Clinical trial NCT05137730
Conditions: Healthy Volunteers
Sponsor: Takeda
Start date: 2021-11-29; Completion date: 2022-04-15
Enrollment: 96 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main aim of Part I of this study is to evaluate the relative bioavailability of a new formulation compared with the approved formulation when a single dose of rhPTH(1-84) is given to healthy volunteers. Bioavailability is the ability of a drug to be absorbed and used by the body. In Part II, the main aim is to assess the dose linearity of the new formulation.

Participants will receive 2 doses in Part I and 4 doses in Part II.

Participants need to visit their doctor approximately 14 days and 30 days after the last dose of study drug.

Detailed description:
This study will be conducted in two parts (Part I and Part II). Part I consists of two treatment periods with 2 sequences and part II consists of four treatment periods with 4 sequences. In Part I, relative bioavailability of Formulation A (Test: 100 microgram \[mcg\] rhPTH\[1-84\]) will be compared with Formulation B (Reference: 100 mcg rhPTH\[1-84\]). In Part II, dose linearity of the new formulation, Formulation A, of rhPTH (1-84) will be assessed based on 4 different dose levels as dose c - f (dose c = 25 mcg, dose d = 50 mcg, dose e = 75 mcg and f = 200 mcg). Both parts may be conducted concurrently.

Arms: arm 1: Participants will receive a single SC injection of 100 microgram (mcg) rhPTH(1-84) (Formulation A) on Day 1 of treatment period 1 followed by 100 mcg rhPTH(1-84) (Formulation B) on Day 1 of treatment period 2. A washout period of 96 hours will be maintained between each treatment period. arm 2: Participants will receive a single SC injection of 100 microgram (mcg) rhPTH(1-84) (Formulation B) on Day 1 of treatment period 1 followed by 100 mcg rhPTH(1-84) (Formulation A) on Day 1 of treatment period 2. A washout period of 96 hours will be maintained between each treatment period. arm 3: Participants will receive a single SC injection of 25 mcg (dose C) rhPTH(1-84) on Day 1 of treatment period 1 followed by 50 mcg (dose D) rhPTH(1-84) on Day 1 of treatment period 2 followed by 75 mcg (dose E) rhPTH(1-84) on Day 1 of treatment period 3 followed 200 mcg (dose F) rhPTH(1-84) on Day 1 of treatment period 4. A washout period of 48 hours will be maintained between each treatment period 1,2,3 and 4. arm 4: Participants will receive a single SC injection of 50 mcg (dose D) rhPTH(1-84) on Day 1 of treatment period 1 followed by 200 mcg (dose F) rhPTH(1-84) on Day 1 of treatment period 2 followed by 25 mcg (dose C) rhPTH(1-84) on Day 1 of treatment period 3 followed by 75 mcg (dose E) rhPTH(1-84) on Day 1 of treatment period 4. A washout period of 48 hours will be maintained between each treatment period 1,2,3 and 4. arm 5: Participants will receive a single SC injection of 75 mcg (dose E) rhPTH(1-84) on Day 1 of treatment period 1 followed by 25 mcg (dose C) rhPTH(1-84) on Day 1 of treatment period 2 followed by 200 mcg (dose F) rhPTH(1-84) on Day 1 of treatment period 3 followed by 50 mcg (dose D) rhPTH(1-84) on Day 1 of treatment period 4. A washout period of 48 hours will be maintained between each treatment period 1,2,3 and 4. arm 6: Participants will receive a single SC injection of 200 mcg (dose F) rhPTH(1-84) on Day 1 of treatment period 1 followed by 75 mcg (dose E) rhPTH(1-84) on Day 1 of treatment period 2 followed by 50 mcg (dose D) rhPTH(1-84) on Day 1 of treatment period 3 followed by 25 mcg (dose C) rhPTH(1-84) on Day 1 of treatment period 4. A washout period of 48 hours will be maintained between each treatment period 1,2,3 and 4.
Interventions: intervention 1: rhPTH(1-84)
Intervention descriptions: intervention 1: Participants in both part I and part II of the study will receive a single SC injection of rhPTH(1-84) depending upon the treatment sequence allocation on Day 1 of each treatment period.

Protocol documents:
Prot_000.pdf: 
NCT Number: NCT05137730
Title: A Randomized, Open-label, Single-center, Single-dose Study to Evaluate the 
Relative Bioavailability of a New Formulation Compared with the Approved 
Formulation of Recombinant Human Parathyroid Hormone (rhPTH[1-84]) and to 
Assess Dose Linearity of the New Formulation in Healthy Subjects
Study Number: TAK-834-1001
Document Version and Date: Final Protocol/Amendment 1; 18-Nov-2021
Certain information within this document has been redacted (ie, specific content is masked 
irreversibly from view) to protect either personally identifiable information or company 
confidential information. 
Clinical Study Protocol
For non-commercial use only


TAKEDA PHARMACEUTICALS PROTOCOL
A Randomized, Open-label, Single-center, Single-dose Study to Evaluate the Relative 
Bioavailability of a New Formulation Compared with the Approved Formulation of 
Recombinant Human Parathyroid Hormone (rhPTH[1-84]) and to Assess Dose Linearity of the 
New Formulation in Healthy Subjects
Study Identifier:
TAK-834-1001
Compound:
rhPTH(1-84)
Date:
18-Nov-2021
Version/Amendment 
Number:
Final Protocol/Amendment 1
Amendment History:
Date
Amendment Number
Region
18-Nov-2021
Amendment 1
United States
15-Oct-2021
Initial version
United states
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her 
staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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TABLE OF CONTENTS
TABLE OF CONTENTS.................................................................................................................2
LIST OF IN-TEXT TABLES ..........................................................................................................7
LIST OF IN-TEXT FIGURES.........................................................................................................7
LIST OF APPENDICES..................................................................................................................7
1.
STUDY SUMMARY ...............................................................................................................8
2.
STUDY SCHEMATIC...........................................................................................................15
3.
SCHEDULE OF STUDY PROCEDURES............................................................................16
4.
INTRODUCTION..................................................................................................................19
4.1
Background ..............................................................................................................19
4.2
Rationale for the Proposed Study.............................................................................21
4.3
Benefit/Risk Profile..................................................................................................22
5.
STUDY OBJECTIVES AND ENDPOINTS..........................................................................23
5.1
Hypothesis................................................................................................................23
5.2
Study Objectives ......................................................................................................23
5.2.1
Study Primary Objectives....................................................................................23
5.2.2
Study Secondary Objectives................................................................................23
5.2.3
Study Exploratory Objectives..............................................................................23
5.3
Endpoints..................................................................................................................24
5.3.1
Primary Endpoints...............................................................................................24
5.3.2
Secondary Endpoints...........................................................................................24
5.3.3
Exploratory Endpoints.........................................................................................24
5.3.4
Additional Endpoints...........................................................................................24
6.
STUDY DESIGN AND DESCRIPTION...............................................................................26
6.1
Study Design ............................................................................................................26
6.2
Dose Escalation........................................................................................................28
6.3
Stopping Rules .........................................................................................................28
6.4
Rationale for Study Design, Dose, and Endpoints...................................................28
6.4.1
Rationale of Study Design...................................................................................28
6.4.2
Rationale for Dose...............................................................................................29
6.4.3
Rationale for Endpoints.......................................................................................29
6.4.3.1
Pharmacokinetic Endpoints....................................................................29
6.4.3.2
Safety Endpoints ....................................................................................29
6.4.3.3
29
6.4.3.4
29
6.4.4
Future Biomedical Research................................................................................30
6.4.5
Critical Procedures Based on Study Objectives: Timing of Procedures .............30
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6.5
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters ................................................................................................................30
6.6
Study Beginning and End/Completion.....................................................................30
6.6.1
Definition of Beginning of the Study..................................................................30
6.6.2
Definition of End of the Study ............................................................................30
6.6.3
Definition of Study Completion..........................................................................30
6.6.4
Definition of Study Discontinuation ...................................................................31
6.6.5
Criteria for Premature Termination or Suspension of the Study.........................31
6.6.6
Criteria for Premature Termination or Suspension of a Site...............................31
7.
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS....................32
7.1
Inclusion Criteria......................................................................................................32
7.2
Exclusion Criteria.....................................................................................................32
7.3
Excluded Medications, Supplements, and Dietary Products....................................34
7.4
Diet, Fluid, Activity .................................................................................................35
7.4.1
Diet and Fluid......................................................................................................35
7.4.2
Activity................................................................................................................35
7.5
Criteria for Discontinuation or Withdrawal of a Subject .........................................36
7.6
Procedures for Discontinuation or Withdrawal of a Subject....................................37
7.7
Subject Replacement................................................................................................37
8.
CLINICAL STUDY MATERIAL MANAGEMENT............................................................38
8.1
Clinical Study Drug..................................................................................................38
8.1.1
Clinical Study Drug Labeling..............................................................................38
8.1.2
Clinical Study Drug Inventory and Storage ........................................................38
8.1.3
Clinical Study Drug Blinding..............................................................................38
8.1.4
Randomization Code Creation and Storage ........................................................38
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure..................................38
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs ..............................39
9.
STUDY PROCEDURES........................................................................................................40
9.1
Administrative Procedures .......................................................................................40
9.1.1
Informed Consent Procedure...............................................................................40
9.1.1.1
Assignment of Screening and Randomization Numbers........................40
9.1.1.2
Study Drug Assignment .........................................................................40
9.1.2
Inclusion and Exclusion ......................................................................................40
9.1.3
Medical History/Demography.............................................................................40
9.1.4
Concomitant Medications....................................................................................40
9.2
Clinical Procedures and Assessments ......................................................................40
9.2.1
Full Physical Exam..............................................................................................41
9.2.2
Height and Weight...............................................................................................41
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9.2.3
BMI......................................................................................................................41
9.2.4
Vital Signs ...........................................................................................................41
9.2.5
12-Lead ECG.......................................................................................................41
9.2.6
Injection Site Evaluation .....................................................................................42
9.2.7
Study Drug Administration .................................................................................42
9.2.8
AE Monitoring.....................................................................................................42
9.2.9
Laboratory Procedures and Assessments ............................................................43
9.2.9.1
Clinical Laboratory Tests.......................................................................43
9.3
Pharmacokinetics, 
..........44
9.3.1
PK Measurements................................................................................................44
9.3.1.1
Plasma for PK Measurements ................................................................44
9.3.2
45
9.3.2.1
45
9.3.3
46
9.3.4
Biomarker Measurements....................................................................................46
9.3.5
PGx Measurements..............................................................................................46
9.3.6
Confinement ........................................................................................................46
10. ADVERSE EVENTS..............................................................................................................47
10.1
Definitions and Elements of AEs.............................................................................47
10.1.1
SAEs....................................................................................................................49
10.1.2
Special Interest AEs ............................................................................................50
10.2
AE Procedures..........................................................................................................50
10.2.1
Assigning Severity/Intensity of AEs ...................................................................50
10.2.2
Assigning Causality of AEs.................................................................................51
10.2.3
Start Date.............................................................................................................51
10.2.4
End Date ..............................................................................................................51
10.2.5
Pattern of Adverse Event (Frequency) ................................................................51
10.2.6
Action Taken With Study Treatment ..................................................................51
10.2.7
Outcome ..............................................................................................................52
10.2.8
Collection and Reporting of AEs, SAEs, Special Interest AEs, and 
Abnormal LFTs ...................................................................................................52
10.2.8.1
Collection Period....................................................................................52
10.2.8.2
Reporting AEs........................................................................................52
10.2.8.3
Reporting SAEs......................................................................................53
10.2.8.4
Reporting Special Interest AEs ..............................................................54
10.2.8.5
Reporting of Abnormal LFTs.................................................................54
10.2.9
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities ...........................................................................................................54
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11. STATISTICAL METHODS...................................................................................................55
11.1
Statistical and Analytical Plans................................................................................55
11.1.1
Analysis Sets .......................................................................................................55
11.1.1.1
PK Set.....................................................................................................55
11.1.1.2
Safety Set................................................................................................55
11.1.1.3
55
11.1.1.4
55
11.1.2
Analysis of Demography and Other Baseline Characteristics ............................55
11.1.3
PK Analysis.........................................................................................................55
11.1.3.1
Relative Bioavailability (Part I [Relative Bioavailability])....................56
11.1.3.2
Dose Linearity (Part II [Dose Linearity])...............................................56
11.1.3.3
Non-Parametric Analysis .......................................................................56
11.1.4
56
11.1.5
56
11.1.6
Safety Analysis....................................................................................................56
11.1.6.1
AEs.........................................................................................................57
11.1.6.2
Clinical Laboratory Evaluation ..............................................................57
11.1.6.3
Vital Signs..............................................................................................57
11.1.6.4
Other Safety Parameters.........................................................................57
11.2
Interim Analysis and Criteria for Early Termination...............................................57
11.3
Determination of Sample Size..................................................................................57
12. QUALITY CONTROL AND QUALITY ASSURANCE .....................................................59
12.1
Study-Site Monitoring Visits ...................................................................................59
12.2
Protocol Deviations..................................................................................................59
12.3
Quality Assurance Audits and Regulatory Agency Inspections ..............................59
13. ETHICAL ASPECTS OF THE STUDY................................................................................60
13.1
IRB and/or IEC Approval ........................................................................................60
13.2
Subject Information, Informed Consent, and Subject Authorization.......................61
13.3
Subject Confidentiality.............................................................................................62
13.4
Publication, Disclosure, and Clinical Study Registration Policy.............................62
13.4.1
Publication and Disclosure..................................................................................62
13.4.2
Clinical Study Registration..................................................................................62
13.4.3
Clinical Study Results Disclosure .......................................................................63
13.5
Insurance and Compensation for Injury...................................................................63
14. ADMINISTRATIVE AND REFERENCE INFORMATION................................................64
14.1
Administrative Information......................................................................................64
14.1.1
Study Contact Information ..................................................................................64
14.1.2
INVESTIGATOR AGREEMENT ......................................................................65
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14.1.3
Study-Related Responsibilities............................................................................66
14.1.4
List of Abbreviations...........................................................................................66
15. DATA HANDLING AND RECORDKEEPING...................................................................68
15.1
CRFs (Electronic and Paper)....................................................................................68
15.2
Record Retention......................................................................................................68
16. REFERENCES .......................................................................................................................70
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LIST OF IN-TEXT TABLES
Table 1.a
Study Scheme for Part I (Relative Bioavailability).........................................8
Table 1.b
Study Scheme for Part II (Dose Linearity)......................................................9
Table 6.a
Study Scheme for Part I (Relative Bioavailability).......................................26
Table 6.b
Study Scheme for Part II (Dose Linearity)....................................................27
Table 6.c
Planned Dose Levels .....................................................................................28
Table 7.a
Study Excluded Medications, Supplements, and Dietary Products ..............35
Table 9.a
Primary Specimen Collections ......................................................................44
Table 10.a
Takeda Medically Significant AE List..........................................................50
LIST OF IN-TEXT FIGURES
Figure 1
Study Schematic (Part I [Relative Bioavailability])......................................15
Figure 2
Study Schematic (Part II [Dose Linearity])...................................................15
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator ...............................................................71
Appendix B
Elements of the Subject Informed Consent...................................................73
Appendix C
Investigator Consent to the Use of Personal Information .............................75
Appendix D
Pregnancy and Contraception........................................................................76
Appendix E
Summary of Changes from Previous Version...............................................80
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1.
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc. (TDC Americas)
95 Hayden Avenue
Lexington, MA 02421
Telephone: +1 (617) 679-7000
Compound:
rhPTH(1-84)
Study Identifier: TAK-834-1001
Phase: 1
Protocol Title: A Randomized, Open-label, Single-center, Single-dose Study to Evaluate the Relative 
Bioavailability of a New Formulation Compared with the Approved Formulation of Recombinant Human 
Parathyroid Hormone (rhPTH[1-84]) and to Assess Dose Linearity of the New Formulation in Healthy Subjects
Study Design:
This is a randomized, open-label, single-center, two-part study to assess the relative bioavailability of a single
subcutaneous (SC) dose of rhPTH(1-84) administered as the new formulation (Formulation A; test) and the
approved formulation (Formulation B; reference) in Part I (Relative Bioavailability) of the study and to assess
dose linearity of Formulation A in Part II (Dose Linearity) of the study. Both parts may be conducted
concurrently.
Part I (Relative Bioavailability)
Part I (Relative Bioavailability) will be conducted as a randomized, two-sequence, two-period, crossover design.
Subjects in each treatment period will receive rhPTH(1-84) as a single 100 μg SC injection administered in the 
mid-thigh as either Formulation A or Formulation B depending on the randomized (1:1) treatment sequence as 
indicated in Table 1.a.
Blood samples for plasma parathyroid hormone (PTH) pharmacokinetics (PK) and serum calcium and albumin 
concentrations will be collected predose and for 24 hours following each rhPTH(1-84) administration at the time
points delineated in the Schedule of Study Procedures (Section 3).
There will be a drug washout of 96 (±1) hours between the administration of rhPTH(1-84) in each period.
Table 1.a
Study Scheme for Part I (Relative Bioavailability)
Treatment 
Sequence
N
Treatment Period 1
Drug Washout
(Hours)
Treatment Period 2
1
42
a
96 (±1)
b
2
42
b
96 (±1)
a
Treatment Definitions: a=100 µg rhPTH(1-84) Formulation A; b=100 µg rhPTH(1-84) Formulation B
Subjects will remain in the clinical research unit (CRU) until completion of the last postdose assessment on 
Day 2 of Treatment Period 2. If clinically significant findings are observed upon discharge, subjects may either 
be kept in the CRU for observation or return to the CRU for re-evaluation per Investigator’s discretion.
 
Safety and tolerability will be assessed by treatment-emergent adverse events (TEAEs) including injection site 
reaction assessments, laboratory evaluations, physical examinations, 12-lead electrocardiograms (ECGs), and 
vital signs.
All subjects who received a dose of study drug (including subjects who terminate from the study early) will 
return to the CRU 16 (±2) days (return visit) and 32 (±2) days (follow-up visit) after the last study drug
administration for collection of blood
to determine if any adverse events (AEs) have 
occurred since the last study visit.
Part II (Dose Linearity)
Part II (Dose Linearity) will be conducted as a randomized, four-sequence, four-period, crossover design.
Subjects in each treatment period will receive rhPTH(1-84) Formulation A as a single SC injection administered 
in the mid-thigh at a dose level depending on the randomized (1:1:1:1) treatment sequence as indicated in 
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Table 1.b. If possible, the same location in the same thigh will be used for all treatment periods. If the same thigh 
cannot be used, the alternative mid-thigh may be used.
Blood samples for plasma PTH PK will be collected predose and for 24 hours following each rhPTH(1-84) 
administration at the time points delineated in the Schedule of Study Procedures (Section 3).
There will be a drug washout of 48 (±1) hours between the administration of rhPTH(1-84) in each period.
Table 1.b
Study Scheme for Part II (Dose Linearity)
Treatment 
Sequence
N
Treatment 
Period 1
Drug 
Washout
(Hours)
Treatment 
Period 2
Drug 
Washout
(Hours)
Treatment 
Period 3
Drug 
Washout
(Hours)
Treatment 
Period 4
1
3
c
48 (±1)
d
48 ±1
e
48 (±1)
f
2
3
d
48 (±1)
f
48 ±1
c
48 (±1)
e
3
3
e
48 (±1)
c
48 ±1
f
48 (±1)
d
4
3
f
48 (±1)
e
48 ±1
d
48 (±1)
c
Treatment Definitions: c=25 µg rhPTH(1-84); d=50 µg rhPTH(1-84); e=75 µg rhPTH(1-84); 
f = 200 µg rhPTH(1-84)
Subjects will remain in the CRU until completion of the last postdose assessment on Day 2 of Treatment 
Period 4. If clinically significant findings are observed upon discharge, subjects may either be kept in the CRU 
for observation or return to the CRU for re-evaluation per Investigator’s discretion.
 
Safety and tolerability will be assessed by TEAEs including injection site reaction assessments, laboratory 
evaluations, physical examinations, 12-lead ECGs, and vital signs.
All subjects who received a dose of study drug (including subjects who terminate from the study early) will 
return to the CRU 16 (±2) days (return visit) and 32 (±2) days (follow-up visit) after the last study drug
administration for collection of blood
to determine if any AEs have occurred since the 
last study visit.
Study Primary Objectives:
Part I (Relative Bioavailability):
To evaluate the relative bioavailability of a new formulation (Formulation A; test) compared with the approved 
formulation (Formulation B; reference) of rhPTH(1-84) following the administration of single SC doses of 
100 µg rhPTH(1-84) in healthy subjects. 
Part II (Dose Linearity):
To assess the dose linearity of the new formulation (Formulation A) of rhPTH(1-84) following the administration 
of SC doses of 25 µg, 50 µg, 75 µg, and 200 µg rhPTH(1-84) in healthy subjects. 
Study Secondary Objectives:
Part I (Relative Bioavailability):
To assess the safety and tolerability of SC injections of rhPTH(1-84) administered as Formulation A and 
Formulation B in healthy subjects.
Part II (Dose Linearity):
To assess the safety and tolerability of SC injections of rhPTH(1-84) administered as Formulation A in healthy 
subjects.
Study Exploratory Objectives:
 
 
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Study Subject Population: Healthy male and female subjects aged 18 to 65 years, inclusive, at screening. Body 
mass index (BMI) 18.5-30.0 kg/m2, inclusive, at screening.
Attempts will be made to enroll at least 20% of each sex in each study part.
Planned Number of Subjects:
Part I (Relative Bioavailability):
Approximately 84 subjects (42 subjects per 
sequence) will be enrolled to ensure at least 
76 subjects complete Study Part I.
Part II (Dose Linearity):
Approximately 12 subjects (3 subjects per sequence) 
will be enrolled to ensure at least 8 subjects 
complete Study Part II.
Planned Number of Sites:
1
Dose Levels:
Part I (Relative Bioavailability):
a: 100 µg rhPTH(1-84) Formulation A (Test)
b: 100 µg rhPTH(1-84) Formulation B (Reference)
Part II (Dose Linearity):
c: 25 µg rhPTH(1-84) Formulation A
d: 50 µg rhPTH(1-84) Formulation A
e: 75 µg rhPTH(1-84) Formulation A
f: 200 µg rhPTH(1-84) Formulation A
Route of Administration:
SC
Duration of Treatment:
Part I (Relative Bioavailability):
Single-dose on Day 1 of each period with 
2 treatment periods.
Part II (Dose Linearity):
Single-dose on Day 1 of each period with 
4 treatment periods.
Planned Study Duration:
Part I (Relative Bioavailability):
Approximately 58 days including screening period and 
follow-up.
Part II (Dose Linearity):
Approximately 60 days including screening period and 
follow-up.
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Criteria for Inclusion:
Subjects must fulfill the following inclusion criteria to be eligible for participation in the study:
1.
Healthy, adult, male or female, 18-65 years of age, inclusive, at screening. Attempts will be made to enroll 
at least 20% of each sex in each study part.
2.
Continuous non-smoker who has not used nicotine containing products for at least 90 days prior to the first 
dosing and throughout the study, based on subject self-reporting.
3.
BMI ≥18.5 and ≤30.0 kg/m2 at screening.
4.
Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, 
vital signs or ECGs, as deemed by the Investigator or designee including the following:

Serum calcium, PTH, phosphate, and magnesium within laboratory normal limits at screening and 
check-in.

Vitamin D (1,25(OH)2D3) levels between lower limit of normal and up to 1.5 x upper limit of normal 
(ULN).

Seated blood pressure is ≥89/49 mmHg and ≤139/89 mmHg at screening.

Seated pulse rate is ≥40 bpm and ≤99 bpm at screening.

QT interval corrected for heart rate using Fridericia’s formula (QTcF) interval is ≤450 msec (males) or 
≤470 msec (females) or ECG findings considered normal or not clinically significant by the Investigator 
or designee at screening.

Estimated creatinine clearance ≥80 mL/minute at screening.
5.
Agrees to comply with any applicable contraceptive requirements of the protocol as detailed in Appendix D.
6.
Understands the study procedures in the Informed Consent Form (ICF), be able to voluntarily provide 
written, signed, and dated informed consent, and be willing and able to comply with the protocol.
Criteria for Exclusion:
Subjects must not be enrolled in the study if they meet any of the following criteria: 
1.
Is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit 
or expected during the conduct of the study in the opinion of the Investigator or designee.
2.
History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the 
Investigator or designee.
3.
History of any hematological, hepatic, respiratory, cardiovascular, renal, neurological or psychiatric disease, 
gall bladder removal, or current or recurrent disease that could affect the action, absorption, or disposition 
of the study drug, or clinical or laboratory assessments.
4.
Subjects who are at increased baseline risk for osteosarcoma such as subjects with Paget’s disease of bone 
or unexplained elevations of alkaline phosphatase (ALP), hereditary disorders predisposing to osteosarcoma 
or a prior history of external beam or implant radiation therapy involving the skeleton.
5.
History of any illness that, in the opinion of the Investigator or designee, might confound the results of the 
study or poses an additional risk to the subject by their participation in the study.
6.
History or presence of alcoholism or drug abuse, in the opinion of the Investigator or designee, within the 
past 2 years prior to the first dosing.
7.
Male subjects who consume more than 21 units of alcohol per week or 3 units per day. Female subjects who 
consume more than 14 units of alcohol per week or 2 units per day. (1 alcohol unit=1 beer or 1 wine 
(5 oz/150 mL) or 1 liquor (1.5 oz/40 mL) or 0.75 oz alcohol).
8.
Positive urine drug or alcohol results at screening or check-in.
9.
History or presence of hypersensitivity or idiosyncratic reaction to the study drug or related compounds.
10. History of abnormalities of calcium homeostasis including hyperparathyroidism, hypoparathyroidism, 
hyperthyroidism, Cushing’s syndrome, hypercalcemia, hypocalcemia, osteoporosis, or any other calcium 
disorder.
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11. Female subjects with a positive pregnancy test or who are lactating.
12. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), or hepatitis C virus (HCV).
13. Has tattoo(s) or scarring at or near the site of injection or any other condition which may interfere with 
injection site examination, in the opinion of the Investigator or designee.
14. Routine consumption of more than 2 units of caffeine per day or subjects who experience caffeine 
withdrawal headaches. A unit of caffeine is contained in the following items: one 6 oz (180 mL) cup of 
coffee, two 12 oz (360 mL) cans of cola, one 12 oz cup of tea, three 1 oz (85 g) chocolate bars.
15. Prior screen failure, randomization, participation, or enrollment in this study or prior exposure to any 
exogenous PTH, PTH fragments or analogs 3 months prior to dosing with rhPTH(1-84).
16. Unable to refrain from or anticipates the use of any medication or substance (including prescription or 
over-the-counter, vitamin supplements, natural or herbal supplements) as indicated in Section 7.3 (Excluded 
Medication, Supplements, and Dietary Products) for the prohibited time period.
17. Has been on a diet incompatible with the study diet or had any substantial changes in eating habits, in the 
opinion of the Investigator or designee, within the 30 days prior to the first dosing and throughout the study.
18. Donation of blood or significant blood loss within 60 days prior to the first dosing. 
19. Plasma donation within 7 days prior to the first dosing.
20. Participation in another clinical study within 30 days or 5 half-lives prior to the first dosing. The 30-day 
window or 5 half-lives will be derived from the date of the last blood collection or dosing, whichever is 
later, in the previous study to Day 1 of Treatment Period 1 of the current study.
Main Criteria for Evaluation and Analyses:
The primary endpoints of the study:
Parts I (Relative Bioavailability) and II (Dose Linearity):
The following PK parameters for baseline-adjusted plasma PTH concentrations for each treatment will be 
derived to evaluate relative bioavailability (Part I) and dose linearity (Part II):

Area under the plasma concentration-time curve from time zero to time of the last quantifiable 
concentration (AUClast)

Area under the plasma concentration-time curve from time zero to infinity (AUC∞)

Maximum observed plasma concentration (Cmax)
The secondary endpoints will be assessed through evaluation of the following parameters: 
The following safety endpoints will be recorded for both Part I (Relative Bioavailability) and Part II (Dose 
Linearity):

Number, severity, seriousness, and causality of treatment-emergent adverse events (TEAEs)

Changes in vital signs, ECGs, and laboratory results (hematology, chemistry, and urinalysis) from 
baseline.
 
 
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Additional Endpoints:
Parts I (Relative Bioavailability) and II (Dose Linearity):
The following additional PK parameters will be estimated for unadjusted and baseline-adjusted plasma PTH 
concentrations for each single-dose treatment for each treatment regimen:

The area under the curve from the last quantifiable concentration to infinity, expressed as a percentage 
of AUC(AUCextrap%)

Time of first occurrence of Cmax (tmax)

Time of the last measurable concentration (tlast)
The following additional PK parameters will be computed for unadjusted plasma PTH concentrations for each 
treatment:

Area under the plasma concentration-time curve from time zero to time of the last quantifiable 
concentration (AUClast)

Area under the plasma concentration-time curve from time zero to infinity (AUC∞)

Maximum observed plasma concentration (Cmax)

Terminal disposition phase half-life (t1/2z).
Statistical Considerations:
Pharmacokinetics:
Part I (Relative Bioavailability):
The baseline-adjusted plasma PK parameters of the different formulations of rhPTH(1-84) will be compared for 
the relative bioavailability assessment. A linear mixed-effects model for crossover designs will be used on the 
natural log (ln)-transformed AUClast, AUC, and Cmax. The 90% confidence intervals (CIs) for the central value 
ratios of AUC and Cmax between the test and reference formulations will be constructed based on the 90% CIs of 
the difference in the least-squares means (LSMs) on the log scale.
Part II (Dose Linearity):
Apparent dose linearity of PK parameters (selected baseline-adjusted AUC and Cmax parameters) will be assessed 
graphically.
Safety:
TEAEs will be tabulated by treatment regimens. Summary statistics for vital signs, safety 12-lead ECGs, and 
laboratory assessments will be computed and provided.
 
 
 
 
 
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Sample Size Justification:
Part I (Relative Bioavailability):
The sample size of 76 subjects was calculated to achieve 90% CI around the geometric mean ratio of the test and 
reference formulations within the limits of 0.80 to 1.25 for AUC and Cmax. The true test to reference ratio was 
assumed to be 0.93, and 90% target power was used for the sample size determination. The intra-subject 
coefficient of variation (ISCV) was assumed to be 32.2%, the upper end of the two-sided 50% confidence limit 
of the ISCV for Cmax estimated in study SHP634-103 (the ISCV observed in study SHP634-103 was higher for 
Cmax than for AUC). Part I (Relative Bioavailability) will enroll 84 subjects to allow for up to eight dropouts.
Part II (Dose Linearity):
The sample size for Part II (Dose Linearity) is not based on any statistical considerations but is considered 
sufficient for dose linearity evaluation. Part II (Dose Linearity) will enroll 12 subjects to ensure at least 
8 subjects complete.
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2.
STUDY SCHEMATIC
Figure 1
Study Schematic (Part I [Relative Bioavailability])
Pretreatment
Treatment Periods 1-2 (a)
Discharge 
(b)
Return 
Visit (c)
Follow up 
(c)
Screening
Predose 
Assessments
Dosing and 
Study 
Assessments
Safety and 
PK 
Assessments
Safety 
 
Safety 
 
Day -21 to 
first dosing
Day -1
Day 1
Days 1-2
Day 2 of last 
treatment 
period
16 (±2) days 
after last 
dose
32 (±2) days 
after last 
dose
Confinement (d) 
(a) There will be a washout period of 96 (±1) hours between rhPTH(1-84) dosing in each treatment period.
(b) If clinically significant findings are observed upon discharge, subjects may either be kept in the CRU for 
observation or return to the CRU for re-evaluation per Investigator’s discretion.
(c) All subjects who received a dose of study drug (including subjects who terminate from the study early) will 
return to the CRU 16 (±2) days (return visit) and 32 (±2) days (follow-up visit) after the last study drug
administration for collection of blood
 to determine if any AEs have occurred since the last 
study visit.
(d) Subjects will start the confinement on Day -1 of Treatment Period 1 and remain confined until Day 2 of 
Treatment Period 2. Subjects may be admitted earlier for Coronavirus disease 2019 (COVID-19) testing not related 
to study protocol as per CRU requirements. 
Figure 2
Study Schematic (Part II [Dose Linearity])
Pretreatment
Treatment Periods 1-4 (a)
Discharge (b)
Return 
Visit (c)
Follow up 
(c)
Screening
Predose 
Assessments
Dosing and 
Study 
Assessments
Safety and 
PK 
Assessments
Safety 
 
Safety 
 
Day -21 to 
first dosing
Day -1
Day 1
Days 1-2
Day 2 of last 
treatment 
period
16 (±2) 
days after 
last dose
32 (±2) 
days after 
last dose
Confinement (d) 
(a) There will be a washout period of 48 (±1) hours between rhPTH(1-84) dosing in each treatment period.
(b) If clinically significant findings are observed upon discharge, subjects may either be kept in the CRU for 
observation or return to the CRU for re-evaluation per Investigator’s discretion.
(c) All subjects who received a dose of study drug (including subjects who terminate from the study early) will 
return to the CRU 16 (±2) days (return visit) and 32 (±2) days (follow-up visit) after the last study drug
administration for collection of blood
to determine if any AEs have occurred since the last 
study visit.
(d) Subjects will start the confinement on Day -1 of Treatment Period 1 and remain confined until Day 2 of 
Treatment Period 4. Subjects may be admitted earlier for COVID-19 testing not related to study protocol as per 
CRU requirements.
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3.
SCHEDULE OF STUDY PROCEDURES
Study Procedures
Sa
Study Days in Each Treatment Periodb
EOT
or 
ETc
FUd
Days →
-1
1
2
16 
(±2)d
32 
(±2)d
Hours →
C-Ie
-1
-0.5
-0.25
0
1
1.25
1.5
2
2.5
3
4
6
8
12
16f
24
Minutes →
5
10
20
30
45
Administrative 
Procedures
Informed Consent
X
Inclusion/Exclusion 
Criteria
X
X
Demographics and 
Medical History
X
Safety Evaluations
Full Physical 
Examinationg
X
X
X
Height
X
Weight
X
X
X
12-lead Safety ECGh
X
X
Xi
X
X
X
X
X
Vital Signs (PR and BP) j
X
X
Xi
X
X
X
X
X
Vital Signs (T)
X
X
X
X
X
X
X
Vital Signs (RR)
X
X
Hem, Serum Chem, and 
UA
X
X
Xi, k
X
X
TSH and free T4
X
Serum Pregnancy Test 
(♀only)
X
X
X
Serum FSH (♀only)
X
Serum PTH l
X
Serum Vitamin D
X
Urine Drug and Alcohol 
Screen
X
X
HIV/Hepatitis Screen
X
AE Monitoringm
X
X
X
X
ConMeds Monitoring
X
X
X
X
Study Drug 
Administration / PK/
Randomization
X
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Study Procedures
Sa
Study Days in Each Treatment Periodb
EOT
or 
ETc
FUd
Days →
-1
1
2
16 
(±2)d
32 
(±2)d
Hours →
C-Ie
-1
-0.5
-0.25
0
1
1.25
1.5
2
2.5
3
4
6
8
12
16f
24
Minutes →
5
10
20
30
45
rhPTH(1-84) 
Administrationn
X
Blood for PTH PK
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Other Procedures
Admission in the CRU
X
Discharge from the CRUp
X
Visits
X
X
X
a
Within 21 days prior to the first study drug administration.
b
For Part I (Relative Bioavailability), there will be a washout period of 96 (±1) hours between doses. For Part II (Dose Linearity), there will be a washout period
of 48 (±1) hours between doses.
c
To be performed at the end of Treatment Period 2 for Part I (Relative Bioavailability) and end of Treatment Period 4 for Part II (Dose Linearity), or prior to 
early termination from the study. Assessments scheduled for both Day 2 and EOT/ET will not be conducted twice. If clinically significant findings are observed 
upon discharge, subjects may either be kept in the CRU for observation or return to the CRU for re-evaluation per Investigator’s discretion.
d
All subjects who received a dose of study drug (including subjects who terminate from the study early) will return to the CRU 16 (±2) days (return visit) and 
32 (±2) days (follow-up visit) after the last study drug administration for collection of blood 
to determine if any AEs have occurred 
since the last study visit.
e
Subjects will be admitted to the CRU on Day -1 of Treatment Period 1, at the time indicated by the CRU. Subjects may be admitted earlier for COVID-19 
testing not related to study protocol as per CRU requirements.
f
The 16-hour postdose may be on either Day 1 or Day 2, depending on the time of dosing on Day 1.
g
Full physical examinations will be performed at scheduled time points. Symptom driven physical examinations may be performed at the Investigator’s or 
designee’s discretion.
h
12-lead ECG should be performed within ±20 minutes of the planned time points. The subject should not have exercised or consumed caffeine, alcohol, or 
nicotine within 30 minutes prior to collection. The subject must be resting in the supine position for at least 5 minutes prior to collecting the ECG
i
Assessments should be performed within ~30 minutes prior to dose administration.
j
Vital signs will be obtained after the subject is seated for at least 5 minutes. Postdose assessments should be performed within a window of ±15 minutes of the 
scheduled time point.
k
The urine collection may be the first void of the day (provided it is predose) but may be outside the 30-minute window if necessary.
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l
Parathyroid hormone at screening is for baseline eligibility use only and not for PK analysis.
m
Abnormal findings in injection site reaction assessments will be reported as AEs.
n
Subjects will fast for approximately 8 hours prior to dose administration in each treatment period for both Part I (Relative Bioavailability) and Part II (Dose 
Linearity) and continue fasting through at least 2 hours after administration of rhPTH(1-84). In each study part, treatment administration in consecutive 
treatment period (ie, Treatment Period 2 in Part I and Treatment Periods 2, 3, and 4 in Part II) will be administered at the same time of day ( ±1 hour) as 
treatment administration in Treatment Period 1.
p
Subjects will remain in the CRU until completion of the last postdose assessment on Day 2 of Treatment Period 2 (Part I [Relative Bioavailability]) or 
Treatment Period 4 (Part II [Dose Linearity]).
Abbreviations: ♀= Females, 
 AE = Adverse events, BP = Blood pressure, C-I = Check-in, Chem = Chemistry, 
ConMeds = Concomitant medication, COVID-19 = Coronavirus disease 2019, CRU = Clinical research unit, ECG = Electrocardiogram, 
EOT/ET = End-of-Treatments or early termination, FSH = Follicle-stimulating hormone, FU = Follow-up, Hem = Hematology, HIV = Human 
immunodeficiency virus,
PK = Pharmacokinetics, PR = Pulse rate, Preg = Pregnancy, PTH= Parathyroid hormone, RR = Respiratory 
rate, S = Screening, T = Temperature, T4 = Thyroxine, TSH = Thyroid stimulating hormone, UA = Urinalysis.
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4.
INTRODUCTION
4.1
Background
Parathyroid hormone (PTH) is synthesized and secreted by the parathyroid glands and is the 
principal regulator of calcium and phosphate homeostasis in humans (Brown, 1994; 
Silver and Kronenberg, 1996). Endogenous PTH is secreted in response to decreased plasma 
calcium and acts to restore normocalcemia through actions on kidney and bone, by increasing 
renal tubular reabsorption of calcium and the efflux of calcium from bone, both from the rapidly 
exchangeable calcium pool and by activating bone turnover and resorption. PTH also regulates 
the activity of the 25-hydroxyvitamin D-1α-hydroxylase enzyme, which stimulates the 
conversion of 25-hydroxyvitamin D to the active form of vitamin D, 1,25-dihydroxyvitamin D3
[1,25(OH)2D3; calcitriol] which in turn increases intestinal calcium and phosphate absorption.
In hypoparathyroidism, impaired endogenous PTH secretory capacity results in chronic 
hypocalcemia and hyperphosphatemia, hypercalciuria, low 1,25(OH)2D3 levels, decreased 
intestinal calcium absorption, and low bone turnover. Depending on its severity, chronic 
hypocalcemia can be associated with increased neuromuscular irritability, impaired cognitive 
function, mood disorders, seizures, cataracts, dry rough skin, coarse brittle hair, alopecia, and 
abnormal dentition. The low bone turnover leads to increased skeletal mineralization and high 
bone mineral density (Goltzman and Cole, 2006). Current therapies for hypoparathyroidism 
include calcium and calcitriol/1α-calcidol; the primary goal of treatment is to control symptoms 
of hypocalcemia while minimizing complications (Shoback, 2008).
Human recombinant parathyroid hormone [rhPTH(1-84)] has an identical amino acid sequence 
as the endogenous human 84-amino-acid hormone. 
rhPTH(1-84) (Natpara®) received orphan designation for the treatment of hypoparathyroidism in 
the US in 2007, followed by approval of rhPTH(1-84) (Natpara®) as an adjunct to calcium and 
vitamin D to control hypocalcemia in patients with hypoparathyroidism by the Food and Drug 
Administration (FDA) in 2015. 
rhPTH(1-84) was granted marketing authorization on 24 April 2006 in the European Union (EU) 
for the therapeutic indication, “Treatment of osteoporosis in postmenopausal women at high risk 
of fractures,” which was later retracted by the owning company for commercial reasons. Orphan 
designation for rhPTH(1-84) for the treatment of hypoparathyroidism was granted in the EU in 
2013. rhPTH(1-84) was also granted approval as an adjunctive treatment of adult patients with 
chronic hypoparathyroidism who cannot be adequately controlled with standard therapy alone, 
by the European Medicines Agency in 2017, under the commercial name Natpar®.
Clinical summary
Up to Nov 2020, 16 clinical studies were conducted in which systemic concentrations of 
PTH(1-84) were measured following administration of rhPTH(1-84). In 11 of these studies, 
serum calcium levels were measured as a PD marker. Most of the studies in healthy subjects 
were single-dose investigations. PK and PD measurements were also made after 7 days, 
12 months, and up to 18 months of daily dosing in subjects with hypoparathyroidism or 
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osteoporosis. The route of administration was SC for most studies. The site of SC administration 
was either the thigh or abdomen across all studies, but was restricted to the thigh for all studies in 
subjects with hypoparathyroidism. Four studies specifically investigated the PK/PD profiles in 
subjects with hypoparathyroidism.
Pharmacokinetics and Pharmacodynamics
The PK of PTH(1-84) following SC administration of rhPTH(1-84) in the thigh was similar in 
normal subjects, in postmenopausal women with or without osteoporosis, and in subjects with 
hypoparathyroidism. When injected in the thigh, the PK of PTH(1-84) is linear and dose 
proportional over a dose range of 50 to 100 μg and the response is reproducible across studies.
Administration to the thigh as opposed to the abdomen showed the same rapid initial increase in 
PTH concentrations, but with a lower peak level. The second peak concentration for the injection 
into the thigh was also lower than that for injection into the abdomen. Despite this longer 
duration, the amount of rhPTH(1-84) absorbed (systemic exposure) was slightly lower following
SC injection in the thigh.
In Study CL1-11-013, the mean half-life was about 1.5 hours for SC injection.
In Study CL1-11-007, plasma concentrations of PTH approached baseline levels by 12 hours 
after dosing with both SC injection into the abdomen or thigh, however, the serum calcium 
profiles were different. The PD profile of dosing in the thigh showed a more-sustained increase 
in calcium levels (return to baseline in 24 hours) as compared to the abdomen (return to baseline 
in ±16 hours) Therefore, the thigh is the preferred administration site in the treatment of patients 
with hypoparathyroidism.
Multiple SC dosing of rhPTH(1-84) in the thigh for 7 days in healthy subjects showed that the
plasma PTH(1-84) concentration-time profiles on the first and seventh day were similar. The
plasma concentration data from the long-term studies in postmenopausal osteoporotic women
and in subjects with hypoparathyroidism showed that there is no apparent change in the PK of 
PTH after up to 15 months of daily therapy.
In an open-label study, 7 subjects with hypoparathyroidism received rhPTH(1-84) 50 μg in the
thigh followed 7 days later by a 100-μg SC dose. Both doses provided a 24-hour calcemic
response. There was a dose-related increase in serum calcium levels, with maximum mean
increases (approximately 0.5 to 0.8 mg/dL) observed at 12 hours. rhPTH(1-84) administration 
resulted in a substantial decrease in serum phosphate by markedly increasing urinary phosphate 
excretion, whereas calcitriol administration had little effect on urinary phosphate and tended to 
increase serum phosphate. As a result, rhPTH(1-84) administration decreased whereas calcitriol 
increased the serum calcium-phosphate product, an important determinant of soft-tissue 
calcification. Serum 1,25(OH)2D3 increased to peak levels at 8 to 12 hours after rhPTH(1-84) 
administration.
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Safety
Completed sponsor-initiated studies for the treatment of hypoparathyroidism include 
CL1-11-040 (REPLACE), PAR-C10-007 (RELAY), PAR-C10-009 (REPEAT), PAR-C10-008 
(RACE), SHP634-101 (PARALLAX), SHP634-402, and SHP634-404. Ongoing 
sponsor-initiated studies in subjects with hypoparathyroidism include PAR-R13-001 
(PARADIGHM) and SHP-634-401.
A review of safety data across the hypoparathyroidism program to date indicated that 
rhPTH(1-84) administered in the dose range of 25 to 100 μg SC once daily (QD) is safe for use 
for the treatment of hypoparathyroidism. Very common adverse drug reactions (ie, reported in 
≥10% of subjects) include hypocalcemia, hypercalcemia, headaches, hypoesthesia, paresthesia, 
diarrhea, nausea, vomiting, arthralgia, and muscle spasms. Common adverse drug reactions 
(ie, reported in ≥1% of subjects, but <10% of subjects) include hypomagnesemia, tetany, upper 
abdominal pain, anxiety, insomnia, palpitations, cough, muscle twitching, musculoskeletal pain, 
myalgia, neck pain, pain in extremity, hypercalciuria, pollakiuria, asthenia, chest pain, fatigue, 
injection site reactions, thirst, anti-PTH antibody positive, decrease in blood 
25-hydroxycholecalciferol levels, decrease in vitamin D levels, somnolence, and hypertension.
There was no suggestion that rhPTH(1-84) causes drug-induced liver injury in humans. There 
were no renal-related AEs or abnormalities in renal function tests or urinalysis tests in clinical 
studies apart from changes expected from the mechanism of action of rhPTH(1-84). Despite 
significant increases in total serum calcium levels and improved calcium homeostasis, treatment 
with rhPTH(1-84) did not result in worsening of hypercalciuria.
Potential risks include those effects which are extensions of the pharmacologic actions of PTH
including hypercalcemia.
Refer to the Investigator’s Brochure (IB) for detailed background information on 
rhPTH(1-84) (rhPTH(I-84) Investigator’s Brochure, Edition 11, 02 November 2020).
4.2
Rationale for the Proposed Study
A new formulation of rhPTH(1-84) has been developed to reduce the occurrence of atypical 
proteinaceous particles in reconstituted drug solution. The purpose of this study is to evaluate the 
PK of the new formulation in two parts:
Part I (Relative Bioavailability) will assess the relative bioavailability of the new formulation 
(Formulation A; test) compared with the approved formulation (Formulation B; reference) of 
rhPTH(1-84) following single-dose SC administration at 100 µg.
Part II (Dose Linearity) will assess the dose-linearity of Formulation A following single SC 
administrations in the dose range of 25 µg to 200 µg rhPTH(1-84).
Utilizing the relative bioavailability of Formulation A with respect to Formulation B at the 
100 µg dose strength (Part I [Relative Bioavailability]) and the dose-exposure characteristics of 
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Formulation A, evaluated over a dose range of 25 µg to 200 µg (Part II [Dose Linearity]), will 
enable extrapolation of the relative bioavailability at different dose levels.
4.3
Benefit/Risk Profile
The initial therapeutic dose of rhPTH(1-84) is 50 µg QD, with a maximum recommended dose 
of 100 µg QD (Natpara® [parathyroid hormone], 2020). In the single ascending dose study 
PBR-930811, doses up to 5.0 µg/kg (equivalent to 350 µg for a 70 kg adult) were found safe and 
well tolerated (rhPTH(I-84) Investigator’s Brochure Edition 11, 02 November 2020). The single 
doses of rhPTH(1-84) administered in this study are well below the highest safe and well 
tolerated doses and are not expected to pose any risk to the subjects.
There will be no direct health benefit for study subjects from receipt of study drugs. An indirect 
health benefit to the healthy subjects enrolled in this study is the free medical tests received at 
screening and during the study.
The inclusion and exclusion criteria, screening, and safety monitoring practices employed by this 
protocol (ie, 12-lead ECG, vital signs, injection site reaction assessments, laboratory tests, AE 
questioning, and physical examinations) are adequate to protect the subject’s safety and should 
detect all TEAEs.
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5.
STUDY OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
Not applicable
5.2
Study Objectives
5.2.1
Study Primary Objectives
Part I (Relative Bioavailability):
To evaluate the relative bioavailability of a new formulation (Formulation A; test) compared 
with the approved formulation (Formulation B; reference) of rhPTH(1-84) following the 
administration of single SC doses of 100 µg rhPTH(1-84) in healthy subjects.
Part II (Dose Linearity):
To assess the dose linearity of the new formulation (Formulation A) of rhPTH(1-84) following 
the administration of SC doses of 25 µg, 50 µg, 75 µg, and 200 µg rhPTH(1-84) in healthy 
subjects.
5.2.2
Study Secondary Objectives
Part I (Relative Bioavailability):
To assess the safety and tolerability of SC injections of rhPTH(1-84) administered as 
Formulation A and Formulation B in healthy subjects.
Part II (Dose Linearity):
To assess the safety and tolerability of SC injections of rhPTH(1-84) administered as 
Formulation A in healthy subjects.
5.2.3
Study Exploratory Objectives
 
 
 
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5.3
Endpoints
5.3.1
Primary Endpoints
Parts I (Relative Bioavailability) and II (Dose Linearity):
The following PK parameters for baseline-adjusted plasma PTH concentrations for each 
treatment will be derived to evaluate relative bioavailability (Part I) and dose linearity (Part II):

AUClast

AUC∞

Cmax
5.3.2
Secondary Endpoints 
The following safety endpoints will be recorded for both Part I (Relative Bioavailability) and 
Part II (Dose Linearity):

Number, severity, seriousness, and causality of TEAEs

Changes in vital signs, ECGs, and laboratory results (hematology, chemistry, and urinalysis) 
from baseline.
5.3.3
Exploratory Endpoints
 
5.3.4
Additional Endpoints
Parts I (Relative Bioavailability) and II (Dose Linearity):
The following additional PK parameters will be estimated for unadjusted and baseline-adjusted 
plasma PTH concentrations for each single-dose treatment regimen:

AUC%extrap

tmax
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
tlast
The following additional PK parameters will be computed for unadjusted plasma PTH 
concentrations for each treatment:

AUClast

AUC∞

Cmax

t1/2z
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6.
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a randomized, open-label, single-center, two-part study to assess the relative
bioavailability of a single SC dose of rhPTH(1-84) administered as the new formulation
(Formulation A; test) and the approved formulation (Formulation B; reference) in Part I 
(Relative Bioavailability) of the study and to assess dose linearity of Formulation A in Part II
(Dose Linearity) of the study. Both parts may be conducted concurrently.
Part I (Relative Bioavailability)
Part I (Relative Bioavailability) will be conducted as a randomized, two-sequence, two-period,
crossover design.
Subjects in each treatment period will receive rhPTH(1-84) as a single 100 μg SC injection 
administered in the mid-thigh as either Formulation A or Formulation B depending on the 
randomized (1:1) treatment sequence as indicated in Table 6.a.
Blood samples for plasma PTH PK and serum calcium and albumin concentrations will be 
collected predose and for 24 hours following each rhPTH(1-84) administration at the time points 
delineated in the Schedule of Study Procedures (Section 3).
There will be a drug washout of 96 (±1) hours between the administration of rhPTH(1-84) in 
each period.
Table 6.a
Study Scheme for Part I (Relative Bioavailability)
Treatment Sequence
N
Treatment Period 1
Drug Washout
(Hours)
Treatment Period 2
1
42
a
96 (±1)
b
2
42
b
96 (±1)
a
The planned dose levels of rhPTH(1-84) to be evaluated are outlined in Table 6.c
Subjects will remain in the CRU until completion of the last postdose assessment on Day 2 of 
Treatment Period 2. If clinically significant findings are observed upon discharge, subjects may
either be kept in the CRU for observation or return to the CRU for re-evaluation per 
Investigator’s discretion.
 
Safety and tolerability will be assessed by TEAEs including injection site reaction assessments, 
laboratory evaluations, physical examinations, 12-lead ECGs, and vital signs.
All subjects who received a dose of study drug (including subjects who terminate from the study 
early) will return to the CRU 16 (±2) days (return visit) and 32 (±2) days (follow-up visit) after 
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the last study drug administration for collection of blood 
 to determine 
if any AEs have occurred since the last study visit.
Part II (Dose Linearity)
Part II (Dose Linearity) will be conducted as a randomized, four-sequence, four-period,
crossover design. 
Subjects in each treatment period will receive rhPTH(1-84) Formulation A as a single SC 
injection administered in the mid-thigh at a dose level depending on the randomized (1:1:1:1) 
treatment sequence as indicated in Table 6.b. If possible, the same location in the same thigh will 
be used for all treatment periods. If the same thigh cannot be used, the alternative mid-thigh may 
be used.
Blood samples for plasma PTH PK will be collected predose and for 24 hours following each 
rhPTH(1-84) administration at the time points delineated in the Schedule of Study Procedures 
(Section 3).
There will be a drug washout of 48 (±1) hours between the administration of rhPTH(1-84) in 
each period.
Table 6.b
Study Scheme for Part II (Dose Linearity)
Treatment 
Sequence
N
Treatment 
Period 1
Drug 
Washout
(Hours)
Treatment 
Period 2
Drug 
Washout
(Hours)
Treatment 
Period 3
Drug 
Washout
(Hours)
Treatment 
Period 4
1
3
c
48 (±1)
d
48 (±1)
e
48 (±1)
f
2
3
d
48 (±1)
f
48 (±1)
c
48 (±1)
e
3
3
e
48 (±1)
c
48 (±1)
f
48 (±1)
d
4
3
f
48 (±1)
e
48 (±1)
d
48 (±1)
c
The planned dose levels of rhPTH(1-84) to be evaluated are outlined in Table 6.c
Subjects will remain in the CRU until completion of the last postdose assessment on Day 2 of 
Treatment Period 4. If clinically significant findings are observed upon discharge, subjects may 
either be kept in the CRU for observation or return to the CRU for re-evaluation per 
Investigator’s discretion.
 
Safety and tolerability will be assessed by TEAEs including injection site reaction assessments, 
laboratory evaluations, physical examinations, 12-lead ECGs, and vital signs.
All subjects who received a dose of study drug (including subjects who terminate from the study 
early) will return to the CRU 16 (±2) days (return visit) and 32 (±2) days (follow-up visit) after 
the last study drug administration for collection of blood 
 to determine 
if any AEs have occurred since the last study visit.
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The planned dose levels of rhPTH(1-84) to be evaluated are outlined in Table 6.c. 
Table 6.c
Planned Dose Levels
Regimen
Formulation
Dose Level
Dose Form
Route of Administration
Part I (Relative Bioavailability)
a
Formulation A 
(test)
100 µg rhPTH(1-84)
Lyophilized powder to be 
reconstituted for SC dosing
SC injection in mid-thigh
b
Formulation B 
(Reference)
100 µg rhPTH(1-84)
Lyophilized powder to be 
reconstituted for SC dosing
SC injection in mid-thigh
Part II (Dose Linearity)
c
Formulation A 
25 µg rhPTH(1-84)
Lyophilized powder to be 
reconstituted for SC dosing
SC injection in mid-thigh
d
Formulation A 
50 µg rhPTH(1-84)
Lyophilized powder to be 
reconstituted for SC dosing
SC injection in mid-thigh
e
Formulation A 
75 µg rhPTH(1-84)
Lyophilized powder to be 
reconstituted for SC dosing
SC injection in mid-thigh
f
Formulation A 
200 µg rhPTH(1-84)
Lyophilized powder to be 
reconstituted for SC dosing
SC injection in mid-thigh
6.2
Dose Escalation
Not applicable.
6.3
Stopping Rules
Not applicable.
6.4
Rationale for Study Design, Dose, and Endpoints
6.4.1
Rationale of Study Design 
The purpose of the study is to assess the relative bioavailability of the new rhPTH(1-84) 
formulation (Formulation A) compared with the currently used formulation (Formulation B) and 
the dose linearity of the new formulation. The relative bioavailability of Formulation A with 
respect to Formulation B at the 100 µg dose strength (Part I [Relative Bioavailability]) and the 
dose-exposure characteristics of Formulation A, evaluated over a dose range of 25 µg to 200 µg 
(Part II [Dose Linearity]), will enable extrapolation of the relative bioavailability of 
Formulation A to different dose levels.
By using healthy subjects, the study will mainly focus on the difference in the exposure between 
the formulations, and limit other factors on the dose-exposure response.
Subjects will be randomized to treatment sequences to minimize assignment bias. A crossover 
design is used to reduce the residual variability as every subject acts as their own control.
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Based on previous clinical data, following SC administration to the thigh of 100 µg 
rhPTH(1-84), PTH levels return to baseline within 16-24 hours and serum calcium levels return 
to baseline levels within 24 hours. Thus, the washout period between doses is considered 
sufficient to prevent carryover effects of the preceding treatment regimen.
 
 
 
 
 
 
 
 
6.4.2
Rationale for Dose 
The recommended therapeutic dose range for rhPTH(1-84) (Natpara®) is 50 µg to 100 µg QD
(Natpara® [parathyroid hormone], 2020). In study PBR 930811, a dose off up to 5.0 µg/kg, 
equivalent to an average dose of 350 µg for a 70 kg adult subject, was found safe and well 
tolerated. Thus, the dose of 100 µg was selected for the assessment of relative bioavailability of 
the new formulation in Part I. 
A series of doses ranging from 25 µg to 200 µg rhPTH(1-84) was selected for Part II (Dose 
Linearity) to acquire a PK profile of the new formulation for a wide dose range. Based on the 
safety profile of the drug, a dose of up to 350 µg is considered safe and well tolerated for a 70 kg 
adult, providing sufficient safety margin in case of higher bioavailability of the new formulation.
6.4.3
Rationale for Endpoints
6.4.3.1
Pharmacokinetic Endpoints
The PK endpoints are standard for this type of relative bioavailability and dose linearity study.
6.4.3.2
Safety Endpoints
The key safety endpoints are typical for Phase 1 studies and will be assessed through monitoring 
of AEs, vital signs, ECGs, laboratory assessments, and physical examinations.
6.4.3.3
 
6.4.3.4
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6.4.4
Future Biomedical Research
Any residual plasma and urine samples will be stored by the Sponsor or Bioanalytical facility for 
up to 15 years, determined by the Sponsor following the last dosing. Tubes or containers will be 
identified with a barcode using an appropriate label.
No diseases/conditions, deoxyribonucleic acid, or ribonucleic acid will be the focus of these 
analyses. Samples will not be submitted to a public database. The Sponsor and contract research 
organizations involved in the clinical conduct, bioanalytical analyses, and PK and statistical 
analysis of the data will have access to the samples and/or the data that resulted from the 
analysis, if performed. 
By signing the ICF, subjects agree to the possible future analysis of these samples. At any time, 
the subjects can contact the CRU staff to request destruction of the residual samples once PK 
assessments required to meet the primary objectives of the study are completed. Any additional 
research on these samples unspecified by this protocol will require approval from the subjects.
6.4.5
Critical Procedures Based on Study Objectives: Timing of Procedures 
For this study, the critical component is the blood collection for plasma concentrations of PTH
and serum concentrations of calcium and albumin. The blood samples are to be collected as close 
to the scheduled times defined in this protocol as possible.
6.5
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
The dose and administration of the study drugs to any subject may not be modified. If necessary, 
a subject may be discontinued for the reasons described in Section 7.5.
6.6
Study Beginning and End/Completion
6.6.1
Definition of Beginning of the Study
The beginning of the study will be defined as the beginning of the screening (ie, signing of the 
ICF) of the first subject.
6.6.2
Definition of End of the Study
The end of study is defined as the date of the last scheduled study procedure as outlined in the 
Schedule of Study Procedures (Section 3)
6.6.3
Definition of Study Completion
The end of the study is scheduled after completion of the evaluations in the follow-up visit for 
the last subject in the study.
This time period may change in the event that the study is terminated early or the last subject is 
lost to follow-up. 
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6.6.4
Definition of Study Discontinuation
The study will be completed as planned unless 1 or more of the criteria indicated in Section 6.6.5
are satisfied that require temporary suspension or early termination of the study.
6.6.5
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study:

New information or other evaluation regarding the safety or efficacy of the study drug 
indicates a change in the known risk/benefit profile for the product, such that the risk is no 
longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) compromises the ability to achieve the 
primary study objectives or compromises subject safety.

A finding (eg, PK, 
) from another nonclinical or clinical study using the study treatment 
results in the study being stopped for a nonsafety-related reason.

Data from drug(s) of the same class or methodology(ies) used in this study become available 
and result in the study being stopped for a nonsafety-related reason.

The study is stopped because of nonscientific and nonsafety reasons, such as slow 
enrollment.

Unanticipated concerns of safety to the study subjects arise from this clinical study or 
additional nonclinical or clinical studies with rhPTH(1-84) or drug(s) of the same class.
6.6.6
Criteria for Premature Termination or Suspension of a Site
Not applicable.
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7.
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the 
study:
1. Healthy, adult, male or female, 18-65 years of age, inclusive, at screening. Attempts will be 
made to enroll at least 20% of each sex in each study part.
2. Continuous non-smoker who has not used nicotine containing products for at least 90 days 
prior to the first dosing and throughout the study, based on subject self-reporting.
3. BMI ≥18.5 and ≤30.0 kg/m2 at screening.
4. Medically healthy with no clinically significant medical history, physical examination, 
laboratory profiles, vital signs or ECGs, as deemed by the Investigator or designee including 
the following:

Serum calcium, PTH, phosphate, and magnesium within laboratory normal limits at 
screening and check-in.

Vitamin D (1,25(OH)2D3) levels between lower limit of normal and up to 1.5x ULN.

Seated blood pressure is ≥89/49 mmHg and ≤139/89 mmHg at screening.

Seated pulse rate is ≥40 bpm and ≤99 bpm at screening.

QTcF interval is ≤450 msec (males) or ≤470 msec (females) or ECG findings considered 
normal or not clinically significant by the Investigator or designee at screening.

Estimated creatinine clearance ≥80 mL/minute at screening.
5. Agrees to comply with any applicable contraceptive requirements of the protocol as detailed 
in Appendix D.
6. Understands the study procedures in the ICF, be able to voluntarily provide written, signed, 
and dated informed consent, and be willing and able to comply with the protocol.
7.2
Exclusion Criteria
Subjects must not be enrolled in the study if they meet any of the following criteria:
1. Is mentally or legally incapacitated or has significant emotional problems at the time of the 
screening visit or expected during the conduct of the study in the opinion of the Investigator 
or designee.
2. History or presence of clinically significant medical or psychiatric condition or disease in the 
opinion of the Investigator or designee.
3. History of any hematological, hepatic, respiratory, cardiovascular, renal, neurological or 
psychiatric disease, gall bladder removal, or current or recurrent disease that could affect the 
action, absorption, or disposition of the study drug, or clinical or laboratory assessments.
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4. Subjects who are at increased baseline risk for osteosarcoma such as subjects with Paget’s 
disease of bone or unexplained elevations of ALP, hereditary disorders predisposing to 
osteosarcoma or a prior history of external beam or implant radiation therapy involving the 
skeleton.
5. History of any illness that, in the opinion of the Investigator or designee, might confound the 
results of the study or poses an additional risk to the subject by their participation in the 
study.
6. History or presence of alcoholism or drug abuse, in the opinion of the Investigator or 
designee, within the past 2 years prior to the first dosing.
7. Male subjects who consume more than 21 units of alcohol per week or 3 units per day. 
Female subjects who consume more than 14 units of alcohol per week or 2 units per day. 
(1 alcohol unit=1 beer or 1 wine (5 oz/150 mL) or 1 liquor (1.5 oz/40 mL) or 0.75 oz 
alcohol).
8. Positive urine drug or alcohol results at screening or check-in.
9. History or presence of hypersensitivity or idiosyncratic reaction to the study drug or related 
compounds.
10. History of abnormalities of calcium homeostasis including hyperparathyroidism, 
hypoparathyroidism, hyperthyroidism, Cushing’s syndrome, hypercalcemia, hypocalcemia, 
osteoporosis, or any other calcium disorder.
11. Female subjects with a positive pregnancy test or who are lactating.
12. Positive results at screening for HIV, HBsAg, or HCV.
13. Has tattoo(s) or scarring at or near the site of injection or any other condition which may 
interfere with injection site examination, in the opinion of the Investigator or designee.
14. Routine consumption of more than 2 units of caffeine per day or subjects who experience 
caffeine withdrawal headaches. A unit of caffeine is contained in the following items: 
one 6 oz (180 mL) cup of coffee, two 12 oz (360 mL) cans of cola, one 12 oz cup of tea, 
three 1 oz (85 g) chocolate bars.
15. Prior screen failure, randomization, participation, or enrollment in this study or prior 
exposure to any exogenous PTH, PTH fragments or analogs 3 months prior to dosing with 
rhPTH(1-84).
16. Unable to refrain from or anticipates the use of any medication or substance (including 
prescription or over-the-counter, vitamin supplements, natural or herbal supplements) as 
indicated in Section 7.3 (Excluded Medication, Supplements, and Dietary Products) for the 
prohibited time period.
17. Has been on a diet incompatible with the study diet or had any substantial changes in eating 
habits, in the opinion of the Investigator or designee, within the 30 days prior to the first 
dosing and throughout the study.
18. Donation of blood or significant blood loss within 60 days prior to the first dosing.
19. Plasma donation within 7 days prior to the first dosing.
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20. Participation in another clinical study within 30 days or 5 half-lives prior to the first dosing. 
The 30-day window or 5 half-lives will be derived from the date of the last blood collection 
or dosing, whichever is later, in the previous study to Day 1 of Treatment Period 1 of the 
current study.
7.3
Excluded Medications, Supplements, and Dietary Products 
Concomitant medications will be prohibited as follows:
Any drug, including prescription and or over-the-counter, vitamin supplements, natural or 
herbal supplements within 14 days prior to the first dosing and throughout the study. 
Medication listed as part of acceptable birth control methods will be allowed (refer to 
Appendix D). After randomization, acetaminophen (up to 2 g per 24 hours), calcium 
gluconate and other medication for the treatment of AEs, may be administered at the 
discretion of the Investigator or designee.
Thiazide diuretics within 14 days prior to the first dosing and throughout the study.
Loop diuretics, lithium, antacids, systemic corticosteroids within 30 days prior to the first 
dosing and throughout the study (medical judgment is required by the Investigator). 
Primarily, high doses of systemic corticosteroids [eg, prednisone] and/or stable doses of 
hydrocortisone [eg, as treatment for Addison’s disease] may be acceptable at the 
Investigator’s or designee’s discretion.
Calcitonin, cinacalcet hydrochloride, treatment with rhPTH(1-84) or N-terminal PTH or 
PTH-related peptide fragments or analogs within 3 months prior to the first dosing and 
throughout the study.
For females: changes in hormone replacement therapy within 3 months prior to the first 
dosing and throughout the study are excluded. Stable (≥3 months) hormone replacement 
therapy is acceptable.
Fluoride tablets, oral bisphosphonates, methotrexate, growth hormone, digoxin, raloxifene or 
similar selective estrogen receptor modulators within 6 month prior to the first dosing and 
throughout the study.
Intravenous bisphosphonates within 12 month prior to the first dosing and throughout the 
study.
If deviations occur, the Investigator or designee in consultation with the Sponsor if needed will 
decide on a case by case basis whether the subject may continue participation in the study.
All medications taken by subjects during the course of the study will be recorded.
Use of excluded agents (prescription or non-prescription) or dietary products is outlined in
Table 7.a.
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Table 7.a
Study Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and First Dosing 
(Days -21 to predose [Day 1 of 
Treatment Period 1])
After First Dosing (Day 1 of 
Treatment Period 1) to Follow-Up
Alcohol
Prohibited from 48 hours prior to first 
dosing
Prohibited from first dosing until the end
of PK collection in the last study period.
Xanthine and/or caffeine
Prohibited from 24 hours prior to first 
dosinga
Prohibited from first dosing until the end 
of PK collection in the last study period.a
Medications
See Section 7.3
Prohibited from first dosing throughout 
the study.
Nicotine- and tobacco-
containing and/or 
cannabis products
Prohibited from 90 days prior to first 
dosing
Prohibited from first dosing until the end 
of PK collection in the last study period.
(a) small amounts of caffeine derived from normal foodstuffs eg, 250 mL/8 oz/1 cup decaffeinated coffee or other 
decaffeinated beverage, per day, with the exception of espresso; 45 g/1.5 oz chocolate bar, per day, would not be 
considered a deviation to this restriction.
7.4
Diet, Fluid, Activity
7.4.1
Diet and Fluid
Water will be allowed ad libitum. Other fluids may be given as part of meals and snacks but will 
be restricted at all other times throughout the confinement period.
Subjects will fast overnight for at least 8 hours prior to each dosing. On Day 1 of each period, 
subjects will continue the fast for at least 2 hours postdose.
When confined, standard meals and snacks will be provided at appropriate times, except when 
they are required to fast. When confined in the CRU, subjects will be required to fast from all 
food and drink except water between meals and snacks.
Each meal and/or snack served at the CRU will be standardized, will be similar in caloric content
and composition, and will be taken at approximately the same time in each period.
7.4.2
Activity
Subjects will remain ambulatory or seated upright for the first 4 hours postdose, except when 
they are supine or semi reclined for study procedures. However, should AEs occur at any time, 
subjects may be placed in an appropriate position or will be permitted to lie down on their right 
side.
Subjects will be instructed to refrain from strenuous physical activity which could cause muscle 
aches or injury, including contact sports at any time from screening until completion of the 
study.
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7.5
Criteria for Discontinuation or Withdrawal of a Subject
1. Pretreatment event (PTE) or AE: The subject has experienced a PTE or AE that requires 
early termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the PTE or AE.

Liver Function Test (LFT) Abnormalities
Study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.2.9.1), if the following circumstances occur at any 
time during study drug treatment:
-
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5x ULN, or
-
ALT or AST >3x ULN in conjunction with elevated bilirubin >2x ULN or 
international normalized ratio (INR) >1.5x ULN, or
-
ALT or AST >3x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%), or
-
ALT >3x ULN twice consecutively at least 24 to 48 hours apart.
2. Significant protocol deviation: The discovery post-randomization that the subject failed to 
meet protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health.
3. Lost to follow-up: Attempts to contact the subject were unsuccessful. Attempts to contact the 
subject must be documented in the subject’s source documents.
4. Voluntary withdrawal: The subject wishes to withdraw from the study. The reason for 
withdrawal, if provided, should be recorded in the case report form (CRF).
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (ie, withdrawal due to 
an AE should not be recorded in the “voluntary withdrawal” category). If a subject chooses 
to withdraw from study participation due to personal concerns related to the COVID-19 
pandemic (other than a COVID-19-related AE), this should be specified as the reason for 
subject withdrawal in the CRF.
5. Study termination: The Sponsor, Institutional Review Board (IRB)/ Independent Ethics 
Committee (IEC), or regulatory agency terminates the study.
6. Pregnancy: as described in Appendix D.
7. Subjects may be withdrawn from the study by the Investigator or designee for the following 
reasons:
-
Positive drug or alcohol screen results.
-
Difficulties in blood collection
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-
Other. The specific reasons for discontinuation should be entered into the CRF including 
unavoidable circumstances such as the COVID-19 pandemic. Subjects may be withdrawn 
from the study at any time at the discretion of the Investigator or Sponsor for safety 
reasons which should be entered into the CRF.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The Investigator may discontinue a subject’s study participation at any time during the study 
when the subject meets the study termination criteria described in Section 7.5. In addition, a 
subject may discontinue his or her participation without giving a reason at any time during the 
study. Should a subject’s participation be discontinued, the primary criterion for termination 
must be recorded by the Investigator. In addition, efforts should be made to perform all 
procedures scheduled for the end-of-treatments or early termination as described in Section 3.
7.7
Subject Replacement
Replacement of discontinued or withdrawn subjects due to any reason will be assessed on a case 
by case basis by the Sponsor and Investigator to ensure a minimum of 76 PK-evaluable subjects 
complete Part I (Relative Bioavailability) of the study, and a minimum of 8 PK-evaluable 
subjects complete Part II (Dose Linearity) of the study.
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8.
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug 
Product Name: rhPTH[1-84]
Strengths:
25 µg, 50 µg, 75 µg, 100 µg 
The 200 µg dose will be achieved using two consecutive injections of the 100 µg
Dosage Form/Formulation: Lyophilized powder to be reconstituted for SC dosing.
Dosing regimen: Single dose
Route of Administration: SC injection in mid-thigh
Investigational product will be supplied as: multiple-dose, dual-chamber glass cartridges 
containing a sterile lyophilized powder and a diluent for reconstitution at a dose of either 25 µg, 
50 µg, 75 µg, or 100 µg using the marketed mixing device. A commercially marketed injector 
pen will be used for SC dosing. A sterile, disposable pen needle will be used for each 
administration. Each individual injector pen will be used for only one subject.
8.1.1
Clinical Study Drug Labeling
Study drug containers will be affixed with a clinical label in accordance with local regulatory 
requirements.
8.1.2
Clinical Study Drug Inventory and Storage
The same lot number will be used throughout the study. The lot numbers and expiration dates 
(where available) of the study drugs supplied will be recorded in the final report. Study drugs 
will be stored according to the product labels provided with the product.
Records will be made of the receipt, preparation, dispensing, and final disposition of the study 
drugs supplied.
8.1.3
Clinical Study Drug Blinding
This is an open-label study. 
8.1.4
Randomization Code Creation and Storage 
A computerized randomization scheme will be created by a Celerion statistician according the 
treatment sequences indicated in Table 6.a (Part I [Relative Bioavailability]) and Table 6.b
(Part II [Dose Linearity]).
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure
Not applicable.
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8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs
Records will be made of the receipt and dispensing of the study drugs supplied. At the 
conclusion of the study, any unused rhPTH(1-84) will be retained by Celerion, returned to the 
Sponsor or designee, or destroyed, as per Sponsor instructions. If no supplies remain, this fact 
will be documented in the pharmacy product accountability records.
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9.
STUDY PROCEDURES
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign, and date 
an ICF summarizing the discussion prior to screening, and will be assured that they may 
withdraw from the study at any time without jeopardizing their medical care.
Subjects will be given a copy of their signed ICF.
9.1.1.1
Assignment of Screening and Randomization Numbers 
Each subject will be assigned a unique identification number upon screening. Subjects who 
complete the study screening assessments and meet all the eligibility criteria will be assigned a 
unique identification number at the time of dosing, different from the screening number.
Subjects in each study part will be randomized to treatment sequence according to Table 6.a
(Part I [Relative Bioavailability]) and Table 6.b (Part II [Dose Linearity]).
If replacement subjects are used, the replacement subject number will be 100 more than the 
original (eg, Subject No. 101 will replace Subject No. 1).
9.1.1.2
Study Drug Assignment
All subjects will receive the treatments as detailed in Section 9.2.6.
9.1.2
Inclusion and Exclusion 
Please refer to Section 7.1 and Section 7.2.
9.1.3
Medical History/Demography
Medical history and demographic data, including name, sex, age, race, ethnicity, and history of 
tobacco use will be recorded.
9.1.4
Concomitant Medications
Concomitant medications will be prohibited as listed in Section 7.3. All medications taken by 
subjects during the course of the study will be recorded.
9.2
Clinical Procedures and Assessments
The Schedule of Study Procedures (Section 3) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the Investigator or designee and/or the Sponsor 
for reasons related to subject safety.
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For this study, collection of blood for plasma concentrations of PTH and serum concentrations of 
calcium and albumin is the critical parameter. Blood samples need to be collected as close to the 
exact time point as possible. All other procedures should be completed as close to the 
prescribed/scheduled time as possible, but can be performed prior to or after the 
prescribed/scheduled time.  
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures.
9.2.1
Full Physical Exam
Full physical examinations will be performed as outlined in the Schedule of Study Procedures 
(Section 3). Symptom-driven physical examinations may be performed at other times, if deemed 
necessary by the Investigator or designee.
9.2.2
Height and Weight
Body height (cm) and weight (kg) will be reported as outlined in the Schedule of Study 
Procedures (Section 3).
9.2.3
BMI
BMI (kg/m2) will be calculated based on the height and weight measured at screening.
9.2.4
Vital Signs
Single measurements of temperature, respiratory rate, blood pressure, and pulse rate will be 
measured as outlined in the Schedule of Study Procedures (Section 3). Additional vital signs may 
be taken at any other times, if deemed necessary.
Blood pressure and pulse rate measurements will be performed with subjects in a seated position, 
except when they are supine or semi-reclined because of study procedures and/or AEs 
(eg, nausea, dizziness) or if deemed necessary by the Investigator or designee.
Blood pressure and pulse rate will be measured within approximately 30 minutes prior to Day 1 
dosing of each period for the predose time point. When scheduled postdose, vital signs will be 
performed within approximately 15 minutes of the scheduled time point. 
9.2.5
12-Lead ECG
Single 12-lead ECGs will be performed as outlined in the Schedule of Study Procedures 
(Section 3). Additional ECGs may be taken at any other times, if deemed necessary by the
Investigator or designee.
ECGs will be performed with subjects in a supine position. All ECG tracings will be reviewed by 
the Investigator or designee.
ECGs will be measured within approximately 30 minutes prior to Day 1 dosing of each period 
for the predose time point. When scheduled postdose, ECGs will be performed within 
approximately 20 minutes of the scheduled time point.
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9.2.6
Injection Site Evaluation
In monitoring AEs, special attention will be paid to potential injection site reactions (ie, local 
tolerability). Any abnormal findings will be reported as AEs. 
9.2.7
Study Drug Administration
rhPTH(1-84) formulations will be provided as described in Section 8.1.
Treatments will be administered as described in Table 6.c.
The pharmacy at the CRU will provide each dose in individual injector pen with a sterile, 
disposable pen needle. Each individual injector pen will be used for only one subject. To 
administer a 200 µg dose of Formulation A, two consecutive injections of the 100 µg strength of 
Formulation A will be administered using the same injector pen and disposable needle for each 
injection to the same subject. The consecutive injections must be administered as soon as 
possible, within no more than 5 minutes of each other, one in each thigh.
In Part I (Relative Bioavailability), the same location in the same thigh will be used for both 
treatment periods, if possible. In Part II (Dose Linearity), alternate thighs may be used in 
successive treatment periods.
All injections will be administered by a qualified designee, eg, a nurse. In the case of an 
incomplete dosing (eg, droplet(s) of study medication on the surface of the skin) as deemed by 
the Investigator and Sponsor or Sponsor’s designee, the subject may be withdrawn.
Additional information regarding drug preparation and administration may be provided in a 
separate pharmacy manual.
The exact clock time of dosing will be recorded.
For Treatments a and b (Part I [Relative Bioavailability]), and Treatments c, d, and e (Part II 
[Dose Linearity]), Hour 0 will be define as the time of injection. For Treatment f (Part II [Dose 
Linearity]), Hour 0 will be define as the time of the second injection.
In each study part, treatment administration in consecutive treatment period 
(ie, Treatment Period 2 in Part I and Treatment Periods 2, 3, and 4 in Part II) will be 
administered time of day (±1 hour) as treatment administration in Treatment Period 1.
9.2.8
AE Monitoring
Subjects will be monitored throughout the study for adverse reactions to the study drugs and/or 
procedures as described in Section 10.
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9.2.9
Laboratory Procedures and Assessments
All tests listed below will be performed as outlined in the Schedule of Study Procedures 
(Section 3). In addition, laboratory safety tests may be performed at various unscheduled time 
points, if deemed necessary by the Investigator or designee.
9.2.9.1
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Hemoglobin
Red blood cell count
Hematocrit 
Platelet count
Total and differential leukocyte count
Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of 
dropouts or rechecks, subjects may not have fasted for 8 hours prior to when the serum chemistry 
sample being taken.
Chemistry evaluations will consist of the following standard chemistry panel:
Amylase
Albumin
Lipase
Potassium
Blood Urea Nitrogen
Chloride
Bilirubin (total and direct)
Glucose 
Alkaline phosphatase (ALP)
Creatinine *
Aspartate aminotransferase (AST)
Magnesium
Alanine aminotransferase (ALT)
Sodium
Calcium
Phosphate
* At screening, creatinine clearance will be calculated using the Cockcroft-Gault formula.
Urinalysis
Urinalysis will consist of the following tests:
pH
Bilirubin
Specific gravity
Blood *
Protein *
Nitrite *
Glucose
Urobilinogen
Ketones
Leukocyte esterase *
* If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for red 
blood cells, white blood cells, bacteria, casts, and epithelial cells) will be performed.
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Other
HIV test
Urine drug screen
-
Opiates (includes morphine, heroin 
(diacetylmorphine), codeine, 6-acetylmorphine, 
dihydrocodeine, hydrocodone, thebaine, and, 
hydromorphone)
-
Amphetamines
-
Barbiturates
-
Benzodiazepines
-
Cocaine
-
Cannabinoids
HBsAg
HCV (if antibody positive, confirm RNA negative)
Urine alcohol screen
Serum pregnancy test (for females only)
FSH (for females only)
Urine cotinine
Vitamin D
PTH
COVID-19 testing (performed according to CRU 
standard procedures, provided in a separate 
document[s])
Thyroid stimulating hormone (TSH)
Free thyroxine (T4)
9.3
Pharmacokinetics,
Instructions for sample collection, processing, and shipping will be provided in a separate 
laboratory manual.
Primary specimen collection parameters are provided in Table 9.a.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of Intended Use
Sample 
Collection
Plasma sample for PK
Blood
Plasma
Plasma sample for PK analysis
Mandatory
9.3.1
PK Measurements 
Samples from all subjects will be assayed even if the subjects do not complete the study. 
Samples for determination of plasma PTH, will be analyzed using validated bioanalytical 
methods.
Pharmacokinetic parameters of PTH will be calculated from the individual concentration-time 
profiles from all evaluable subjects using noncompartmental analysis methods. Actual sampling 
times, rather than scheduled sampling times, will be used in all computations involving sampling 
times. 
9.3.1.1
Plasma for PK Measurements
The following PK parameters will be calculated from unadjusted and baseline-adjusted plasma 
concentrations of PTH, unless otherwise specified:
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AUClast:
The area under the concentration-time curve, from time 0 to the last 
quantifiable concentration, as calculated by the linear-log trapezoidal 
method.
AUC∞:
The area under the concentration-time curve, from time 0 extrapolated to 
infinity. AUCis calculated as AUClast plus the ratio of the last 
measurable blood concentration to the elimination rate constant.
AUCextrap%:
The area under the curve from the last quantifiable concentration to 
infinity, expressed as a percentage of AUC
Cmax:
Maximum observed concentration.
tlast:
Time of the last measurable concentration.
tmax:
Time to reach Cmax. If the maximum value occurs at more than one time 
point, tmax is defined as the first time point with this value.
t½z:
Terminal disposition phase half-life will be calculated as 0.693/λz, where
λz is the apparent first order terminal disposition phase rate constant 
calculated from a semilog plot of the plasma concentration versus time 
curve. The parameter will be calculated by linear least-squares-regression 
analysis using the maximum number of points in the terminal log-linear 
phase (eg, three or more non-zero plasma concentrations).
No value for AUC∞, AUCextrap%, or t½z will be reported for cases that do not exhibit a terminal 
log-linear phase in the concentration versus time profile.
No PK parameters will be calculated for subjects with detectable concentrations at 2 or fewer 
consecutive time points. 
Individual and mean plasma concentration-curves (both linear and log-linear) will be included in 
the final report. 
Additional PK parameters may be estimated as appropriate.
9.3.2
 
 
 
 
 
9.3.2.1
 
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9.3.3
 
 
 
9.3.4
Biomarker Measurements 
Not applicable.
9.3.5
PGx Measurements 
Not applicable.
9.3.6
Confinement
Subjects will be housed on Day -1 of Treatment Period 1, at the time indicated by the CRU, until 
after the 24-hour blood draw and/or study procedures in Treatment Period 2 (Part I [Relative 
Bioavailability]) or Treatment Period 4 (Part II [Dose Linearity]). Subjects may be admitted 
earlier for COVID-19 testing not related to study protocol as per CRU requirements.
At all times, a subject may be required to remain at the CRU for longer at the discretion of the 
Investigator or designee.
All subjects who received a dose of study drug (including subjects who terminate from the study 
early) will return to the CRU 16 (±2) days (return visit) and 32 (±2) days (follow-up visit) after 
the last study drug administration for collection of blood
to determine 
if any AEs have occurred since the last study visit.
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10.
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, 
whether or not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant 
medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. 
In addition, repeated or additional noninvasive testing for verification, evaluation or 
monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is 
an overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
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Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, X-ray, etc) should NOT be recorded as an AE unless 
related to a study procedure. However, if the subject experiences a worsening or 
complication of such a concurrent medical history condition, the worsening or complication 
should be recorded appropriately as an AE (worsening or complication occurs after informed 
consent is signed). Investigators should ensure that the event term recorded captures the 
change in the condition (eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change from Baseline in the condition (eg, “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent 
to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of an AE after the first administration 
of study medication or after any change in study medication, the worsening or complication 
should be recorded as a new AE. Investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a 
change in study medication, the event should be captured once with the maximum severity 
recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening 
of the condition should be captured appropriately as an AE. Complications resulting from 
any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
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Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. It is up to the investigator or the reporting physician to 
decide whether a dose is to be considered an overdose, in consultation with the Sponsor.

All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the (e)CRF, in order to capture this important safety information consistently in the 
database. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.

Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.8.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).

Considered an IMPORTANT MEDICAL EVENT in the opinion of the investigator or 
designee.
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Table 10.a
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory 
distress syndrome
Hepatic necrosis
Acute liver failure
Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent 
by a medicinal product
Toxic epidermal necrolysis/
Stevens-Johnson syndrome
COVID-19 pneumonia
Neuroleptic malignant syndrome / malignant 
hyperthermia
COVID-19-related disease
Spontaneous abortion / stillbirth and fetal death
AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Section 10.1 and Section 10.1.1).
10.1.2
Special Interest AEs
The special interest AEs will include hyper- and hypocalcemia as determined by the investigator 
or designee.
10.2
AE Procedures
10.2.1
Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
An AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the 
research participant.
Severe:
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
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10.2.2
Assigning Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a 
drug (including the course after withdrawal of the drug), or for which a 
causal relationship is at least a reasonable possibility, ie, the relationship 
cannot be ruled out, although factors other than the drug, such as underlying 
diseases, complications, concomitant drugs and concurrent treatments, may 
also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from 
administration of a drug and/or that can reasonably be explained by other 
factors, such as underlying diseases, complications, concomitant 
medications, and concurrent treatments.
10.2.3
Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
10.2.4
End Date 
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.2.5
Pattern of Adverse Event (Frequency) 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days 
are intermittent. All other events are continuous.
10.2.6
Action Taken With Study Treatment

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study medication was stopped for a reason other than the particular AE 
eg, the study has been terminated, the subject died, dosing with study medication had not yet 
started or dosing with study medication was already stopped before the onset of the AE.

Dose reduced – the dose was reduced due to the particular AE.

Dose increased – the dose was increased due to the particular AE.

Drug interrupted – the dose was interrupted due to the particular AE.
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10.2.7
Outcome 

Recovered/resolved – subject returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the subject died from a cause other 
than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; 
the subject died from another cause with the particular AE state remaining “Not 
recovered/not resolved.”

Recovered/ Resolved with sequelae – the subject recovered from an acute AE but was left 
with permanent/significant impairment (eg, recovered from a cardiovascular accident but 
with some persisting paresis).

Fatal – an AE that is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2.8
Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs
10.2.8.1
Collection Period
Collection of AEs (ie, AEs, SAEs, Special Interest AEs, and Abnormal LFTs) will commence at 
the time the subject signs the informed consent. Routine collection of AEs will continue until the 
follow-up visit 32 (±2) days after the last dose of study drug. For subjects who discontinue prior 
to the administration of study medication, AEs will be followed until the subject discontinues 
study participation. 
10.2.8.2
Reporting AEs
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing an 
SAE prior to the first exposure to investigational product must be monitored until the symptoms 
subside and any clinically relevant changes in laboratory values have returned to Baseline or 
there is a satisfactory explanation for the change. Nonserious AEs that begin prior to the first 
exposure to investigational product, related or unrelated to the study procedure, need not be 
followed-up for the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to Baseline or until there is a satisfactory explanation 
for the changes observed. All AEs will be documented in the AE page of the CRF, whether or 
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not the investigator concludes that the event is related to the drug treatment. The following 
information will be documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/Intensity.

Causality (Investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]).

Action taken with study drug.

Outcome of event.

Seriousness.
10.2.8.3
Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below:
A Takeda SAE form must be completed, in English and signed by the investigator immediately 
or within 24 hours of first onset or notification of the event. The information should be 
completed as fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours using the fax number or email address to 
the attention of the contact listed in Section 14.1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the Sponsor if considered related to study participation.
Reporting of SAEs that begin before first administration of investigational product will follow 
the same procedure for SAEs occurring on treatment.
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SAE Follow-Up
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax or email it immediately within 24 hours of receipt. Copies of any relevant data from the 
hospital notes (eg, ECGs, laboratory tests, discharge summary, postmortem results) should be 
sent to the addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report.
10.2.8.4
Reporting Special Interest AEs 
When a special interest AE occurs through the AE collection period it should be reported within 
24 hours using the fax number or email address to the attention of the contact listed in 
Section 14.1.1.
10.2.8.5
Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases CRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.8.3. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease. Follow-up laboratory tests as described in Section 9.2.9.1 must also be 
performed. In addition, an LFT Increases CRF must be completed and transmitted with the 
Takeda SAE form (as per Section 10.2.9). 
10.2.9
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The Sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the Sponsor or 
Sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening 
events and 15 days for other serious events, unless otherwise required by national regulations. 
The Sponsor will also prepare an expedited report for other safety issues where these might 
materially alter the current benefit-risk assessment of an investigational medicinal product or that 
would be sufficient to consider changes in the investigational medicinal products administration 
or in the overall conduct of the study. The investigational site also will forward a copy of all 
expedited reports to his or her IRB or IEC in accordance with national regulations.
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11.
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a statistical analysis plan (SAP). The SAP will be prepared by Celerion and 
agreed upon with the Sponsor. This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoints definition and/or its analysis will 
also be reflected in a protocol amendment. Additional statistical analyses other than those 
described in this section may be performed if deemed appropriate.
11.1.1
Analysis Sets
11.1.1.1
PK Set
All subjects who have at least one measurable predose (baseline) and one postdose concentration 
of PTH will be included in the statistical analyses.
11.1.1.2
Safety Set
All subjects who received at least one dose of the study drug will be included in the safety 
evaluations.
11.1.1.3
 
11.1.1.4
 
11.1.2
Analysis of Demography and Other Baseline Characteristics
Continuous demographic data (ie, age, weight, height, and BMI) will be listed and summarized 
using appropriate summary statistics. Categorical demographic data (ie, gender, race, and 
ethnicity) will also be listed and tabulated.
11.1.3
PK Analysis
Statistical analysis of PK data will be based on the PK analysis data set. 
Values will be reported for the unadjusted and baseline-adjusted PTH concentrations for each 
subject. Concentrations will be summarized by scheduled time points for PTH. PK parameters 
for the plasma concentrations will be calculated for each subject as described in Section 9.3.1.1. 
PK parameters for each subject will be listed and summarized by treatment using descriptive 
statistics.
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11.1.3.1
Relative Bioavailability (Part I [Relative Bioavailability])
Analysis of Variance
A linear mixed-effects model will be used for the analysis on the ln-transformed AUClast, AUC,
and Cmax for PTH. The model will include sequence, treatment, and period as fixed effects and 
subject nested within sequence as a random effect. The analysis will include calculation of LSMs 
as well as the difference between treatment regimen LSMs.
Ratios and Confidence Intervals
GMR and 90% CI, consistent with the two one-sided test (Schuirmann, 1987), will be calculated 
using the exponentiation of the difference between treatment regimen LSMs from the analyses 
on the ln-transformed AUC, AUClast, and Cmax for PTH. These ratios will be expressed as a 
percentage relative to the appropriate reference formulation or treatment regimen. 
11.1.3.2
Dose Linearity (Part II [Dose Linearity])
Apparent dose linearity of PK parameters (selected baseline-adjusted AUC and Cmax parameters) 
will be assessed graphically.
11.1.3.3
Non-Parametric Analysis
The PK parameter tmax will be analyzed using an appropriate nonparametric analysis; tmax will 
not be ln-transformed. 
11.1.4
 
 
 
 
11.1.5
 
11.1.6
Safety Analysis
All safety data will be populated in the individual CRFs.
Dosing dates and times will be listed by subject.
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Statistical analysis of safety data will be based on the safety analysis data set. 
TEAEs will be tabulated. The remaining quantitative safety data as well as the difference to 
baseline, when appropriate, will be summarized using the appropriate descriptive statistics.
11.1.6.1
AEs
AEs will be coded using the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA®) available at Celerion and summarized by treatment for the number of 
subjects reporting the TEAE and the number of TEAEs reported. A by-subject AE data listing 
including verbatim term, coded term, treatment, severity, and relationship to treatment will be 
provided.
11.1.6.2
Clinical Laboratory Evaluation
Clinical laboratory results will be summarized by treatment and point of time of collection and a 
shift table describing out of normal range shifts will be provided.
11.1.6.3
Vital Signs
Vital signs assessments will be summarized by treatment and point of time of collection.
11.1.6.4
Other Safety Parameters
Physical examination findings will be presented in the data listings.
ECGs will be summarized by treatment and point of time of collection.
Medical history, and concurrent conditions will be coded using the MedDRA® and concomitant 
medications will be coded using the World Health Organization (WHO) drug dictionary and will 
be listed by subject.
11.2
Interim Analysis and Criteria for Early Termination
In Part I (Relative Bioavailability), an interim PK analysis will be conducted following 
completion of Treatment Period 2 for approximately 25 subjects. Full details will be described in 
the SAP.
The interim analyses will be conducted for informational purposes only and to provide 
preliminary study results. No changes to the design or conduct will be made as a result of interim 
analysis.
11.3
Determination of Sample Size
Part I (Relative Bioavailability):
The sample size of 76 subjects was calculated to achieve 90% CI around the geometric mean 
ratio of the test and reference formulations within the limits of 0.80 to 1.25 for AUC and Cmax. 
The true test to reference ratio was assumed to be 0.93, and 90% target power was used for the 
sample size determination. The ISCV was assumed to be 32.2%, the upper end of the two-sided 
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50% confidence limit of the ISCV for Cmax estimated in study SHP634-103 (the ISCV observed 
in study SHP634-103 was higher for Cmax than for AUC). Part I (Relative Bioavailability) will 
enroll 84 subjects to allow for up to eight dropouts.
Part II (Dose Linearity):
The sample size for Part II (Dose Linearity) is not based on any statistical considerations but is 
considered sufficient for dose linearity evaluation.
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12.
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the CRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the Sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the Sponsor or the 
Sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study drug, subject medical records, informed consent documentation, and 
review of CRFs and associated source documents. It is important that the investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to 
the process.
12.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria.
For COVID-19-related protocol deviations, the specific protocol deviation, the reason for the 
deviation, and the relationship to COVID-19 should be documented using CRU standard 
processes. 
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment. 
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the Sponsor or designees. In 
this circumstance, the Sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the FDA, the United Kingdom Medicines and 
Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of 
Japan). If the study site is contacted for an inspection by a regulatory body, the Sponsor should 
be notified immediately. The Investigator guarantees access for quality assurance auditors to all 
study documents as described in Section 12.1.
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13.
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the International Council on Harmonisation (ICH) Harmonised Tripartite 
Guideline for GCP. Each investigator will conduct the study according to applicable local or 
regional regulatory requirements and align his or her conduct in accordance with the 
“Responsibilities of the Investigator” that are listed in Appendix A. The principles of Helsinki 
are addressed through the protocol and through appendices containing requirements for informed 
consent and investigator responsibilities.
13.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local 
requirements of each participating region. The Sponsor or designee will require documentation 
noting all names and titles of members who make up the respective IRB or IEC. If any member 
of the IRB or IEC has direct participation in this study, written notification regarding his or her 
abstinence from voting must also be obtained. Those Americas sites unwilling to provide names 
and titles of all members due to privacy and conflict of interest concerns should instead provide a 
Federal Wide Assurance Number or comparable number assigned by the Department of Health 
and Human Services.
The Sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the ICF, and, if applicable, subject recruitment materials and/or advertisements and other 
documents required by all applicable laws and regulations, must be submitted to a central or 
local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and subject 
informed consent must be obtained and submitted to the Sponsor or designee before 
commencement of the study (ie, before shipment of the Sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, ICF) reviewed; and state the 
approval date. The Sponsor will ship drug/notify site once the Sponsor has confirmed the 
adequacy of site regulatory documentation and, when applicable, the Sponsor has received 
permission from competent authority to begin the study. Until the site receives drug/notification 
no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by subjects, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the Sponsor or its 
designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and Sponsor.
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13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, subject authorization form (if applicable), and subject 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF and the subject information sheet (if applicable) further explain the nature of 
the study, its objectives, and potential risks and benefits, as well as the date informed consent is 
given. The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF
and, if applicable, the subject authorization form. The ICF, subject authorization form (if 
applicable), and subject information sheet (if applicable) must be approved by both the IRB or 
IEC and the Sponsor prior to use.
The ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, subject 
authorization form (if applicable), and subject information sheet (if applicable) to the subject. 
Information should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject must be given ample opportunity to: (1) inquire about details of the study, and 
(2) decide whether or not to participate in the study. If the subject determines he or she will 
participate in the study, then the ICF and subject authorization form (if applicable) must be 
signed and dated by the subject at the time of consent and prior to the subject entering into the 
study. The subject should be instructed to sign using their legal names, not nicknames, using blue 
or black ballpoint ink. The investigator must also sign and date the ICF and subject authorization 
(if applicable) at the time of consent and prior to subject entering into the study; however, the 
Sponsor may allow a designee of the investigator to sign to the extent permitted by applicable 
law.
Once signed, the original ICF, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the subject signs the informed consent in the subject’s medical record. Copies of the 
signed ICF, the signed subject authorization form (if applicable), and subject information sheet 
(if applicable) shall be given to the subject.
All revised ICF s must be reviewed and signed by relevant subjects in the same manner as the 
original informed consent. The date the revised consent was obtained should be recorded in the 
subject’s medical record, and the subject should receive a copy of the revised ICF.
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13.3
Subject Confidentiality
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the Sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
Sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the Sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study 
participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process (see Section 13.2).
Copies of any subject source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s CRF).
13.4
Publication, Disclosure, and Clinical Study Registration Policy
13.4.1
Publication and Disclosure
The investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the Sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor.
The Sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement. In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail.
13.4.2
Clinical Study Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
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contact information, along with investigator’s city, state (for Americas investigators), country, 
and recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the Sponsor.
Any investigator who objects to the Sponsor providing this information to callers must provide 
the Sponsor with a written notice requesting that their information not be listed on the registry 
site.
13.4.3
Clinical Study Results Disclosure 
Takeda will post the results of clinical studies on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the Sponsor or 
Sponsor’s designee will obtain clinical study insurance against the risk of injury to study 
subjects. Refer to the study site agreement regarding the Sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the Sponsor or Sponsor’s designee.
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14.
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1
Study Contact Information 
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
Pharmacovigilance
Takeda Development Center Americas, Inc.
Fax: 1-484-595-8155
Email: GPSE@takeda.com
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14.1.2
INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
package insert and any other product information provided by the Sponsor. I agree to conduct 
this study in accordance with the requirements of this protocol and also to protect the rights, 
safety, privacy, and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council on Harmonisation, E6 Good Clinical Practice: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.2.9 of this protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix A).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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14.1.3
Study-Related Responsibilities 
The Sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the Sponsor.
14.1.4
List of Abbreviations
µg
Microgram(s)
1,25(OH)2D3
1,25-dihydroxyvitamin D3
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUC
The area under the concentration-time curve, from time 0 to infinity
AUCextrap%
Percent of AUCextrapolated
AUC24
The area under the concentration-time curve, from time 0 to 24 hours postdose
AUClast
The area under the concentration-time curve, from time 0 to the last quantifiable 
concentration, as calculated by the linear-log trapezoidal method.
BMI
Body mass index
bpm
Beats per minute
CFR
Code of Federal Regulations
CI
Confidence interval
cm
Centimeter
Cmax
Maximum observed concentration 
COVID-19
Coronavirus disease 2019
CRF
Case report form
CRO
Contract research organization
CRU
Clinical Research Unit
ECG
Electrocardiogram
EU
European Union
FDA
Food and Drug Administration
FSH
Follicle stimulating hormone
g
Gram
GCP
Good Clinical Practice
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus 
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
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IEC
Independent Ethics Committee
Ig
Immunoglobulin(s)
INR
International normalized ratio
IRB
Institutional Review Board
ISCV
Intra-subject coefficient of variation
kg
Kilogram
L
Liter
LFT
Liver function test
ln
Natural log
LSM
Least-squares means
m2
Meters squared
MedDRA®
Medical Dictionary for Regulatory Activities®
mL
Milliliter
mmHg
Millimeter of mercury
msec
Millisecond
oz
Ounce
PK
Pharmacokinetic(s)
PTE
Pretreatment event
PTH
Parathyroid hormone
QD
Once daily
QTcF
QT interval corrected for heart rate using Fridericia’s formula
rhPTH
Recombinant human parathyroid hormone
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Subcutaneous
SUSAR
Suspected unexpected serious adverse reaction
t½z
Terminal disposition phase half-life
T4
Thyroxine
TEAE
Treatment-emergent adverse event
tlast
Time of the last measurable concentration
tmax
Time of first occurrence of Cmax
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
US
United States
USA
United States of America
WHO
World Health Organization
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15.
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, medical history, and concurrent conditions will be coded using the MedDRA®. Drugs 
will be coded using the WHO Drug Dictionary.
15.1
CRFs (Electronic and Paper)
Completed CRFs are required for each subject who signs an informed consent.
The Sponsor or its designee will supply investigative sites with access to CRFs. The Sponsor will 
make arrangements to train appropriate site staff in the use of the CRF. These forms are used to 
transmit the information collected in the performance of this study to the Sponsor and regulatory 
authorities. CRFs must be completed in English. Data are transcribed directly onto CRFs.
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the 
reason for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the CRFs for completeness and accuracy and must sign 
and date the appropriate CRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the CRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the 
data on the CRFs should be made by the investigator with use of change and modification 
records of the CRFs. The principal investigator must review the data change for completeness 
and accuracy, and must sign and date. 
CRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The Sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the CRFs. The completed CRFs 
are the sole property of the Sponsor and should not be made available in any form to third 
parties, except for authorized representatives of appropriate governmental health or regulatory 
authorities, without written permission of the Sponsor.
15.2
Record Retention
The investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copy of CRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from 
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regulatory authorities, the Sponsor or its designees. Any source documentation printed on 
degradable thermal sensitive paper should be photocopied by the site and filed with the original 
in the subject’s chart to ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires 
the investigator to retain essential documents specified in ICH E6 (Section 8) until at least 
2 years after the last approval of a marketing application for a specified drug indication being 
investigated or, if an application is not approved, until at least 2 years after the investigation is 
discontinued and regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that 
the study records should be retained until an amount of time specified by applicable regulatory 
requirements or for a time specified in the Clinical Study Site Agreement between the 
investigator and Sponsor.
Refer to the Clinical Study Site Agreement for the Sponsor’s requirements on record retention. 
The investigator and the head of the institution should contact and receive written approval from 
the Sponsor before disposing of any such documents.
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16.
REFERENCES
Brown, E. 1994. Homeostatic mechanisms regulating extracellular and intracellular calcium 
metabolism. In: Bilezikian, J., Marcus, R. & Levine, M. (eds.) The Parathyroids. Raven 
Press.
Goltzman, D. and Cole, D. 2006. Hypoparathyroidism. In: Favus, M. (ed.) Primer on the 
Metabolic Bone Diseases and Disorders of Mineral Metabolism. 6th ed.: American 
Society for Bone and Mineral Research.
Natpara® [parathyroid hormone] 2020. Full Prescribing Information. (electronic monograph; 
document revised: 06/2020). Available at 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125511s020lbl.pdf. Takeda 
Pharmaceutical Company Limited.
Schuirmann, D. J. 1987. A comparison of the two one-sided tests procedure and the power 
approach for assessing the equivalence of average bioavailability. J Pharmacokinet 
Biopharm, 15, 657-80.
Shoback, D. 2008. Hypoparathyroidism. N Engl J Med, 359, 391-403.
Silver, J. and Kronenberg, H. 1996. Parathyroid hormone- molecular biology and regulation. In:
Bilezikian, J. P., Raisz, L. & Rodan, G. (eds.) Principles of Bone Biology. Academic 
Press.
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Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the Sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the Investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this 
individual or party is qualified to perform those trial-related duties and functions and should 
implement procedures to ensure the integrity of the trial-related duties and functions 
performed and any data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of 
written approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to 21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to subjects. Make at least yearly reports on the progress of the study to 
the IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a subject authorization section 
that describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not 
include such a subject authorization, then the investigator must obtain a separate subject 
authorization form from each subject or the subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
CRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the Sponsor that all investigations have been discontinued 
or that the regulatory authority has approved the marketing application. The investigator 
should contact and receive written approval from the Sponsor before disposing of any such 
documents.
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11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of Sponsor-supplied 
drugs, and return all unused Sponsor-supplied drugs to the Sponsor. 
13. Report adverse reactions to the Sponsor promptly. In the event of an SAE, notify the Sponsor 
within 24 hours.
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Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might 
be advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), 
IRB/IEC, and the monitor may inspect the records. By signing a written ICF, the subject or 
the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any 
compensation and an explanation as to whether any medical treatments are available if injury 
occurs and, if so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty 
or loss of benefits to which the subject otherwise is entitled, and that the subject or the 
subject’s legally acceptable representative may discontinue participation at any time without 
penalty or loss of benefits to which the subject is otherwise entitled.
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20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be 
informed in a timely manner if information becomes available that may be relevant to the 
subject’s willingness to continue participation in the study.
22. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
23. A written subject authorization (either contained within the ICF or provided as a separate 
document) describing to the subject the contemplated and permissible uses and disclosures of 
the subject’s personal information (including personal health information) for purposes of 
conducting the study. The subject authorization must contain the following statements 
regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
24. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective/effective contraception (as defined in the 
informed consent) from signing the informed consent and throughout the duration of the 
study, and for 28 days after the last dose of study drug. Regular pregnancy tests will be 
performed throughout the study for all female subjects.
25. A statement that clinical trial information from this trial will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov.
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Appendix C
Investigator Consent to the Use of Personal Information 
Takeda will collect and retain personal information of Investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may 
contain the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s 
own country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Female Subjects and Their Male Partners
From signing of informed consent, throughout the duration of the study, and for 28 days after last 
dose of study drug, female subjects of childbearing potential** who are sexually active with a 
nonsterilized male partner* must use a highly effective/effective method of contraception (from 
the list below). 
In addition they must be advised not to donate ova during this period.
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* Sterilized males should be at least 1 year post-bilateral vasectomy and have confirmed that 
they have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
** A woman is considered a woman of childbearing potential, ie, fertile, following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, and bilateral oophorectomy. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause. A high FSH level in the 
postmenopausal range (FSH >40 IU/L) will be used to confirm a post-menopausal state
including in younger women (eg, those <45 year old) or women who are not using hormonal 
contraception or hormonal replacement therapy.
A female of non-childbearing potential, must have undergone one of the following sterilization 
procedures at least 6 months prior to the first dosing:
o
hysteroscopic sterilization;
o
bilateral tubal ligation or bilateral salpingectomy;
o
hysterectomy;
o
bilateral oophorectomy;
or be postmenopausal with amenorrhea for at least 1 year prior to the first dosing and FSH serum 
levels consistent with postmenopausal status. A postmenopausal state is defined as no menses for 
12 months without an alternative medical cause. A high FSH level in the postmenopausal range 
(FSH >40 IU/L) will be used to confirm a post-menopausal state in younger women (eg, those 
<45 year old) or women who are not using hormonal contraception or hormonal replacement 
therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.
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The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those, alone or in combination, 
that result in a low failure rate (ie, less than 1% failure rate per year when used consistently 
and correctly)”:

Non-Hormonal Methods: 
–
Intrauterine device at least 3 months prior to the first dosing.
–
Bilateral tubal occlusion.
–
Vasectomised partner * (provided that partner is the sole sexual partner of the study
participant and that the vasectomised partner has received medical assessment of the 
surgical success).
–
True sexual abstinence, only if this is in line with the preferred and usual lifestyle of 
the subject. True abstinence is defined as refraining from heterosexual intercourse 
during the entire period of the study, from 1 month prior to the first dose until 28 days 
after last dose.

Hormonal Methods: Hormonal contraception may be susceptible to interaction with the 
investigative compound, comparator, concomitant medications, which may reduce the 
efficacy of the contraception method (Evaluate on compound-by-compound and protocol 
–by-protocol basis and obtain clinical pharmacology justification).
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months prior to the first dose of study drug 
OR combined with a barrier method (male condom, female condom or diaphragm) if 
for shorter duration until she has been on contraceptive for 3 months;

Oral.

Intravaginal (eg, ring).

transdermal.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation 
initiated at least 3 months prior to the first dose of study drug OR combined with a 
barrier method (male condom, female condom or diaphragm) if shorter till she has 
been on contraceptive for 3 months;

oral.

Injectable.

Implantable.
2. Effective methods of contraception methods of contraception are defined as “those, alone or 
in combination, that may result in a failure rate less than 1%”:

Double-barrier method (contraceptive sponge, diaphragm or cervical cap with 
spermicidal jellies or creams PLUS male condom).
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
Progestogen only hormonal contraception, where inhibition of ovulation is not the 
primary mode of action PLUS condom with or without spermicide.
3. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.
4. Subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova, {and sperm donation} during the course of the study.
5. During the course of the study, regular serum human chorionic gonadotropin (hCG) 
pregnancy tests will be performed only for women of childbearing potential and all subjects 
(male and female) will receive continued guidance with respect to the avoidance of 
pregnancy and sperm donation as part of the study procedures. Such guidance should include 
a reminder of the following:
a) contraceptive requirements of the study
b) reasons for use of barrier methods (ie, condom) in males with pregnant partners
c) assessment of subject compliance through questions such as
i. Have you used the contraception consistently and correctly since the last visit?
ii. Have you forgotten to use contraception since the last visit?
iii. Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)
iv. Is there a chance you could be pregnant?
6. In addition to a negative serum hCG pregnancy test at Screening, female subjects of 
childbearing potential must also have confirmed menses in the month before first dosing (no 
delayed menses; with the exception of female subjects using a protocol acceptable 
contraception method that has a known side effect of delayed or irregular menses). In 
addition, subjects must also have a negative serum hCG pregnancy test within 1 day prior to 
receiving first dose of study drug as close as possible and prior to first dose of study drug, 
preferably on the same day.
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General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the following:

contraceptive requirements of the study.

reasons for use of barrier methods (ie, condom) in males with pregnant partners.

assessment of subject compliance through questions such as:
–
Have you used the contraception consistently and correctly since the last visit?
–
Have you forgotten to use contraception since the last visit? 
–
Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)
–
Is there a chance you could be pregnant?
Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male subject during the study or for 90 days after the last dose, should also be 
recorded following authorization from the subject’s partner. 
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the female 
subject/female partner of the subject was participating in a clinical study at the time she became 
pregnant and provide details of the study drug the subject received (blinded or unblinded, as 
applicable).
All pregnancies, including female partners of male subjects, will be followed up to final 
outcome, using the pregnancy form. Pregnancies will remain blinded to the study team. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted.
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Appendix E
Summary of Changes from Previous Version 
The protocol is amended to address updates as requested by The Food and Drug Administration
based on the communication dated 03 Nov 2021.
A summary of changes incorporated into Amendment 1 is provided in the table below.
Summary of Changes(s) Since Last Version of Approved Protocol
Description of Change
Section(s) Affected by Change
The protocol is updated to include 
assessment of
Section 1 (Study Summary)
Section 2 (Study Schematic)
Section 3 (Schedule of Study Procedures)
Section 5.2.3 (
)
Section 5.3.3 (
)
Section 6.1 (Study Design)
Section 6.4.1 (Rationale of Study Design)
Section 6.4.3.4 (
) 
(new section)
Section 7.3 (Excluded Medications, Supplements, 
Dietary Products)
Section 9.2.8 (AE Monitoring)
Section 9.3 (Pharmacokinetics,
 
Section 9.3.3 (
) (new section)
Section 9.3.6 (Confinement)
Section 10.2.8.1 (Collection Period)
Section 11.1.1.4 (
) (new section)
Section 11.1.5 (
) (new section)
Section 14.1.4 (List of Abbreviations)
Section 16 (References)
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Summary of Changes(s) Since Last Version of Approved Protocol
Description of Change
Section(s) Affected by Change
The protocol is updated to include 
baseline-adjusted Cmax in the primary 
endpoints of the study.
Section 1 (Study Summary)
Section 5.3.1 (Primary Endpoints)
Section 5.3.4 (Additional Endpoints)
Section 11.1.3.1 (Relative Bioavailability ([Part I 
(Relative Bioavailability)])
Sample size for Part I was increased 
from 80 to 84 subjects to conform with 
the inclusion of Cmax as a primary 
endpoint of the study.
Section 1 (Study Summary)
Section 6.1 (Study Design)
Section 7.7 (Subject Replacement)
Section 11.3 (Determination of Sample Size)
Resting position prior to vital signs 
measurements was updated from supine 
to seated position.
Section 3 (Schedule of Study Procedures)
List of prohibited medication and 
supplements was updated to align with 
the indication in the exclusion criterion.
Section 7.3 (Excluded Medication, Supplements, 
Dietary Products)
For non-commercial use only

SAP_001.pdf: 
NCT Number: NCT05137730
Title: A Randomized, Open-label, Single-center, Single-dose Study to Evaluate the 
Relative Bioavailability of a New Formulation Compared with the Approved 
Formulation of Recombinant Human Parathyroid Hormone (rhPTH[1-84]) and to 
Assess Dose Linearity of the New Formulation in Healthy Subjects
Study Number: TAK-834-1001
Document Version and Date: Final; 21 December 2021
Certain information within this document has been redacted (ie, specific content is masked 
irreversibly from view) to protect either personally identifiable information or company 
confidential information. 
Statistical Analysis Plan
For non-commercial use only


 
 
 
STATISTICAL ANALYSIS PLAN 
Study Number: TAK-834-1001 
A Randomized, Open-label, Single-center, Single-dose Study to Evaluate the Relative 
Bioavailability of a New Formulation Compared with the Approved Formulation of 
Recombinant Human Parathyroid Hormone (rhPTH[1-84]) and to Assess Dose Linearity of the 
New Formulation in Healthy Subjects 
Phase 1 
Version: Final  
Date: 21 December 2021 
 
 
 
Prepared by: 
 
Biostatistician II 
Data Management and Biometrics 
Celerion 
  
Pharmacokinetic Scientist II, Clinical Pharmacology and Pharmacometrics 
Data Management and Biometrics  
Celerion 
Based on: 
Original Protocol Dated: 15-Oct-2021 
Protocol Amendment 1 Dated: 18-Nov-2021 
 
 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda. 
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TAK-834-1001 
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Celerion Study Number CA34277 
Statistical Analysis Plan Final 
21 December 2021
 
CONFIDENTIAL 
REVISION HISTORY 
 
Version  
Approval Date 
Primary Rationale for Revision 
Original version 
21-DEC-2021 
[Not Applicable] 
 
 
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TAK-834-1001 
Page 3 of 29
Celerion Study Number CA34277 
Statistical Analysis Plan Final 
21 December 2021
 
CONFIDENTIAL 
Approval Signatures 
 
Study Title: 
A Randomized, Open-label, Single-center, Single-dose Study to Evaluate 
the Relative Bioavailability of a New Formulation Compared with the 
Approved Formulation of Recombinant Human Parathyroid Hormone 
(rhPTH[1-84]) and to Assess Dose Linearity of the New Formulation in 
Healthy Subjects 
 
 
Approvals: 
 
Signature: 
 
 
 
 
Senior Medical Director, Clinical Sciences 
Takeda Development Center Americas, Inc.   
 
 
Signature: 
 
 
 
 
Associate Scientific Director, Quantitative Clinical 
Pharmacology 
Takeda Development Center Americas, Inc.   
 
 
 
 
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TAK-834-1001 
Page 4 of 29
Celerion Study Number CA34277 
Statistical Analysis Plan Final 
21 December 2021
 
CONFIDENTIAL 
Approval Signatures 
 
Study Title: 
A Randomized, Open-label, Single-center, Single-dose Study to Evaluate 
the Relative Bioavailability of a New Formulation Compared with the 
Approved Formulation of Recombinant Human Parathyroid Hormone 
(rhPTH[1-84]) and to Assess Dose Linearity of the New Formulation in 
Healthy Subjects 
 
 
Approvals: 
 
Signature: 
 
 
 
 
Director, Biostatistics Team Lead 
Takeda Development Center Americas, Inc.   
 
 
 
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Celerion Study Number CA34277 
Statistical Analysis Plan Final 
21 December 2021
 
CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS ............................................................9 
1.1 
Objectives ......................................................................................................................9 
1.1.1 
Study Primary Objectives ......................................................................................9 
1.1.2 
Study Secondary Objectives ..................................................................................9 
1.1.3 
Study Exploratory Objectives ................................................................................9 
1.2 
Endpoints .....................................................................................................................10 
1.2.1 
Primary Endpoints ...............................................................................................10 
1.2.2 
Secondary Endpoints ...........................................................................................10 
1.2.3 
Exploratory Endpoints .........................................................................................10 
1.2.4 
Additional Endpoints ...........................................................................................11 
1.3 
Estimand(s) ..................................................................................................................11 
2.0 
STUDY DESIGN...............................................................................................................11 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES .............................................15 
3.1 
Statistical Hypotheses ..................................................................................................15 
3.2 
Statistical Decision Rules ............................................................................................15 
3.3 
Multiplicity Adjustment ...............................................................................................15 
4.0 
SAMPLE-SIZE DETERMINATION ................................................................................15 
5.0 
ANALYSIS SETS .............................................................................................................15 
5.1 
Safety Set .....................................................................................................................15 
5.2 
Pharmacokinetic Set.....................................................................................................15 
5.3 
16 
5.4 
16 
6.0 
STATISTICAL ANALYSIS .............................................................................................16 
6.1 
General Considerations ................................................................................................16 
6.1.1 
Handling of Treatment Misallocations ................................................................18 
6.2 
Study Information ........................................................................................................18 
6.3 
Disposition of Subjects ................................................................................................18 
6.4 
Demographic and Other Baseline Characteristics .......................................................19 
6.4.1 
Demographics ......................................................................................................19 
6.4.2 
Medical History and Concurrent Medical Conditions .........................................19 
6.5 
Medication History and Concomitant Medications .....................................................19 
6.6 
Efficacy Analysis .........................................................................................................19 
6.7 
Safety Analysis ............................................................................................................20 
6.7.1 
Adverse Events ....................................................................................................20 
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Statistical Analysis Plan Final 
21 December 2021
 
CONFIDENTIAL 
6.7.2 
Adverse Events of Special Interest (AESI) (if applicable) ..................................21 
6.7.3 
Clinical Laboratory Evaluation ...........................................................................21 
6.7.4 
Vital Signs ...........................................................................................................22 
6.7.5 
12-Lead Electrocardiogram .................................................................................22 
6.7.6 
Physical Examination ..........................................................................................22 
6.7.7 
22 
6.7.8 
Overdose ..............................................................................................................23 
6.7.9 
Extent of Exposure and Compliance ...................................................................23 
6.8 
Pharmacokinetic 
 Analyses .....................................................23 
6.8.1 
Pharmacokinetic Analysis ...................................................................................23 
6.8.2 
26 
6.9 
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis........................................................................................................................29 
6.10 
Preliminary Analysis ....................................................................................................29 
6.11 
Interim Analyses ..........................................................................................................29 
6.12 
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees] .................................................................................................................29 
7.0 
REFERENCES ..................................................................................................................29 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES ...................................................29 
9.0 
APPENDIX ........................................................................................................................29 
9.1 
Changes From the Previous Version of the SAP .........................................................29 
9.2 
Analysis Software ........................................................................................................29 
 
LIST OF IN-TEXT TABLES 
Table 2.a 
Study Scheme for Part I (Relative Bioavailability) ...............................................12 
Table 2.b 
Study Scheme for Part II (Dose Linearity) ............................................................12 
Table 2.c 
Planned Dose Levels ..............................................................................................13 
Table 6.a 
Collection of Blood Samples for Pharmacokinetic Analysis .................................24 
Table 6.b 
26 
 
LIST OF IN-TEXT FIGURES 
Figure 2.a 
Study Schematic (Part I [Relative Bioavailability]) ..............................................14 
Figure 2.b 
Study Schematic (Part II [Dose Linearity]) ...........................................................14 
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CONFIDENTIAL 
ABBREVIATIONS 
 
 
AE 
adverse event 
AESI 
adverse event of special interest 
ANOVA 
analysis of variance  
AUCextrap% 
area under the curve from the last quantifiable concentration to infinity, expressed as a 
percentage of AUC∞ 
AUCextrap%_obs 
area under the curve from the last quantifiable concentration to infinity, calculated using the 
observed value of the last quantifiable concentration, expressed as a percentage of AUC∞ 
AUCextrap%_pred 
area under the curve from the last quantifiable concentration to infinity, calculated using the 
predicted value of the last quantifiable concentration, expressed as a percentage of AUC∞_pred 
AUClast 
area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration 
AUC∞ 
area under the concentration-time curve from time 0 to infinity 
AUC∞_obs 
area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration 
AUC∞_pred 
area under the concentration-time curve from time 0 to infinity, calculated using the 
predicted value of the last quantifiable concentration 
AUC24 
area under the concentration-time curve from 0 to 24 hours postdose 
BLQ 
below the lower limit of quantitation  
BMI 
body mass index 
CI 
confidence interval 
Cmax 
maximum observed concentration 
COVID-19 
coronavirus disease 2019  
CPAP 
Clinical Pharmacology Analysis Plan 
CRF 
case report form 
CRU 
clinical research unit 
CV% 
coefficient of variation  
ECG 
electrocardiogram 
 
  
EOT 
end of treatment 
ET 
early termination 
Geom CV% 
geometric percent coefficient of variation 
Geom mean 
geometric mean 
GMR 
geometric mean ratio 
ICF 
informed consent form 
ISCV 
intra-subject coefficient of variation 
LSM 
least-squares mean 
mean 
arithmetic mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
n 
number of observations 
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PK 
pharmacokinetic 
PT 
preferred term 
PTH 
parathyroid hormone  
rhPTH 
recombinant human parathyroid hormone 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SEM 
standard error of the mean 
SOC 
System Organ Class 
SOP 
Standard Operating Procedures 
t1/2z 
terminal disposition phase half-life  
TEAE  
treatment-emergent adverse event 
 
  
TFL 
table, figure, and listing 
tlast 
time of the last measurable concentration 
tmax 
time of first occurrence of Cmax 
WHO 
World Health Organization 
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1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
1.1 
Objectives 
1.1.1 
Study Primary Objectives 
Part I (Relative Bioavailability):  
To evaluate the relative bioavailability of a new formulation (Formulation A; test) compared 
with the approved formulation (Formulation B; reference) of recombinant human parathyroid 
hormone (rhPTH) (1-84) following the administration of single subcutaneous (SC) doses of 
100 μg rhPTH(1-84) in healthy subjects. 
Part II (Dose Linearity): 
To assess the dose linearity of the new formulation (Formulation A) of rhPTH(1-84) following 
the administration of SC doses of 25 μg, 50 μg, 75 μg, and 200 μg rhPTH(1-84) in healthy 
subjects. 
1.1.2 
Study Secondary Objectives 
Part I (Relative Bioavailability):  
To assess the safety and tolerability of SC injections of rhPTH(1-84) administered as 
Formulation A and Formulation B in healthy subjects. 
Part II (Dose Linearity):  
To assess the safety and tolerability of SC injections of rhPTH(1-84) administered as 
Formulation A in healthy subjects. 
1.1.3 
Study Exploratory Objectives 
  
 
 
 
 
 
 
  
 
 
 
 
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1.2 
Endpoints 
Note: AUC∞ and AUCextrap% refer to AUC∞_obs and AUCextrap%_obs unless stated otherwise. 
1.2.1 
Primary Endpoints 
Parts I (Relative Bioavailability) and II (Dose Linearity):  
The following pharmacokinetic (PK) parameters for baseline-adjusted plasma parathyroid 
hormone (PTH) concentrations for each treatment will be derived to evaluate relative 
bioavailability (Part I) and dose linearity (Part II): 
x Maximum observed concentration (Cmax) 
x Area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration (AUClast) 
x Area under the concentration-time curve from time 0 to infinity (AUC∞) 
1.2.2 
Secondary Endpoints  
The following safety endpoints will be recorded for both Part I (Relative Bioavailability) and 
Part II (Dose Linearity):  
x Number, severity, seriousness, and causality of treatment-emergent adverse events 
(TEAEs) 
x Change in vital signs, electrocardiograms (ECGs), and laboratory results (hematology, 
chemistry, and urinalysis) from baseline 
1.2.3 
Exploratory Endpoints 
  
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
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1.2.4 
Additional Endpoints  
Parts I (Relative Bioavailability) and II (Dose Linearity):  
The following additional PK parameters will be estimated for unadjusted and baseline-adjusted 
plasma PTH concentrations for each single-dose treatment: 
x Area under the curve from the last quantifiable concentration to infinity, expressed as a 
percentage of AUC∞ (AUCextrap%) 
x Time of first occurrence of Cmax (tmax) 
x Time of the last measurable concentration (tlast) 
x AUC∞_pred (Part I only) 
x AUCextrap%_pred (Part I only) 
x Terminal disposition phase half-life (t1/2z; baseline-adjusted only) 
The following additional PK parameters will be computed for unadjusted plasma PTH 
concentrations for each treatment:  
x Cmax  
x AUClast  
x AUC∞ 
1.3 
Estimand(s) 
Not applicable.  
2.0 
STUDY DESIGN 
This is a randomized, open-label, single-center, two-part study to assess the relative 
bioavailability of a single SC dose of rhPTH(1-84) administered as the new formulation 
(Formulation A; test) and the approved formulation (Formulation B; reference) in Part I 
(Relative Bioavailability) of the study and to assess dose linearity of Formulation A in Part II 
(Dose Linearity) of the study. Both parts may be conducted concurrently. 
Part I (Relative Bioavailability) 
Part I (Relative Bioavailability) will be conducted as a randomized, two-sequence, two-period, 
crossover design. 
Subjects in each treatment period will receive rhPTH(1-84) as a single 100 μg SC injection 
administered in the mid-thigh as either Formulation A or Formulation B depending on the 
randomized (1:1) treatment sequence as indicated in Table 2.a. 
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Blood samples for plasma PTH PK and serum calcium and albumin concentrations will be 
collected predose and for 24 hours following each rhPTH(1-84) administration. 
There will be a drug washout of 96 (±1) hours between the administration of rhPTH(1-84) in 
each period. 
Table 2.a 
Study Scheme for Part I (Relative Bioavailability) 
Treatment Sequence 
N 
Treatment Period 1 
Drug Washout 
(Hours) 
Treatment Period 2 
1 
42 
A 
96 (±1) 
B 
2 
42 
B 
96 (±1) 
A 
The planned dose levels of rhPTH(1-84) to be evaluated are outlined in Table 2.c.  
Subjects will remain in the clinical research unit (CRU) until completion of the last postdose 
assessment on Day 2 of Treatment Period 2. If clinically significant findings are observed upon 
discharge, subjects may either be kept in the CRU for observation or return to the CRU for re-
evaluation per Investigator’s discretion. 
Part II (Dose Linearity) 
Part II (Dose Linearity) will be conducted as a randomized, four-sequence, four-period, 
crossover design.  
Subjects in each treatment period will receive rhPTH(1-84) Formulation A as a single SC 
injection administered in the mid-thigh at a dose level depending on the randomized (1:1:1:1) 
treatment sequence as indicated in Table 2.b. If possible, the same location in the same thigh will 
be used for all treatment periods. If the same thigh cannot be used, the alternative mid-thigh may 
be used. 
Blood samples for plasma PTH PK will be collected predose and for 24 hours following each 
rhPTH(1-84) administration. 
There will be a drug washout of 48 (±1) hours between the administration of rhPTH(1-84) in 
each period. 
Table 2.b 
Study Scheme for Part II (Dose Linearity) 
Treatment 
Sequence 
N 
Treatment 
Period 1 
Drug 
Washout 
(Hours) 
Treatment 
Period 2 
Drug 
Washout 
(Hours) 
Treatment 
Period 3 
Drug 
Washout 
(Hours) 
Treatment 
Period 4 
1 
3 
C 
48 (±1) 
D 
48 (±1) 
E 
48 (±1) 
F 
2 
3 
D 
48 (±1) 
F 
48 (±1) 
C 
48 (±1) 
E 
3 
3 
E 
48 (±1) 
C 
48 (±1) 
F 
48 (±1) 
D 
4 
3 
F 
48 (±1) 
E 
48 (±1) 
D 
48 (±1) 
C 
The planned dose levels of rhPTH(1-84) to be evaluated are outlined in Table 2.c. 
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Subjects will remain in the CRU until completion of the last postdose assessment on Day 2 of 
Treatment Period 4. If clinically significant findings are observed upon discharge, subjects may 
either be kept in the CRU for observation or return to the CRU for re-evaluation per 
Investigator’s discretion. 
Parts I (Relative Bioavailability) and II (Dose Linearity): 
 
Safety and tolerability will be assessed by TEAEs including injection site reaction assessments, 
laboratory evaluations, physical examinations, 12-lead ECGs, and vital signs. 
All subjects who received a dose of study drug (including subjects who terminate from the study 
early) will return to the CRU 16 (± 2) days (return visit) and 32 (± 2) days (follow-up visit) after 
the last study drug administration for collection of blood
to determine 
if any adverse events (AEs) have occurred since the last study visit. 
The planned dose levels of rhPTH(1-84) to be evaluated in both study parts are outlined in Table 
2.c.  
Table 2.c 
Planned Dose Levels 
Treatment 
Formulation 
Dose Level 
Dose Form 
Route of 
Administration 
Part I (Relative Bioavailability) 
A 
Formulation A 
(Test) 
100 μg rhPTH(1-
84) 
Lyophilized powder to be 
reconstituted for SC dosing 
SC injection in mid-
thigh 
B 
Formulation B 
(Reference) 
100 μg rhPTH(1-
84) 
Lyophilized powder to be 
reconstituted for SC dosing 
SC injection in mid-
thigh 
Part II (Dose Linearity) 
C 
Formulation A  
25 μg rhPTH(1-
84) 
Lyophilized powder to be 
reconstituted for SC dosing 
SC injection in mid-
thigh 
D 
Formulation A  
50 μg rhPTH(1-
84) 
Lyophilized powder to be 
reconstituted for SC dosing 
SC injection in mid-
thigh 
E 
Formulation A  
75 μg rhPTH(1-
84) 
Lyophilized powder to be 
reconstituted for SC dosing 
SC injection in mid-
thigh 
F 
Formulation A  
200 μg rhPTH(1-
84) 
Lyophilized powder to be 
reconstituted for SC dosing 
SC injection in mid-
thigh 
 
 
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The study schematic for Part I is presented in Figure 2.a:  
Figure 2.a 
Study Schematic (Part I [Relative Bioavailability]) 
Pretreatment 
Treatment Periods 1-2 (a) 
Discharge 
(b) 
Return 
Visit (c) 
Follow up 
(c) 
Screening 
Predose 
Assessments 
Dosing and  
Study 
Assessments 
Safety and 
PK 
Assessments 
 
Safety 
 
Safety 
 
Day -21 to 
first dosing 
Day -1 
Day 1 
Days 1-2 
Day 2 of last 
treatment 
period 
16 (±2) days 
after last 
dose 
32 (±2) days 
after last 
dose 
 
Confinement (d)  
 
 
 
(a) There will be a washout period of 96 (±1) hours between rhPTH(1-84) dosing in each treatment period. 
(b) If clinically significant findings are observed upon discharge, subjects may either be kept in the CRU for 
observation or return to the CRU for re-evaluation per Investigator’s discretion. 
(c) All subjects who received a dose of study drug (including subjects who terminate from the study early) will 
return to the CRU 16 (± 2) days (return visit) and 32 (± 2) days (follow-up visit) after the last study drug 
administration for collection of blood 
 to determine if any AEs have occurred since the last 
study visit. 
(d) Subjects will start the confinement on Day -1 of Treatment Period 1 and remain confined until Day 2 of 
Treatment Period 2. Subjects may be admitted earlier for coronavirus disease 2019 (COVID-19) testing not related 
to study protocol as per CRU requirements.  
The study schematic for Part II is presented in Figure 2.b:  
Figure 2.b 
Study Schematic (Part II [Dose Linearity]) 
Pretreatment 
Treatment Periods 1-4 (a) 
Discharge (b) 
Return 
Visit (c) 
Follow up 
(c) 
Screening 
Predose 
Assessments 
Dosing and  
Study 
Assessments 
Safety and 
PK 
Assessments 
 
Safety 
 
Safety 
 
Day -21 to 
first dosing 
Day -1 
Day 1 
Days 1-2 
Day 2 of last 
treatment 
period 
16 (±2) 
days after 
last dose 
32 (±2) 
days after 
last dose 
 
Confinement (d)  
 
 
 
(a) There will be a washout period of 48 (±1) hours between rhPTH(1-84) dosing in each treatment period. 
(b) If clinically significant findings are observed upon discharge, subjects may either be kept in the CRU for 
observation or return to the CRU for re-evaluation per Investigator’s discretion. 
(c) All subjects who received a dose of study drug (including subjects who terminate from the study early) will 
return to the CRU 16 (± 2) days (return visit) and 32 (± 2) days (follow-up visit) after the last study drug 
administration for collection of blood 
 to determine if any AEs have occurred since the last 
study visit.. 
(d) Subjects will start the confinement on Day -1 of Treatment Period 1 and remain confined until Day 2 of 
Treatment Period 4. Subjects may be admitted earlier for COVID-19 testing not related to study protocol as per 
CRU requirements. 
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3.0 
STATISTICAL HYPOTHESES AND DECISION RULES  
3.1 
Statistical Hypotheses 
Not applicable.  
3.2 
Statistical Decision Rules 
Not applicable.  
3.3 
Multiplicity Adjustment 
Not applicable.  
4.0 
SAMPLE-SIZE DETERMINATION 
Part I (Relative Bioavailability): 
The sample size of 76 subjects was calculated to achieve 90% confidence interval (CI) around 
the geometric mean ratio of the test and reference formulations within the limits of 0.80 to 1.25 
for AUC and Cmax. The true test to reference ratio was assumed to be 0.93, and 90% target 
power was used for the sample size determination. The intra-subject coefficient of variation 
(ISCV) was assumed to be 32.2%, the upper end of the two-sided 50% confidence limit of the 
ISCV for Cmax estimated in study SHP634-103 (the ISCV observed in study SHP634-103 was 
higher for Cmax than for AUC). Part I (Relative Bioavailability) will enroll 84 subjects to allow 
for up to eight dropouts. 
Part II (Dose Linearity): 
The sample size (N=12) for Part II (Dose Linearity) is not based on any statistical 
considerations but is considered sufficient for dose linearity evaluation. 
5.0 
ANALYSIS SETS 
5.1 
Safety Set 
All subjects who received at least one dose of the study drug will be included in the safety 
evaluations. 
5.2 
Pharmacokinetic Set 
All subjects who have at least one measurable predose (baseline) and one postdose 
concentration of PTH will be included in the statistical analyses. 
Subjects who do not comply sufficiently with the protocol or who do not display an evaluable 
PK profile (eg, exposure to treatment, availability of measurements, and absence of major 
protocol violations) will be excluded from the descriptive statistics and statistical analyses. 
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Details on criteria for excluding subjects from the PK analysis will be described in the Clinical 
Pharmacology Analysis Plan (CPAP). 
5.3 
 
 
 
 
 
5.4 
 
 
 
6.0 
STATISTICAL ANALYSIS  
6.1 
General Considerations 
All PK analyses will be conducted using Phoenix® WinNonLin® Version 8.1, or higher. All 
statistical analyses will be conducted using SAS® Version 9.4, or higher. All data recorded on the 
case report form (CRF) will be listed by subject. All tables, figures, and listings (TFLs) shells 
and numbering list will be included and specified in the TFL Shells document. 
The number of observations (n) will be presented as an integer (no decimal places), arithmetic 
mean (mean), median, and geometric mean (geom mean) values will be presented to 1 more 
level of precision than the individual values. Standard deviation (SD) and standard error of the 
mean (SEM) will be presented to 2 more levels of precision than the individual values. Minimum 
and maximum values will be presented to the same precision as the individual values. Arithmetic 
percent coefficient of variation (CV%) and geometric percent coefficient of variation (geom 
CV%) will be presented to 1 decimal place. 
Geometric least-squares means (LSMs) will be reported with 1 more level of precision than the 
individual data. The geometric mean ratios (GMRs) and 90% CIs around the ratios will be 
reported using 2 decimal places. 
Concentration values below the lower limit of quantitation (BLQ) will be presented as ‘BLQ’ in 
the concentration table listings and footnoted accordingly. The BLQ values associated with PTH, 
calcium, and albumin concentrations will be set to ½ the lower limit of quantitation for the 
calculation of summary statistics, the generation of concentration plots, the calculation of 
albumin-corrected concentrations (
 only), and the calculation of PK 
 parameters, as 
appropriate, in accordance with Celerion Standard Operating Procedures (SOPs). 
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A subject’s PK parameter data will be included in the listings but may be excluded from the 
descriptive and inferential (analysis of variance [ANOVA]) statistics if one or more of the 
following criteria are met: 
x A subject did not meet inclusion/exclusion criteria that may have an effect on the PK (as 
determined by the Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic 
Scientist) 
x A subject deviates substantially from the protocol defined study procedures including but 
not limited to dosing, dose timing, sample collection, meal timing, etc. (as determined by 
the Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic Scientist) 
The details on PTH PK parameter calculations and TFLs will be outlined in the CPAP and TFL 
Shells document including specifics on the following:  
x Insufficient data to determine a reliable t½z value and other λz-dependent parameters 
x Unadjusted and baseline-adjusted PK parameters presented by part and treatment, 
including the units, precision, and summary statistics that will be presented in in-text and 
end-of-text tables 
x Unadjusted and baseline-adjusted concentration data presented by part and treatment, 
including the units, precision, and summary statistics that will be presented in end-of-text 
tables 
x Concentration data file used for PK analysis 
x PK parameter WinNonlin® output file used to generate the TFLs 
x ANOVA results presented in in-text and end-of-text tables (Part I only) 
x The non-parametric analysis of tmax will be presented as end-of-text table (Part I only) 
x Dose linearity analysis presented in in-text and end-of-text tables (Part II only) 
x Dose linearity of PK parameters (baseline-adjusted AUC and Cmax) will also be assessed 
graphically (Part II only) 
x Mean unadjusted and baseline-adjusted concentration-time figures presented as in-text 
and end-of-text figures 
x Individual unadjusted and baseline-adjusted concentration-time figures presented in 
Appendix 16.2.6. 
The details on 
 TFLs will be outlined 
in the CPAP and TFL Shells document including specifics on the following:  
 
 
 
 
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x Unadjusted and baseline-adjusted concentration data, 
 
 presented by treatment, including the units, precision, and 
summary statistics that will be presented in end-of-text tables 
 
 
 
 
 
x ANOVA results presented in in-text and end-of-text tables 
x Mean unadjusted and baseline-adjusted concentration-time figures, 
 
 presented as in-text and end-of-text figures 
x Individual unadjusted and baseline-adjusted concentration-time figures, 
 
 presented in Appendix 16.2.6. 
Continuous demographic and safety data will be summarized descriptively. For the categorical 
variables, the count and percentages of each value will be tabulated, where applicable. The 
denominator for the percent calculation will be the safety set for overall summaries, and the 
number of subjects dosed for each treatment in by-treatment summaries. For continuous 
variables, the number of observations, mean, SD, minimum, median, and maximum values will 
be tabulated. The level of precision will be presented as follows: minimum/maximum in the 
same precision as in the database, mean/median in one more precision level than 
minimum/maximum, SD in one more precision level than mean/median, and n will be presented 
as an integer. Counts and percentages will be presented as integers. Study baseline is defined as 
the last observation prior to the first dose of the study, and period baseline is defined as the last 
observation prior to dosing in each period. When calculating change from baseline, period 
baseline will be used when available. 
6.1.1 
Handling of Treatment Misallocations 
Subject data will be analyzed according to the treatments administered. 
6.2 
Study Information 
A study information table will be generated including the following items for each study part: 
date of first subject’s signed informed consent form, date of dosing, date of last subject’s last 
visit/contact, date of last subject’s last procedure for collection of data for primary endpoint, the 
version of Medical Dictionary for Regulatory Activities (MedDRA®), the version of World 
Health Organization (WHO) Drug Dictionary, and SAS® version used for creating the datasets. 
6.3 
Disposition of Subjects 
For each study part, disposition of subjects (number of subjects dosed, completed the study, 
discontinued from the study and/or study drug, and reason(s) for discontinuation(s)) will be 
summarized and listed by subject.  
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6.4 
Demographic and Other Baseline Characteristics 
6.4.1 
Demographics 
Demographic and baseline characteristics will be summarized by study part based on the safety 
set. Summary statistics (n, mean, SD, minimum, median, and maximum) will be generated for 
continuous variables (age, weight, height, and body mass index [BMI]) and the number and 
percentages of subjects within each category will be presented for categorical variables (sex, 
race, and ethnicity). Height, weight, and BMI measured at screening will be used in the 
summaries. Demographic data will also be listed as recorded on the CRF, including the date of 
informed consent and protocol version.  
6.4.2 
Medical History and Concurrent Medical Conditions 
Medical history to be recorded will include determining whether the subject has any significant 
conditions or diseases that resolved at or before signing the informed consent form (ICF). All 
medical history reported by the subject will be recorded regardless of how long ago it may have 
occurred. Concurrent medical conditions are those significant ongoing conditions or diseases that 
are present at signing the ICF. Each subject’s medical history and concurrent medical conditions 
will be listed. 
Any medical condition starting or worsening after taking the first dose of study drug will be 
classified as a TEAE. All medical history will be coded using MedDRA® Version 24.1. All 
medical history and concurrent medical conditions will be listed. If available, the medical history 
and concurrent medical condition listings will include the coded term (preferred term [PT] and 
system organ class [SOC]), start date (if known) and end date (if known) or whether the 
condition was ongoing, and a description of the condition or event. No summaries or statistical 
analysis will be performed for these data.  
6.5 
Medication History and Concomitant Medications  
Medication history to be obtained includes any medication stopped at or within 28 days prior to 
signing the ICF. Concomitant medication includes any medication other than study drug taken at 
any time between ICF and the end of the study. All medication history and concomitant 
medications recorded during the study will be coded with the World Health Organization (WHO) 
Drug Dictionary Version 01Sep2021_b3 and listed. If available, the listings will include the 
medication name, coded term, dosage, route of administration, start date and time (if known), 
end date and time (if known), or whether it continued after study completion, and indication for 
use. No summaries or statistical analysis will be performed for these data. 
6.6 
Efficacy Analysis 
Not applicable. 
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6.7 
Safety Analysis 
Safety will be evaluated by the incidence of TEAEs, severity and relationship of TEAEs, and 
changes from baseline in the subjects’ clinical laboratory results, vital signs, and 12-lead ECGs 
using the safety set. Clinically significant laboratory values, vital signs, and ECG results will be 
reported as AEs. All clinical safety data will be listed by study part, subject, period, and 
assessment time points, including rechecks, unscheduled assessments, and early termination 
(ET), chronologically. Subjects from both parts will be included in the same listing, but will be 
delineated by study part. 
Continuous variables will be summarized using n, mean, SD, minimum, median, and maximum. 
Frequency counts and percentages will be reported for categorical data when appropriate. Where 
individual data points are missing because of dropouts or other reasons, the data will be 
summarized based on reduced denominators. Summaries will be presented separately for each 
part. 
6.7.1 
Adverse Events 
All AEs captured in the database will be listed in by-subject data listings including verbatim 
term, coded term, severity (mild, moderate, severe), relationship to study drug (related or not 
related), frequency, action relative to the study drug, and whether the AE is of special interest, as 
recorded in the CRF. All AEs occurring during this study will be coded using the MedDRA® 
Version 24.1. Only TEAEs will be summarized. 
A TEAE is defined as an AE that is starting or worsening at the time of or after the first dose of 
study drug administered in the study. Each TEAE will be attributed to the treatment prior to and 
the closest to the AE based on the AE onset date and time. 
If the onset time of an AE is missing and the onset date is the same as a treatment dosing date, 
then the AE will be counted under the treatment given on the same day. If onset time of an AE is 
missing and the onset date does not fall on a dosing date, then the AE will be considered 
treatment emergent for the most recent treatment administered. If the onset date of an AE is 
missing, then the AE will be considered treatment emergent and attributed to the first treatment 
received.  If severity is missing, the AE will be counted as severe, and if relationship is missing, 
the AE will be counted as related. 
Summary of TEAEs will be presented for each study part. TEAEs will be tabulated by treatment 
(including overall), SOC, and PT. Summary tables will include number of subjects reporting the 
TEAE and as percent of safety set by treatment and overall. The most commonly reported non-
serious TEAEs (ie, those events reported by >5% of subjects [or >1 subject if fewer than 20 
subjects] in one or more treatments, excluding serious adverse events [SAEs]) will also be 
summarized. The denominators for percent calculations will be the number of subjects dosed for 
each treatment. In a similar way, TEAEs will be summarized as number of TEAEs and 
percentage of TEAEs for each treatment and overall.  
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Additional TEAE summary tables will be presented by severity and relationship to study drugs. 
If a subject has multiple TEAEs with different severity levels within the same PT, the subject 
will be counted in the most severe category only. If a subject has both related and unrelated 
TEAEs with the same PT, the subject will be counted as having related TEAEs. 
An overview summary of TEAEs table, including number of subjects with TEAEs, SAEs, 
treatment-related TEAEs, treatment-related SAEs, TEAEs by severity, and AEs leading to 
discontinuation will be provided. 
Should any SAEs (including all-cause mortalities) occur, they will be summarized the same way 
as TEAEs. All AEs will be displayed in the data listings and TEAEs will be discussed in the text 
of the study report. 
6.7.2 
Adverse Events of Special Interest (AESI) (if applicable) 
The AESIs will include hyper- and hypocalcemia as determined by the investigator or designee. 
If applicable, AESIs will be summarized similarly to TEAEs in tables reporting number of 
subjects and number of events. AESIs will be identified in the listing and discussed in the text of 
the study report. 
6.7.3 
Clinical Laboratory Evaluation 
In each study part, serum chemistry, hematology, and urinalysis will be performed at screening, 
check-in, at predose and 24 hours postdose in each period, and at end of treatment (EOT) (or ET, 
if applicable). 
Urine drug screening will be carried out at screening and Period 1 Day -1 only, in both study 
parts. TSH, free T4, PTH, and serum Vitamin D will be tested at screening. In addition, 
laboratory safety tests may be performed at various unscheduled time points, if deemed 
necessary by the investigator.  
For baseline and post-baseline laboratory values that are numeric, summary statistics (n, mean, 
SD, minimum, median, and maximum) will be presented for laboratory test results and change 
from period baseline by time point of collection for each study part. Period baseline is defined as 
the last assessment including rechecks or unscheduled assessments taken prior to the first dose in 
each period. Post-baseline unscheduled or recheck assessments will not be used in analysis. All 
clinical laboratory data will be listed by study part and subject.  
Out-of-normal range flags will be recorded as follows: high (H) and low (L) for numerical 
results and did-not-match (*) for categorical results. For each laboratory test, a shift table will be 
developed comparing the frequency and percentage of the results at baseline (above reference 
range [H], within reference range [N], or below reference range [L]) with the postdose time 
points for each treatment. For urinalysis tests, the categories are normal (N) and abnormal (A). 
Out-of-range values and corresponding recheck results will be listed. 
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6.7.4 
Vital Signs 
In each study part, vital sign measurements of pulse rate and blood pressure will be recorded at 
screening, check-in, at predose and 1, 4, 8, and 24 hours postdose in each period, and at EOT (or 
ET, if applicable). Temperature will be recorded at screening, check-in, at 1, 4, 8, and 24 hours 
postdose in each period, and at EOT (or ET if applicable). Respiration rate will be recorded at 
screening and check-in. Additional unscheduled vital signs measurements may be taken at other 
times, if deemed necessary by the investigator. 
For baseline and post-baseline, summary statistics (n, mean, SD, minimum, median, and 
maximum) will be presented for pulse rate and blood pressure results and change from period 
baseline by time point of collection for each study part. Period baseline is defined as the last 
assessment including rechecks or unscheduled assessments taken prior to the first dose in each 
period. Post-baseline unscheduled or recheck assessments will not be used in analysis. Vital sign 
data will be listed by study part and subject. 
6.7.5 
12-Lead Electrocardiogram 
In each study part, single 12-lead ECGs will be collected at screening, check-in, at predose and 
1, 4, 8, and 24 hours postdose in each period, and at EOT (or ET, if applicable). Additional 
unscheduled ECGs may be taken at other times, if deemed necessary by the investigator. 
For baseline and post-baseline, summary statistics (n, mean, SD, minimum, median, and 
maximum) will be presented for ECG results and change from period baseline by time point of 
collection for each study part. Period baseline is defined as the last assessment including 
rechecks or unscheduled assessments taken prior to the first dose in each period. Post-baseline 
unscheduled or recheck assessments will not be used in analysis. ECG data will also be listed by 
study part and subject. 
6.7.6 
Physical Examination 
In each study part, a full physical examination will be performed at screening, check-in and at 
EOT (or ET, if applicable). Symptom-driven physical examinations may be performed at other 
times at the discretion of the investigator. Physical examination findings will be presented in the 
data listings by study part and subject. 
6.7.7 
  
 
 
 
 
 
 
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6.7.8 
Overdose 
All cases of overdose will be presented in a data listing by study part and subject. Any AEs 
associated with overdose will be documented. 
6.7.9 
Extent of Exposure and Compliance 
The dates, times, and dosages of rhPTH(1-84) will be listed by study part and subject. 
6.8 
Pharmacokinetic 
 Analyses 
6.8.1 
Pharmacokinetic Analysis 
Blood samples for assessment of plasma PTH concentrations will be collected as outlined in 
Table 6.a below:  
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Table 6.a 
Collection of Blood Samples for Pharmacokinetic Analysis 
Analyte 
Matrix 
Period 
Scheduled Time (Hours)* 
PTH 
Plasma 
1, 2, 3, and 4# Predose (-1, -0.5, and -0.25 hours) and 0.083, 0.167, 0.333, 0.5, 0.75, 1, 1.25, 
1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours postdose.  
*The actual date and time of sample collection will be recorded on the source document in the CRF.  
#Periods 1 and 2 (for Part I) and 1, 2, 3, and 4 (for Part II) 
Unadjusted and baseline-adjusted PTH concentrations will be listed and summarized 
descriptively by part and either treatment (for Part I) or dose level (for Part II), and PK sampling 
time using the following descriptive statistics: n, mean, SD, CV%, SEM, minimum, median, and 
maximum. Excluded concentrations will be presented and footnoted as such in the concentration 
table listings, and those values will be excluded from the descriptive statistics. 
Individual subject unadjusted and baseline-adjusted concentration-time curves will be plotted by 
part on linear and semi-log scales. The mean profiles of the unadjusted and baseline-adjusted 
concentration-time data will be plotted by part on linear (with and without SD) and semi-log 
scales. For summary statistics and mean plots by sampling time, the nominal PK sampling time 
will be used, for individual subject plots by time, the actual PK sampling time will be used.  
The PK parameters will be calculated from unadjusted and baseline-adjusted PTH concentration-
time profiles using non-compartmental analysis methods where all calculations will be based on 
actual sampling times after dosing. The PK parameters will be summarized by part and treatment 
using the following descriptive statistics: n, mean, SD, CV%, SEM, minimum, median, 
maximum, geom mean, and geom CV%. Excluded parameters will be presented and footnoted as 
such in the PK parameter table listings, and those values will be excluded from descriptive 
statistics. 
Baseline-adjusted PTH concentrations will be calculated by subtracting the average of the 
measured PTH values from the 3 predose time points (-1, -0.5, and -0.25 hours) from all 
postdose PTH concentrations. Negative baseline-adjusted PTH values will be set to 0, and any 
positive baseline-adjusted PTH concentration following occurrence of the first negative baseline-
adjusted concentration will also be set to 0.  
Relative Bioavailability (Part I Only) 
For the evaluation of relative bioavailability in Part I, a linear mixed-effects model will be used 
for the analysis on the ln-transformed unadjusted and baseline-adjusted Cmax, AUClast, AUCf, 
and AUC∞_pred for PTH. The model will include sequence, treatment, and period as fixed effects 
and subject nested within sequence as a random effect. The analysis will include calculation of 
LSMs as well as the difference between treatment LSMs. The GMR and 90% CI will be 
calculated using the exponentiation of the difference between treatment LSMs from the analyses 
on the ln-transformed unadjusted and baseline-adjusted Cmax, AUClast, AUC∞, and AUC∞_pred for 
PTH. These ratios will be expressed as a ratio relative to the reference formulation.  
The comparison of interest is as follows:  
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x Formulation A (Test) compared to Formulation B (Reference) 
The 90% CIs around the GMRs for plasma Cmax, AUClast, and AUC∞ will be assessed whether 
they fall within the 0.80-1.25 limits. 
The following SAS® code will be used to perform the analysis in Part I:  
PROC MIXED DATA=xxx; 
CLASS TREAT SEQUENCE PERIOD SUBJECT; 
MODEL ln(<param>) = TREAT SEQUENCE PERIOD; 
RANDOM SUBJECT(SEQUENCE); 
ESTIMATE “Treatment A vs. Treatment B” TREAT 1 -1 / CL ALPHA=0.1 E;  
LSMEANS TREAT / CL ALPHA=0.05; 
RUN; 
Non-Parametric Analysis of tmax (Part I Only) 
The tmax will be analyzed using nonparametric analysis for paired samples (the Wilcoxon Signed 
Rank Test statistic). The difference of medians (treatment effect) and the corresponding 90% CI 
will be estimated using the Hodges-Lehmann method and Walsh Averages. The tmax will not be 
ln-transformed. The comparison of interest is the same as for the relative bioavailability 
assessment listed above. 
Dose Linearity (Part II Only) 
For the evaluation of dose linearity in Part II, a linear regression model will be used for the 
analysis on the ln-transformed unadjusted and baseline-adjusted Cmax, AUClast, and AUCf for 
PTH. The model will include sequence, treatment, and period as fixed effects and subject nested 
within sequence as a random effect, with ln(dose) as a covariate.  
 
As a first step, the significance of a quadratic term, [ln(dose)]2, will be tested. If the quadratic 
term is not significant, then it will be noted in the table and discussed.  Secondly, the quadratic 
term will be removed from the model and the final model will be used to assess the linear 
relationship between ln-transformed PK parameters and ln(dose). 
 
The following SAS® code will be used to perform the analysis in Part II:  
Step 1: Check significance of the quadratic term: 
PROC MIXED DATA=xxx; 
CLASS SEQUENCE PERIOD SUBJECT; 
MODEL LNPKPARAM = LNDOSE LNDOSE*LNDOSE SEQUENCE PERIOD / DDFM = 
KR SOLUTION CL ALPHA=0.10; 
RANDOM SUBJECT(SEQUENCE); 
 
Step 2: assess dose linearity: 
PROC MIXED DATA=xxx; 
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CLASS SEQUENCE PERIOD SUBJECT; 
MODEL LNPKPARAM = LNDOSE SEQUENCE PERIOD / DDFM = KR SOLUTION CL 
ALPHA=0.10; 
RANDOM SUBJECT(SEQUENCE); 
 
 
 
 
 
6.8.2 
 
 
  
Table 6.b 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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6.9 
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis 
Not applicable.  
6.10 
Preliminary Analysis 
A preliminary PK analysis will be completed after database lock as described in the CPAP and 
Section 6.8.1 of the SAP, with the following changes: 1) unblinded QCed data will be used 
(unless the QAed data is available, in which case the QAed data will be used); 2) nominal times 
will be used for the calculation of PK parameters (not actual sampling times); 3) tables and 
figures will be created using Phoenix® WinNonlin® Version 8.1 or higher, except for the 
ANOVA tables which will be generated using SAS® Version 9.4 or higher. 
6.11 
Interim Analyses 
No formal interim analysis is planned for this study. 
6.12 
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees] 
Not applicable. 
7.0 
REFERENCES 
Not applicable. 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES 
 
 
Based on the study design in Part 2, a linear regression model will be used to account for the 
effects of period, sequence, and subject in the dose proportionality analysis, which is not the 
power model.  
9.0 
APPENDIX  
9.1 
Changes From the Previous Version of the SAP 
Not applicable. 
9.2 
Analysis Software  
SAS® Version 9.4 or higher will be used for all statistical analyses provided in the clinical study 
report. 
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