usual daily activities 
o Moderate:  usually ameliorated by simple therapeutic maneuvers and 
impairs usual activities 
o Severe:  requires vigorous therapeutic intervention and interrupts usual 
activities.  Hospitalization may or may not be required. 
 Relationship to study drug (not related, related): identify relationship as 
“related” if a causal relationship between the investigational product and an AE 
is at least a reasonable possibility (ie, the relationship cannot be ruled out) 
 Whether the AE is serious (ie, an SAE).  If identified as an SAE, the AE should 
be reported on the SAE form according to Section 6.2.2.2 below. 
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 Actions taken (none; study drug dose changed, interrupted, or discontinued; 
other medication change; nondrug therapy)  
 Outcome (resolved, resolved with sequelae, ongoing, fatal).  An individual AE 
receives only one outcome. 
Adverse events that are related to study drug and that have not resolved at the end of 
treatment will be followed by the site until resolution or until the AE is judged by the 
investigator to have stabilized. 
Laboratory values, blood pressure, ECG evaluations, and clinical findings at the 
scheduled physical examinations must be reported as AEs if they: 
 Are considered clinically significant by the investigator 
 Fulfill SAE criteria, and/or 
 Cause patient discontinuation from the study. 
6.2.2 
Serious Adverse Events 
A serious event must be recorded on the sponsor’s Serious Adverse Event Report Form.  
An SAE requires expeditious handling to comply with regulatory requirements.  Any 
SAEs occurring from the signing of the ICF through 30 days after the last dose of study 
drug will be captured in the SAE database and must be reported within 24 hours after the 
investigator is made aware of the event. 
6.2.2.1 
Serious Adverse Event Definition 
An SAE is an AE that results in any of the following outcomes: 
 Death  
 Is life-threatening.  A life-threatening AE is any AE that places the subject—in 
the investigator’s opinion—at immediate risk of death from the reaction as it 
occurred.  It does not include a reaction that, had it occurred in a more serious 
form, might have caused death. 
 Persistent or significant incapacity or substantial disruption of ability to conduct 
normal life functions 
 Hospitalization or prolongation of existing hospitalization 
 Congenital anomaly/birth defect 
 Important medical events that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject or may require 
medical or surgical intervention to prevent one of the other outcomes listed in 
this definition.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood 
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dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse. 
Scheduled and/or elective hospitalizations occurring under the following circumstances 
will not be defined as SAEs for this clinical study:  
 planned before entry into the clinical study  
 are for elective treatment of a condition unrelated to the studied indication or its 
treatment 
 occur on an emergency, outpatient basis and do not result in admission (unless 
fulfilling the previous criteria) 
 are part of the normal treatment or monitoring of the studied indication and not 
associated with any deterioration in condition 
6.2.2.2 
Procedures for Reporting Serious Adverse Events 
Within 24 hours of becoming aware of ANY SAE (regardless of its relationship to 
investigational product) that occurs during the course of the clinical study from the time 
the patient signs the ICF through 30 days after the study drug is completed, the 
investigator must complete the sponsor’s SAE form (even if all information regarding the 
SAE is unknown or incomplete) and forward the SAE form via FAX to the sponsor or 
designee.  This ensures timely reporting of applicable reports to Health Authorities.   
Note:  Minimum criteria for reporting an SAE are the SAE term, an identifiable subject, a 
suspect investigational medical product (study drug), and a reporter.  Hospitalization is 
not an AE, but a serious event criterion.  The SAE term is the medical event that led to 
the hospitalization.  Surgery is not an adverse event, but the event that required the 
patient to have surgery is the SAE term.  Death is not an SAE, but an outcome. 
The sponsor or designee will provide a FAX cover sheet for the investigators in the Study 
Reference Manual. 
Autopsy reports, if applicable, will be forwarded as they become available.  All pertinent 
laboratory results should be entered on the sponsor’s SAE form. 
All SAEs must be reported, whether or not they are considered causally related to the 
study drug.  Appropriate clinical, diagnostic, and laboratory measures should be 
performed to delineate the cause of the SAE in question and the results reported.  Follow-
up for the SAE should occur at appropriate intervals until the event/laboratory 
abnormality: 
 Returns to baseline or 
 Becomes stable to a clinically acceptable level that is safe for the subject. 
The investigator is required to assess the causal relationship of each reported SAE, to the 
study drug (see Section 6.2.1.2).  A causality assessment should always be included on 
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the sponsor’s SAE form.  The investigator should make the causality assessment based on 
the information available at the time of the event.  The causality can be updated at a 
future date if additional information is received. 
The causality categories are: 
Not related 
 May or may not follow a reasonable temporal sequence from administration of 
the study product 
 Is biologically implausible and does not follow a known response pattern to the 
suspect study product (if response pattern is previously known) 
 Can be explained by the known characteristics of the subject’s clinical state or 
other modes of therapy administered to the subject 
 
Related (Possibly Related/Probably Related/Related)  
 A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson 
Syndrome) 
 Follows a reasonable temporal sequence from administration of the study 
product 
 May follow a known response pattern to the study product (if response pattern is 
previously known) 
 Could not be reasonably explained by the known characteristics of the subject’s 
clinical state or other modes of therapy administered to the subject, if applicable 
 Recurs upon rechallenge after withholding and then reintroducing study product 
Contact information for SAE reporting and emergency contact details can be found at the 
beginning of the protocol and in the Study Reference Manual. 
As required by International Conference of Harmonisation (ICH) guidelines and global 
health authorities, the sponsor or designee will notify investigators of all adverse drug 
reactions that are serious, unexpected, and deemed by the reporting investigator or 
sponsor to be related to study drug (suspected, unexpected, serious, adverse reaction 
[SUSAR]).  Causality, while assessed, does not negate reporting requirements to the 
sponsor.  An AE, whether serious or not serious, is designated unexpected (unlabeled) if 
it is not reported in the clinical safety section of the Investigator Brochure (IB) or if the 
event is of greater frequency, specificity, or severity than is mentioned in the IB.  The 
investigator will receive a copy of the current valid version of the IB prior to the start of 
the study; however, the investigator will not be required to assess expectedness, nor 
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should expectedness impact the investigator reporting SAEs within the timeframe herein 
defined. 
Upon receiving such notices, the investigator must review and retain the notice.  As per 
the Food and Drug Administration (FDA) Guidance for Clinical Investigators, Sponsors, 
and IRBs, Adverse Event Reporting to IRBs-Improving Human Subject Protection, 
January 2009 if it is determined that there is an unanticipated signal, the NPS SMT will 
analyze the data and prepare a summary supporting the determination and interpretation 
of the findings.  The sponsor or designee will send this summary to the investigators with 
instructions to provide it to their IRB. 
The investigator should also comply with the IRB procedures for reporting any other 
safety information (ie, autopsy reports).   
NPS Pharmaceuticals (sponsor) will be responsible for submitting SUSAR reports to the 
appropriate health authorities.  These reports will be submitted within the expedited 
timeframe.  All fatal and life-threatening SUSAR reports will be submitted by  the 
sponsor or designee within 7 days of receipt (Day 0) of the initial report.  All other 
SUSAR reports will be submitted by Day 15 following the event.   
6.2.3 
Laboratory Evaluations  
The following laboratory tests will be performed with patients in a fasted state (6 to 
8 hours) at baseline and Week 52 (End of Treatment), unless otherwise noted.  Final 
RELAY study parameters may be used as baseline parameters for this study.  All 
laboratory tests will be analyzed by a central laboratory, with the exception of all urine 
pregnancy tests and total serum calcium levels obtained at baseline, Week 53, and interim 
time points for safety checks, which will be done at the investigators’ or patients’ local 
laboratories.  The following laboratory parameters will be collected: 
 Hematology: hemoglobin concentration, hematocrit, erythrocyte count, platelet 
count, and leukocyte counts with differential 
 Serum Chem-20 panel: alanine transaminase, aspartate transaminase, alkaline 
phosphatase, lactate dehydrogenase, inorganic phosphorus, total and direct 
bilirubin, creatine kinase, blood urea nitrogen, glucose, electrolytes (sodium, 
potassium, chloride, and bicarbonate), creatinine, calcium (standard and 
albumin-corrected), magnesium, total protein, albumin, and uric acid  
 Urinalysis: specific gravity, pH, protein, glucose, ketones, bilirubin, 
urobilinogen, blood, and microscopic analysis of sediment 
 Creatinine clearance will be done at baseline and Weeks 16, 32, and 52. 
 Total serum calcium (local) will be drawn at baseline and at the Week 53 (Visit 
10) follow-up visit. 
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 Total serum calcium, albumin, and phosphorus will be drawn at baseline and at 
each subsequent scheduled study visit through Week 52.   
 All patients will have local blood draws to assess  total serum calcium levels 
during Week 1, 3 to 5 days (± 2 days) after baseline and again during Week 53, 
3 to 5 days (± 2 days) after the last dose of study drug.  Following any 
adjustment of NPSP558 or a significant change in calcium/calcitriol 
supplements, a local total serum calcium level will also be drawn after 
3 to 5 days. 
 Serum 25-hydroxyvitamin D additional levels will be drawn at baseline and at 
each subsequent scheduled study visit through Week 52.  
 24-hour urine calcium, phosphate, sodium, and creatinine will be done at 
baseline and Weeks 16, 32, and 52. 
 Serum bone turnover markers (BSAP, s-CTx, P1NP, and osteocalcin) will be 
done at baseline and Weeks 8, 16, 24, 40, and 52. 
 Serum beta human chorionic gonadotropin (-HCG) pregnancy test will be 
done at  baseline and Weeks 16, 24, 32, 40, 48, and 52 (women of child-bearing 
potential [WOCBP] only) 
 An FSH test to confirm postmenopausal status, if patients have met the 
definition of postmenopausal after the beginning of the RELAY study (newly 
postmenopausal females only) will be done at baseline only, if necessary. 
 Urine pregnancy test (WOCBP only) will also be collected at baseline and 
Weeks 4 and 8. 
 PTH  antibodies will be done at  baseline and Weeks 24,  40, and 52  
Clinically significant (as determined by the investigator) abnormal laboratory test results 
will be considered AEs.  A result outside of the normal range may be repeated for 
confirmation.  Any laboratory test result that meets the criteria for an SAE (see 
Section 6.2.2.1) must also be recorded in an SAE report so that the sponsor or designee 
can collect additional information about that abnormality, including information 
regarding relationship to investigational product or other causes, any action taken, and 
outcome.  
6.2.4 
Vital Signs and Body Weight 
Vital signs will be measured at baseline and each clinic study visit through Week 52 and 
will include systolic and diastolic blood pressure (mm Hg), pulse (beats per minute or 
bpm), and body temperature (ºC) after the patient has been sitting for 5 minutes.  Body 
weight will also be recorded. 
If any of the patient’s measurements are outside of the normal range at screening (prior to 
receiving the first dose) the investigator will determine, based on medical history, 
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whether the patient can safely continue in the study.  A measurement outside the normal 
range may be repeated during the course of the visit for confirmation. 
6.2.5 
Electrocardiograms   
A 12-lead ECG will be done at baseline and Week 52, at the study center on the same 
model unit.  Recorded data will include general findings, ventricular rate (bpm) and P-R, 
QRS, and QTc intervals (seconds).  Any ECG abnormalities, as determined by the 
investigator, at screening will be recorded as medical history.  Any clinically significant 
adverse change from the status at the screening visit and noted to be clinically significant 
by the investigator should be captured as an AE.  All ECGs will be assessed by a central 
reader and this assessment will be used as the primary data readout for the study.  
However, investigators are also responsible for providing their own interpretation of the 
ECG, and this will be captured on the ECG print out and the eCRF.  Two copies of the 
ECG tracings should be retained in the patient source record. 
6.2.6 
Physical Examinations 
Physical examinations will be performed at baseline and Week 52 and will consist of 
general assessments of the head, eyes, ears, nose, throat, lymph nodes, skin, extremities, 
and respiratory, gastrointestinal, musculoskeletal, cardiovascular, nervous, and 
dermatologic systems.  The physical examination should be performed by the same 
person each time, whenever possible.  
Physical examination abnormalities determined by the investigator to be clinically 
significant at screening should be recorded as medical history if they developed since the 
RELAY study.  
Any clinically significant adverse change from the status at the baseline visit and noted to 
be clinically significant by the investigator should be captured as an AE. 
6.2.7 
Dual-energy X-ray Absorptiometry  
DXA scans will be performed at baseline and Week 52 and will evaluate BMD of the 
lumbar vertebra (L1-L4), hip (total, trochanter, intertrochanter, Ward’s triangle, and 
femoral neck), and ⅓ distal radius (arm).  Calcium supplements should be withheld for 
24 hours prior to the scan, if possible.  If a patient cannot withhold the calcium 
supplements due to safety concern, the DXA should be performed 2 hours after the last 
calcium tablet has been ingested. 
6.2.8 
Women of Childbearing Potential 
Any patient that has become postmenopausal since entering the RELAY study should be 
re-evaluated at baseline for this study.  For a woman to be considered postmenopausal 
there must have been an absence of menses for 12 consecutive months with appropriate 
serum FSH levels (ie, > 40 IU/L).   
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If the result is not in the postmenopausal range and the patient is not surgically sterile, 
then the patient should be considered a woman of childbearing potential (WOCBP). 
A WOCBP may be included in the study, but must have a negative serum pregnancy test 
at baseline.  Lack of pregnancy will be confirmed by urine pregnancy tests at baseline 
and Weeks 4 and 8 (Visits 2 and 3).  A serum pregnancy test will be repeated at 
Weeks 16, 24, 32, 40, 48, and 52.  Pregnancy occurring during the trial will necessitate 
immediately withdrawal from study.  A WOCBP must be willing to use two medically 
acceptable methods of contraception for the duration of the study (see Appendix 3).  
Female partners of male patients should also use medically acceptable means to avoid 
pregnancy during their partner’s participation in the study.  
6.2.9 
Pregnancy Reporting 
Pregnant and lactating women are excluded from participation in this study.  In the event 
a patient becomes pregnant during the study, study drug will be discontinued, and an 
SAE supplemental form will be completed to capture potential drug exposure during 
pregnancy and will be reported to the sponsor or designee within 24 hours of becoming 
aware of the pregnancy.  The pregnant patient will be followed until an outcome is 
known (ie, normal delivery, abnormal delivery, spontaneous/voluntary/therapeutic 
abortion).  If a pregnant patient also experiences an SAE, an additional SAE form will be 
completed and submitted to the sponsor or designee within 24 hours as discussed above.  
An SAE supplemental form should be completed in the event that a female partner of a 
male patient becomes pregnant within 30 days after his last dose of study drug or study 
completion, if agreed upon and consented to by the pregnant partner.  The pregnancy 
(mother and fetus) will be followed up through delivery with regard to outcome. 
6.3 
Schedule of Evaluations and Procedures 
All clinical study evaluations will be performed according to Table 6-1.  Details of the 
exact date and time of medical assessments (day/month/year) will be documented in the 
eCRF.  Any deviations from protocol requirements will be documented in the eCRF. 

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

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6.4 
Description of Study Procedures 
6.4.1 
Visit 1 Baseline Procedures  
Patients must sign an ICF for this study prior to having any study-related procedures 
performed.  Baseline procedures may be performed at the same time as the RELAY study 
Week 8 procedures.   
Patients will be instructed to come into the study center after having fasted for 
approximately 6 to 8 hours.  Appointments should be scheduled accordingly to 
accommodate this fasting status (ie, in the morning).  The following procedures will be 
performed prior to enrollment: 
 Update the patient’s medical history, demographic information, ongoing 
concomitant medications, and ongoing AEs from the RELAY study. 
 Review inclusion/exclusion criteria. 
 Record all new prescription and nonprescription medications, dietary and 
nutritional supplements, and vitamins and their doses, frequencies, and 
durations. 
 The occurrence of any new or continuing AE, including episodes of 
hypocalcemia or hypercalcemia, will be recorded following the signing of the 
ICF, regardless of whether or not study drug had been administered. 
 Vital signs measurements (prior to blood draws) and weight 
 Physical examination 
 12-lead electrocardiogram 
 Blood samples for serum chemistries (including calcium, phosphorus, and 
albumin), hematology, serum 25(OH) vitamin D, creatinine clearance, and bone 
turnover markers.  The blood sample for serum chemistries will be split and a 
local total serum calcium will also be performed. 
 Blood sample for PTH antibodies  
 Urinalysis and 24-hour urine calcium, phosphate, sodium, and creatinine 
 Serum -HCG pregnancy test (WOCBP only) 
 Urine pregnancy test for immediate confirmation of nonpregnant status 
(WOCBP only) 
 A BMD test by DXA  
 An FSH test to confirm postmenopausal status, EXCEPT if patients have met 
the definition of postmenopausal after the beginning the RELAY study (for 
newly postmenopausal females only). 
 The first dose of study medication will be administered after appropriate fasting 
laboratory evaluations have been taken. 
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 Patients will be provided with the following study supplies: 
o Study medication cartridges in sufficient number to supply daily doses until 
the next scheduled clinic visit  
o Two injection pens 
o Ancillary injection supplies (ie, alcohol swabs, needles, etc.) 
o Paper diaries  
o Calcium (carbonate or citrate) and calcitriol supplements in sufficient 
quantity to supply daily doses until the next scheduled clinic visit 
6.4.2 
Week 1 Interim Safety Check   
Patients will have blood drawn locally to assess total serum calcium levels between 
3 to 5 days (± 2 days) following baseline.  Adjustments of supplemental calcium and 
calcitriol will be made (see Appendix 2, NPSP558 and Supplement Titration Guideline) 
based on this value.  If further adjustments are made to the NPSP558 dose or there are 
significant changes in calcium or calcitriol supplements, serum calcium will be retested at 
approximately 3 to 5 days following that change. 
6.4.3 
Weeks 4, 8, 16, 24, 32, 40, and 48 (Visits 2 through 8) Study Clinic Visits 
The following procedures will be performed as indicated: 
 Record any change in concomitant medications on the appropriate concomitant 
medication eCRF, including dose and frequency (all visits) 
 Adverse event evaluation/update, including any incidences of hypocalcemia or 
hypercalcemia (all visits) 
 Review the patient’s diary for compliance with protocol procedures and 
dosing/supplement regimens (all visits) 
 Collect used and unused drug cartridges and supplements (calcium and 
calcitriol) for assessment of accountability (all visits). 
 Vital signs measurements (prior to blood draws) and weight (all visits) 
 Serum 25(OH) vitamin D (all visits) 
 Serum calcium, phosphorus, and albumin (all visits) 
 Serum bone turnover markers (Weeks 8, 16, 24, and 40) 
 Serum -HCG pregnancy test (Weeks 16, 24, 32, 40, and 48) 
 Urine pregnancy test (WOCBP only) (Weeks 4 and 8) 
 Creatinine clearance (Weeks 16 and 32)  
 24-hour urine calcium, phosphate, sodium, and creatinine (Weeks 16 and 32)  
 Blood sample for PTH antibodies (predose on Weeks 24 and 40) 
 Patients will be provided with the following study supplies: 
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o Study medication cartridges in sufficient number to supply daily doses until 
the next scheduled clinic visit  
o Ancillary injection supplies (ie, alcohol swabs, needles, etc.) 
o Calcium (carbonate or citrate) and calcitriol supplements in sufficient 
quantity to supply daily doses until the next scheduled clinic visit 
o Collection container for 24-hour urine (Weeks 16 and 32) 
6.4.4 
Week 52 (Visit 9) End of Study Visit  
Patients will be instructed to come into the study center after having fasted for 
approximately 6 to 8 hours and prior to taking their last dose of study medication.  
Appointments should be scheduled accordingly to accommodate this fasting status (ie, in 
the morning).  The following procedures will be performed: 
 Record any change in concomitant medications on the appropriate concomitant 
medication eCRF, including dose and frequency 
 Adverse event evaluation/update, including any incidences of hypocalcemia or 
hypercalcemia 
 Vital signs measurements (prior to blood draws) and weight 
 Physical examination 
 12-lead electrocardiogram 
 Blood samples for serum chemistries (including calcium, phosphorus, and 
albumin), hematology, serum 25(OH) vitamin D, creatinine clearance, and bone 
turnover markers  
 Blood sample for PTH antibodies (predose) 
 Administration of the last dose of study medication following the predose PTH 
samples 
 Urinalysis  
 24-hour urine calcium, phosphate, sodium, and creatinine 
 A BMD test by DXA  
 Serum -HCG pregnancy test (females only) 
 Review the patient’s diary to assess compliance to protocol procedures and 
dosing/supplement regimens. 
 Collect used and unused drug cartridges, supplements (calcium and calcitriol), 
and injection pens for assessment of accountability and patient diaries. 
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6.4.5 
Week 53 Interim Safety Check 
Patients will have a total serum calcium level drawn locally between 3 to 5 days 
(± 2 days) following the last dose of study drug.  Poststudy adjustments of supplemental 
calcium and calcitriol will be made (see Appendix 2, NPSP558 and Supplement Titration 
Guideline) based on this value.   
6.4.6 
End of Week 53 (Visit 10) Follow-up Safety Visit  
Patients will have blood drawn for total serum calcium, phosphorus, and albumin levels.  
This sample will be split in order to provide blood for a local total serum calcium to be 
done at the investigator’s local laboratory.  Further adjustment of patients’ supplemental 
calcium and calcitriol doses will be made based on these values (see Appendix 2, 
NPSP558 and Supplement Titration Guideline).  Patients will also be monitored for 
follow-up on any study drug-related AE or any SAE that may have occurred during the 
study period or any SAE that may have occurred since the last study drug injection. 
6.4.7 
Week 56 (Visit 11) Follow-up Telephone Contact  
Patients will be contacted approximately 30 days following the last dose of study 
medication to monitor for and/or follow-up on any study drug-related AE or any SAE 
that may have occurred during the study period or any SAE that may have occurred since 
the last study drug injection. 
7 
DATA MANAGEMENT 
7.1 
Data Collection  
Data collected during the study will be recorded in the patient’s eCRF by the study 
center’s research team.  The research team will keep records of the patient’s visit in the 
files considered as source documents for that center, eg, hospital chart, research chart, 
etc.  To ensure that data have been entered correctly on the eCRF, eCRFs will be 100% 
source-data verified by a monitor from the sponsor/designee, who will notify the 
investigator regarding questions or missing data.  The investigator or designee will be 
responsible for the timely recording of patient data. 
The investigator will review all eCRFs (including the termination page after the patient’s 
final visit) for completeness and accuracy, and will electronically sign the eCRFs 
attesting to this prior to submitting them to the sponsor.  The investigator will be 
responsible for submitting the data to the sponsor (or designee) in a timely manner, on the 
eCRFs provided by the sponsor (or designee) for this purpose.  Non-CRF data including, 
but not limited to central laboratory tests, ECG, and radiographic (DXA) results will be 
sent to the sponsor or designee via a data transfer from the appropriate vendor for 
assimilation into the database.  SAE reporting must be done within the times described in 
Section 6.2.2.2. 
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All data collected in this study will be integrated into an appropriate preformatted 
database by the sponsor or designee for subsequent statistical evaluation.  Data validation 
and edit checks will be conducted on the data.  Any discrepancies will be noted and 
queries will be generated by the sponsor or designee to be resolved by the center.  
Queries should be completed by the investigational center and signed by the investigator 
or approved designee in a timely manner. 
When all patients’ data have been entered into the database, verified, and all outstanding 
issues have been resolved with the center, the data will be evaluated for quality purposes.  
A clean file is defined as when the data in the database and the reference values are 
complete and logical according to the clinical study protocol, general guidelines, data 
management plan, and data entry instructions.  Once the sponsor acknowledges that all 
data are acceptable, the data will be declared to represent a “clean file” and the database 
will be frozen. 
A quality assurance audit will be performed on the data by the Data Management group.  
When all issues from the audit are resolved, and all data management processes are 
completed for finalizing the database, the database will be locked and ready for analysis.  
The investigator and clinical center must permit study-related monitoring, audits, 
IRB/IEC review, and regulatory inspections by providing direct access to source 
data/documents. 
Patients will retain the patient number utilized in the RELAY study.  The first four digits 
consist of the center number.  An additional suffix of “E” will be added to this number to 
distinguish this study data from that in the RELAY study.  This number is the main 
identifier for patients. 
7.2 
Record Retention 
The clinical investigators will maintain drug records, copies of eCRFs, laboratory 
records, data sheets, correspondence records, and signed patient consent documents for at 
least 5 years or until instructed in writing by the sponsor that records may be destroyed or 
forwarded to the sponsor.  In accordance with US Federal Regulations, these records will 
be available for inspection and copying if requested by a properly authorized employee of 
the FDA. 
8 
STATISTICAL METHODOLOGY AND SAMPLE SIZE   
Statistical analyses will be conducted as described in the SAP for this study.  Deviations 
from the SAP (if any) will be described and justified in the clinical study report (CSR).  
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8.1 
Demographic and Baseline Variables 
Demographic variables (such as sex, age, race, birthdate, etc.) will be obtained from the 
REPLACE or RELAY study, if available.   Medical history from the RELAY study will 
be reviewed and updated as necessary.  Visit 1 (baseline) for this study (PAR-C10-008, 
RACE) may be the same day as Visit 4 of the RELAY study.  Demographic and/or other 
variables at baseline will be summarized for medical history, demography, physical 
examination, vital signs, prior medications, ECG, and laboratory test results. 
Prior and concomitant medications will be coded using the World Health Organization 
Drug Dictionary with regard to drug class and drug name.  The number and percentage of 
patients with specific prior medications will be summarized.  Medical and surgical 
history will be coded using the Medical Dictionary for Regulatory Activities.  The 
number and percentage of patients with specific histories will be summarized by system 
organ class and by high-level term and preferred term for each condition.  
8.2 
Safety Variables 
Safety data including vital signs assessments, physical examinations, AEs, SAEs, 
concomitant medications, clinical laboratory tests, ECG monitoring, and termination 
from study will be summarized by treatment group and point of time of collection.  
Descriptive statistics (arithmetic mean, standard deviation, median, minimum and 
maximum) will be calculated for quantitative safety data as well as for the difference 
from baseline, if applicable.  Frequency counts will be compiled for classification of 
qualitative safety data.  
8.2.1 
Efficacy Variables 
Primary Efficacy Endpoint: 
The proportion of patients in whom the following three conditions are fulfilled at 
Week 52 (Visit 9) will be summarized: 
 A ≥ 50% reduction from baseline in dose of oral calcium supplementation or an 
oral calcium dose of ≤ 500 mg 
AND 
 A ≥ 50% reduction from baseline in dose of oral calcitriol supplementation or an 
oral calcitriol dose of ≤ 0.25 μg 
AND 
 An albumin-corrected total serum calcium concentration that is normalized or 
maintained compared to the baseline value (≥7.5 mg/dL) and does not exceed the 
ULN of the central laboratory 
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In addition, the following efficacy variables will be summarized:  
 Mean percentage changes from baseline in supplemental oral calcium and 
supplemental calcitriol dosages at each visit 
 Proportion of patients achieving the primary endpoint at each visit 
 Mean change from baseline in 24-hour urine calcium excretion 
 Impact of calcium source (carbonate vs. citrate) on response 
 Impact of calcium-sparing diuretics on serum and urinary calcium 
 Proportion of patients that maintain a calcium phosphate product in the range of 
35 to 55 mg2/dL2        
 Distribution of patients by NPSP558 doses at the End of Treatment Visit 
 Change from baseline in bone turnover markers (BSAP, s-CTx, P1NP, and 
osteocalcin), PTH antibodies, and BMD by DXA 
 Additional subgroup analyses that are specified in the SAP 
Note that the baseline parameters for the efficacy variables for the RACE study will be 
the end of study and baseline parameters from the RELAY study.  The visits will be 
defined in the SAP.  No between-group comparisons with p-values are planned. 
8.3 
Other Variables  
Other variables to be analyzed will include the following:  
 Patient accounting 
 Duration of study medication exposure  
 Patient compliance  
 The number and percentage of patients who complete the study, are lost to 
follow-up, and who are discontinued from the study (including reason for study 
withdrawal) will be summarized.  
Patients will be considered compliant if study drug was taken according to protocol for 
≥ 80% to ≤ 120% of doses.  The number and percentage of patients who were compliant 
will be summarized. 
8.4 
Analysis Populations, Data Sets, and Time Points 
8.4.1 
Analysis Populations  
The primary and secondary efficacy analyses will be based on the intention-to-treat (ITT) 
population.  This population includes all patients who received at least one dose of study 
drug and had at least one efficacy measurement.  
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The safety analyses will be based on the Safety population.  This population includes all 
patients who received at least one dose of study drug with any follow-up information. 
8.5 
Statistical/Analytical Issues  
8.5.1 
Adjustments for Covariates 
No preselected covariates are selected for adjustments. 
8.5.2 
Handling of Dropouts or Missing Data 
No safety data will be imputed. The missing patterns of the efficacy variables will be 
assessed and an unbiased imputations method will be documented in the SAP. 
8.5.3 
Interim Analyses and Data Monitoring 
No interim analyses are planned. 
8.5.4 
Multiple Comparisons/Multiplicity 
No adjustment for multiplicity in treatment is planned. 
8.5.5 
Use of a Pharmacokinetic Subset of Patients 
No pharmacokinetic subset of patients was selected for analysis. 
8.5.6 
Examination of Subgroups 
Subgroup analyses (if any), in addition to the possible ones by gender, will be discussed 
in the SAP.  
8.6 
Determination of Sample Size 
Approximately 40 patients are anticipated to be enrolled.  Sample sizes were not 
estimated for this extension study.  
8.7 
Changes to Planned Statistical Analyses 
Changes made to planned statistical analyses (if any) described within this protocol will 
be incorporated into the SAP and any deviations from the SAP will be documented and 
justified in the final CSR.  
9 
ADMINISTRATIVE AND ETHICAL REQUIREMENTS 
9.1 
Declaration of Helsinki and Ethical Review 
This protocol will be conducted in accordance with the applicable ICH Guidelines, Good 
Clinical Practice, and the World Medical Association (WMA) Declaration of Helsinki 
and its amendments concerning medical research in humans (Declaration of Helsinki, 
'Recommendations Guiding Physicians in Biomedical Research Involving Human 
Patients', Helsinki 1964, amended in Tokyo 1975, Venice 1983, Hong Kong 1989, 
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Somerset West, Republic of South Africa 1996, and Edinburgh 2000 (5th revision), and 
Notes of Clarification added by the WMA General Assembly in Washington 2002 and in 
Tokyo 2004). 
In accordance with guidelines, the protocol, any advertisements and ICFs will be 
reviewed and approved by the IRB/IEC. The sponsor will supply relevant material for the 
investigator to submit to the IRB/IEC for the protocol’s review and approval.  
Verification of the IRB/IEC approval of the protocol and the written ICF will be 
forwarded to the sponsor (or designee). 
The investigator will inform the IRB/IEC of subsequent protocol amendments and any 
SUSARs if the NPS SMT has assessed it as an unanticipated problem.  Approval for 
protocol amendments will be transmitted in writing to the investigator. 
The investigator will provide the IRB/IEC with progress reports at appropriate intervals 
(not to exceed 1 year) and a study summary report following the completion, termination, 
or discontinuation of the investigator’s participation in the study. 
9.2 
Patient Information and Consent 
In accordance with applicable guidelines, informed consent shall be documented by the 
use of a written consent form approved by the IRB and signed by the patient before any 
screening and protocol-specific procedures are performed.  A consent form model will be 
provided by the sponsor or designee and adapted by the investigator to meet center, state, 
and country ethical guidelines, as appropriate. 
The investigator (or designee) will explain to the patient the nature of the study, the 
action of the test product, and any risks and benefits.  The patient will be informed that 
participation is voluntary and that he or she can withdraw from the study at any time 
without prejudice to their subsequent care.  Information for a WOCBP (and a female 
partner of male patients who is a WOCBP) and lactating females should be provided in 
the ICF regarding unintended pregnancy and methods of contraception. 
The patient will be given a copy of the fully executed consent form and the original will 
be maintained with the patient’s records. 
9.3 
Patient Data Protection 
All data provided to the sponsor or designee will be identified only by patient number 
and initials, thereby ensuring that the patient’s identity remains unknown.  Patients 
should be informed in writing, that their data will be stored and analyzed in a computer, 
with confidentiality maintained in accordance with national and local legislation.  
Center-specific information must be added to the ICF as appropriate. 
Patients also should be informed in writing that authorized representatives of the 
sponsor/designee and/or regulatory authorities may require access to those parts of the 
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hospital/clinic records which are relevant to the study, including medical history, for data 
verification purposes. 
The principal investigator is responsible for keeping a patient identification list of all 
patients screened and enrolled which includes the following information: patient number, 
full name, and a secondary unique identifier (ie, hospital/clinic number).  A list of 
patients who failed screening must also be maintained and be available for inspection. 
9.4 
Financial Disclosure 
In 2001, the FDA issued a guidance document entitled “Financial Disclosure by Clinical 
Investigators” which provides guidance to industry on its final rule on financial 
disclosure that became effective 02 February 1999 and was published as Title 21 Code of 
Federal Regulations Part 54.  This rule applies to all investigators participating in clinical 
studies to be submitted to the FDA in support of an application for market approval.  The 
financial disclosure statement must be updated annually during the course of the study 
and for 1 year after the completion of the study. 
According to the guidance, disclosable financial arrangements are defined as the 
following:  
 Compensation made to the investigator in which the value of compensation 
could be affected by study outcome  
 A proprietary interest in the tested product, including, but not limited to, a 
patent, trademark, copyright, or licensing agreement 
 Any equity interest in the sponsor of a covered study (ie, any ownership interest, 
stock options, or other financial interest whose value cannot be readily 
determined through reference to public prices)  
 An equity interest in a publicly held company that exceeds $50,000 in value  
 Significant payments of other sorts, which are payments that have a cumulative 
monetary value of $25,000 or more made by the sponsor of a covered study to 
the investigator or the investigator’s institution to support activities of the 
investigator exclusive of the costs of conducting the clinical study or other 
clinical studies, (eg, a grant to fund ongoing research, compensation in the form 
of equipment or retainers for ongoing consultation, or honoraria) during the 
time the clinical investigator is carrying out the study and for 1 year after 
completion of the study 
Clinical investigator means only a listed or identified investigator or subinvestigator who 
is directly involved in the treatment or evaluation of research patients.  The term also 
includes the spouse and each dependent child of the investigator.  Participating 
investigators must provide this information and complete necessary documentation as 
requested by the sponsor. 
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The intent of this regulation is to ensure the proper identification and disclosure of 
financial interests of clinical investigators that could affect the reliability of data 
submitted to the FDA in support of a market application.  Companies must meet these 
financial disclosure requirements, and failure to do so may result in the refusal by the 
FDA to accept an application for market approval of the study drug. 
9.5 
Changes to the Protocol 
No change in the study procedures shall be effected without the mutual agreement of the 
sponsor and the investigator.  All changes must be documented as signed protocol 
amendments, or as a revised protocol.  Changes to the protocol may require notification 
to or approval by the IRB/IEC and the regulatory authorities before implementation. 
Local regulatory requirements must be followed.  Instructions for reporting deviations 
from the protocol can be found in the Study Reference Manual. 
The sponsor or designee is responsible for the distribution of protocol amendment(s) to 
the principal investigator(s) and those concerned within the conduct of the study.  The 
principal investigator is responsible for the distribution of all amendments to the IRB/IEC 
and all staff concerned at his/her center. 
9.6 
Investigator Obligations 
The principal investigator at each center must provide the following to the 
sponsor/designee prior to the start of the study: 
 A completed and signed FDA Form 1572.  If during the course of the study any 
changes are made that are not reflected on the original FDA Form 1572, a 
revised FDA Form 1572 form must be completed and returned to the sponsor 
for submission to the FDA. 
 A current (within 2 years) signed and dated curriculum vitae for the principal 
investigator and all subinvestigators listed on FDA Form 1572, including a 
current office address 
 Financial disclosure statement for the principal investigator, and 
subinvestigators (listed on the FDA Form 1572).  An updated financial 
disclosure statement must be provided to the sponsor 1 year after completion of 
the study. 
 A copy of the original approval for conducting the study from the IRB/IEC. 
Renewals must be submitted at yearly intervals if the study is ongoing or as 
required by the institution. 
 A copy of the IRB/IEC-approved ICF 
 IRB/IEC membership list or Department of Health and Human Services General 
Assurance Number, which must be maintained current during the trial 
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 Laboratory certification and normal ranges, unless a central laboratory is being 
used exclusively 
The “Principal Investigator Protocol Agreement Page” of this protocol must be signed 
and dated by the principal investigator for the center. 
9.7 
Confidentiality/Publication of the Study 
Any information shared by the sponsor regarding this study, including this protocol, is 
considered proprietary information and should be kept confidential. 
The data generated by this clinical study are the property of the sponsor.  These data may 
be used by the sponsor, now and in the future, for presentation or publication at the 
sponsor’s discretion and/or for submission to regulatory agencies.  In addition, the 
sponsor reserves the right to review data from this study relative to the potential release 
of proprietary information 30 days prior to submission to any publication or for any 
presentation. 
9.8 
Selection of a Primary Principal Investigator 
The sponsor will select one primary principal investigator as a representative of all 
investigators for this study.  The selection will be based on a variety of factors, including 
rate of enrollment, overall enrollment totals, and patient retention.  The principal 
investigator selected will be identified in the synopsis of the CSR as the principal 
investigator for the study.  Roles, affiliations, and qualifications for the principal 
investigators will be included in the CSR appendices.  Where the signature of the 
principal investigator is required by regulatory authorities, this will also be included in 
the CSR appendices. 
9.9 
Study Termination 
The sponsor reserves the right to discontinue the study for medical and/or administrative 
reasons at any time. 
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10 
REFERENCES 
Bilezikian J. PTH(1-84): A therapy for hypoparathyroidism. Independent Investigator 
Study Report, 2008. 
Bilezikian JP, Marcus R, Levine MA (eds). The Parathyroids. Basic and Clinical 
Concepts 2nd ed. San Diego: Academic Press;2001. 
Horwitz MJ, Stewart AF. Hypoparathyroidism: is it time for replacement therapy? J Clin 
Endocrinol Metab. 2008 Sep;93(9):3307-9.  
Langdahl BL, Mortensen L, Vesterby A, Eriksen EF, Charles P. Bone histomorphometry 
in hypoparathyroid patients treated with vitamin D. Bone. 1996;18(2):103-8. 
Rubin MR, Dempster DW, Zhou H, Shane E, Nickolas T, Sliney J, et al. Dynamic and 
structural properties of the skeleton in hypoparathyroidism. J Bone Miner Res. 2008a 
Aug 4;23(12):2018-24.  
Rubin MR, Cremers S, Dempster DW, Sliney J, McMahon DJ, Zhou H, et al. PTH 
increases bone turnover in hypoparathyroidism [abstract]. J Bone Miner Res. 
2008b;23:S128. 
Rubin MR, Dempster DW, Cremers S, Zhou H, McMahon DJ, Sliney J, et al. Circulating 
osteoblast lineage cells increase with PTH treatment of hypoparathyroidism [abstract]. J 
Bone Miner Res. 2008c;23:S42. 
Rubin MR, Dempster DW, Sliney J, McMahon DJ, Zhou H, Nickolas T, et al. PTH 
reverses abnormal bone remodeling and structure in hypoparathyroidism [abstract]. J 
Bone Miner Res. 2008d;23:S12. 
Rubin MR, Sliney J Jr, McMahon DJ, Silverberg SJ, Bilezikian JP.  Therapy of 
hypoparathyroid with intact parathyroid hormone.  Osteoporos Int. 2010;21(11):1927-34. 
Shoback D. Clinical practice. Hypoparathyroidism. N Engl J Med. 2008 Jul 24; 
359(4):391-403. Review.  
Winer KK, Yanovski JA, Sarani B, Cutler GB Jr. A randomized, cross-over trial of once-
daily versus twice-daily parathyroid hormone 1-34 in treatment of hypoparathyroidism. J 
Clin Endocrinol Metab. 1998 Oct;83(10):3480-6. 
Winer KK, Ko CW, Reynolds JC, Dowdy K, Keil M, Peterson D, et al. Long-term 
treatment of hypoparathyroidism: a randomized controlled study comparing parathyroid 
hormone-(1-34) versus calcitriol and calcium. J Clin Endocrinol Metab. 2003 
Sep;88(9):4214-20. 
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Winer KK, Sinaii N, Peterson D, Sainz B Jr, Cutler GB Jr. Effects of once versus twice-
daily parathyroid hormone1-34 therapy in children with hypoparathyroidism. J Clin 
Endocrinol Metab. 2008 Sep;93(9):3389-95. Epub 2008 May 20.  
 
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APPENDIX 1 
INSTRUCTIONS FOR USE FOR THE PTH 
YPSOMED INJECTION PEN  
 
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APPENDIX 2 
NPSP558 AND SUPPLEMENT TITRATION 
GUIDELINE 
In this study the goal is to continue NPSP558 dosing and to reduce calcitriol and oral 
calcium (carbonate or citrate) supplementation to as low as safely possible, while 
maintaining total serum calcium levels.  In patients with hypoparathyroidism treated with 
oral calcium and calcitriol, it is suggested to maintain total serum calcium levels in the 
lower half of the normal range (eg, between 8.0 and 9.0 mg/dL; Shoback, 2008).  This is 
to reduce symptoms and to avoid the hypercalciuria which can occur in the 
hypoparathyroid patient on calcitriol and oral calcium supplementation (Horwitz and 
Stewart, 2008).  In the current trial, all patients will receive NPSP558.  Hence, down-
titration of calcitriol and oral calcium must be undertaken, where appropriate, to avoid 
hypercalcemia.  At all times, changes in calcitriol and oral calcium dosing should be 
undertaken at the discretion of the investigator, based on total serum calcium 
concentrations and the patient’s clinical condition. 
To help facilitate a more standardized approach to dose adjustment across study centers, 
the following guideline has been prepared.  The guideline is non-mandatory but the 
approach suggested should be assessed when adjustments in calcitriol and oral calcium 
are being considered.  In the guideline, all references to total serum calcium levels 
indicate “predose” (trough) values drawn in a fasting state prior to administration of 
study drug, NPSP558. 
The order and magnitude of subsequent reductions in either calcitriol or oral calcium 
supplementation is left to the investigator’s discretion, based on individual patient 
response.  After any change in the NPSP558 dose, or a significant change in calcitriol or 
oral calcium supplement dose, a total serum calcium level MUST be measured 
3 to 5 days later for safety purposes (unless earlier or more frequent testing is clinically 
required) and to guide further changes in supplement doses. 
At the end of the study (this includes any patient that terminates early) patients must be 
assessed clinically at their study center to ensure that they return safely to an appropriate 
calcium and calcitriol supplementation level.  This includes the performance of necessary 
testing for total serum calcium 3 to 5 days later for safety purposes (unless earlier or more 
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frequent testing is clinically required) to ensure a stable total serum calcium level has 
been achieved.  The completion of these procedures should be documented by the site. 
 
Significant Hypercalcemia 
Any instances of significant hypercalcemia, which is defined as any total serum calcium 
level of > 11.9 mg/dL (even on a non-trough measurement), require MANDATORY 
immediate stopping of NPSP558 treatment.  Suspension of dosing with calcitriol and oral 
calcium as clinically appropriate and testing of serum total calcium levels at least daily 
should be undertaken until the patient’s serum total calcium returns to the normal range.  
Other clinically appropriate actions for the treatment of significant hypercalcemia should 
be undertaken as usual by the investigator to ensure patient safety.  Thereafter, NPSP558 
can be reintroduced with clinically appropriate doses of calcitriol and oral calcium, with 
the aim to avoid further episodes of abnormal serum calcium.   
 
Hypocalcemia  
If the total serum calcium level falls below 8.0 mg/dL (or below the baseline values, if 
the patient entered the study with a total serum calcium < 8.0 mg/dL), then the patient’s 
calcitriol and oral calcium doses should be checked and the injection technique of 
NPSP558 reviewed with the patient to ensure proper administration.  At planned study 
visits (Week 4, 8 etc until Week 48) the NPSP558 dose can be uptitrated if indicated in 
the opinion of the Investigator following discussion with the Sponsor.  During interim 
safety checks, hypocalcemia should be addressed by clinically indicated increases in 
calcitriol or supplemental oral calcium doses according to the guideline below, with the 
goal of attaining a total serum calcium level of 8.0 to 9.0 mg/dL.  Laboratory testing 
should be repeated as indicated in order to ensure that changes in dosing are accompanied 
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APPENDIX 3   METHOD OF BIRTH CONTROL  
 
Patients who are sexually active, or considering sexual activity, will be instructed to use 
two acceptable methods of birth control from the list below:  
 Hormonal methods of contraception such as oral, injected, vaginal rings, transdermal 
patch, implanted.  
 Placement of an intrauterine device (IUD) or intrauterine system (IUS).  
 Barrier methods of contraception:  Condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.  
 Male partner sterilization (vasectomy) .  
Female partners (who are of childbearing potential) of male study patients must also use 
acceptable forms of contraception during their partner’s participation.   
True sexual abstinence is defined as not having any type of intercourse or sex play with a 
partner. 
 
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