Conditions: Osteoporosis
Keywords: Osteoporosis Phase 3 Chinese Patients Romosozumab
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 327
Healthy volunteers: no

Brief summary:
The purpose of the study is to evaluate the effect of treatment with romosozumab for 6 months compared with placebo on the percent changes in bone mineral density (BMD) at the lumbar spine, at the total hip and femoral neck in postmenopausal Chinese women with osteoporosis.

Detailed description:

Arms:
arm 1: Subjects randomized to this arm will receive romosozumab during all treatment Periods. arm 2: Subjects randomized to this arm will receive placebo during the Double-Blind-Placebo controlled Period and romosozumab during the Open-Label treatment Period

Interventions: intervention 1: Romosozumab intervention 2: Placebo
Intervention descriptions: intervention 1: Subjects will receive romosozumab in a specified sequence during the treatment Period. intervention 2: Subjects will receive Placebo in a specified sequence during the treatment Period.

Protocol document:
Prot_000.pdf: 
UCB 
 
23 Mar 2022 
Clinical Study Protocol 
Romosozumab 
OP0002 
 
 
 
Confidential 
Page 1 of 108 
PROTOCOL OP0002 AMENDMENT 3 
 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE 
EFFICACY, SAFETY AND TOLERABILITY OF 
ROMOSOZUMAB TREATMENT IN POSTMENOPAUSAL 
CHINESE WOMEN WITH OSTEOPOROSIS 
 
PHASE 3 
  
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
 
Protocol/Amendment number 
Date 
Type of amendment 
Final Protocol 
05 Apr 2019 
Not applicable 
Protocol Amendment 1 
22 May 2019 
Nonsubstantial 
Protocol Amendment 2  
14 Jan 2020 
Substantial 
Protocol Amendment 3 
23 Mar 2022 
Substantial 
Confidential Material 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
 
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Clinical Study Protocol 
Romosozumab 
OP0002 
 
 
 
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STUDY CONTACT INFORMATION 
Sponsor 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Sponsor Study Physician 
Name: 
 
Address: 
UCB Pharma,  
Yintai Office Tower C, 
Beijing Yintai Centre No. 2 Jianguomenwai Street, Chaoyang 
District, 
Beijing, 3802 28,  
PR CHINA 
Phone: 
 
Lead Clinical Development Representative 
Name: 
 
Address: 
UCB BIOSCIENCES GmbH,  
Alfred-Nobel-Str.10, 
40789 Monheim am Rhein,  
GERMANY 
Phone: 
 
Clinical Project Manager 
Name: 
 
Address: 
UCB Pharma,  
Suite 
, Raffles City,  
No 268, Xizang M Road, 
Shanghai, 200001, 
PR CHINA 
Phone: 
 
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Clinical Study Protocol 
Romosozumab 
OP0002 
 
 
 
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Clinical Trial Biostatistician 
Name: 
 
Address: 
UCB Pharma,  
Suite 
, Raffles City,  
Shanghai Office Tower,  
268 Tibet Road Central,  
Shanghai, 200001,  
PR CHINA 
Phone: 
 
Clinical Monitoring Contract Research Organization 
Name: 
PAREXEL China Co. Ltd. 
Address: 
20F, Taiping Finance Tower No. 488,  
Middle Yincheng Road 
Pudong, Shanghai 200120,  
PR CHINA 
Phone: 
+86-21-5111-8000 
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Clinical Study Protocol 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
Europe and Rest of the World: +32 2 386 24 21 
Email 
Global: DS_ICT@ucb.com (for interventional clinical studies)  
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Romosozumab 
OP0002 
 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................. 11 
1 
SUMMARY ..................................................................................................................... 14 
2 
INTRODUCTION ........................................................................................................... 15 
2.1 
Background of product ................................................................................................ 15 
2.2 
Global clinical development program .......................................................................... 15 
2.3 
Osteoporosis ................................................................................................................. 18 
2.3.1 
Prevalence of osteoporosis .................................................................................. 18 
2.3.2 
Burden of the disease ........................................................................................... 18 
2.3.3 
Prevalence of osteoporosis in China .................................................................... 19 
2.3.4 
Current treatments for osteoporosis and their limitations .................................... 20 
2.3.5 
Current treatment approach for osteoporosis in China ........................................ 21 
2.4 
Rationale for the study ................................................................................................. 23 
3 
STUDY OBJECTIVES .................................................................................................... 23 
3.1 
Objectives for the Double-Blind, Placebo-Controlled Period ..................................... 23 
3.1.1 
Primary objective ................................................................................................. 23 
3.1.2 
Secondary objective ............................................................................................. 23 
3.1.3 
Other objectives ................................................................................................... 23 
3.1.4 
Safety objective ................................................................................................... 23 
3.2 
Objectives for the Open-Label Treatment Period ........................................................ 23 
3.2.1 
Secondary objective ............................................................................................. 23 
3.2.2 
Other objectives ................................................................................................... 24 
3.2.3 
Safety objectives .................................................................................................. 24 
4 
STUDY VARIABLES ..................................................................................................... 25 
4.1 
Study variables for the Double-Blind, Placebo-Controlled Period .............................. 25 
4.1.1 
Efficacy variables ................................................................................................ 25 
4.1.1.1 
Primary efficacy variable .......................................................................... 25 
4.1.1.2 
Secondary efficacy variables ..................................................................... 25 
4.1.1.3 
Other efficacy variables ............................................................................. 25 
4.1.2 
Pharmacokinetic and pharmacodynamic variables .............................................. 25 
4.1.2.1 
Other pharmacokinetic variables ............................................................... 25 
4.1.2.2 
Other pharmacodynamic variables ............................................................ 25 
4.1.3 
Safety variables .................................................................................................... 25 
4.1.3.1 
Primary safety variable .............................................................................. 25 
4.1.3.2 
Other safety variables ................................................................................ 25 
4.2 
Study variables for the Open-Label Treatment Period ................................................ 26 
4.2.1 
Efficacy variables ................................................................................................ 26 
4.2.1.1 
Secondary efficacy variables ..................................................................... 26 
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4.2.1.2 
Other efficacy variables ............................................................................. 26 
4.2.2 
Pharmacokinetic and pharmacodynamic variables .............................................. 26 
4.2.2.1 
Other pharmacokinetic variables ............................................................... 26 
4.2.2.2 
Other pharmacodynamic variables ............................................................ 27 
4.2.3 
Safety variables .................................................................................................... 27 
4.2.3.1 
Primary safety variable .............................................................................. 27 
4.2.3.2 
Other safety variables ................................................................................ 27 
5 
STUDY DESIGN ............................................................................................................. 27 
5.1 
Study description ......................................................................................................... 27 
5.1.1 
Screening Period .................................................................................................. 28 
5.1.2 
Double-Blind, Placebo-Controlled Period ........................................................... 28 
5.1.3 
Open-Label Treatment Period ............................................................................. 28 
5.1.4 
Follow-Up Period ................................................................................................ 29 
5.1.5 
Study duration per subject ................................................................................... 29 
5.1.6 
Planned number of subjects and sites .................................................................. 30 
5.1.7 
Anticipated regions and countries ....................................................................... 30 
5.2 
Schedule of study assessments..................................................................................... 30 
5.3 
Schematic diagram ....................................................................................................... 35 
5.4 
Rationale for study design and selection of dose ......................................................... 36 
5.4.1 
Rationale for the dose selected for romosozumab ............................................... 36 
5.4.2 
Rationale for selecting the BMD endpoint .......................................................... 36 
5.4.3 
Rationale for 6-month duration of Double-Blind Period as primary efficacy 
endpoint ............................................................................................................... 37 
5.4.4 
Rationale for placebo-controlled study with an Open-Label Treatment Period. . 38 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 38 
6.1 
Inclusion criteria .......................................................................................................... 38 
6.2 
Exclusion criteria ......................................................................................................... 39 
6.3 
Withdrawal criteria ...................................................................................................... 42 
6.3.1 
Withdrawal of IMP .............................................................................................. 42 
6.3.2 
Withdrawal from study ........................................................................................ 42 
6.3.3 
Potential drug-induced liver injury IMP discontinuation criteria ........................ 43 
6.4 
Retesting ...................................................................................................................... 44 
6.5 
Lateral spine x-ray at Screening .................................................................................. 44 
7 
STUDY TREATMENT ................................................................................................... 44 
7.1 
Description of investigational medicinal product ........................................................ 44 
7.2 
Treatments to be administered ..................................................................................... 45 
7.3 
Packaging ..................................................................................................................... 45 
7.4 
Labeling ....................................................................................................................... 46 
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7.5 
Handling and storage requirements ............................................................................. 46 
7.6 
Drug accountability ...................................................................................................... 46 
7.7 
Procedures for monitoring subject compliance ............................................................ 47 
7.8 
Concomitant medications/treatments ........................................................................... 47 
7.8.1 
Permitted concomitant treatments (medications and therapies) .......................... 47 
7.8.1.1 
Calcium and vitamin D supplementation .................................................. 47 
7.8.2 
Prohibited concomitant treatments (medications and therapies) ......................... 48 
7.8.3 
Rescue medication ............................................................................................... 48 
7.9 
Blinding........................................................................................................................ 48 
7.9.1 
Procedures for maintaining and breaking the treatment blind ............................. 49 
7.9.1.1 
Double-Blind, Placebo-Controlled Period ................................................ 49 
7.9.1.2 
Open-Label Treatment Period ................................................................... 49 
7.9.1.3 
Maintenance of study treatment blind ....................................................... 49 
7.9.1.4 
Breaking the treatment blind in an emergency situation ........................... 49 
7.10 
Randomization and numbering of subjects .................................................................. 50 
8 
STUDY PROCEDURES BY VISIT ............................................................................... 50 
8.1 
Screening Visit (Visit 1) (up to 35 days) ..................................................................... 50 
8.2 
Double-Blind, Placebo-Controlled Period ................................................................... 52 
8.2.1 
Visit 2 (Day 1) ..................................................................................................... 52 
8.2.2 
Visit 3 (Month 1) and Visit 5 (Month 3) ............................................................. 53 
8.2.3 
Visit 4 (Month 2), Visit 6 (Month 4), and Visit 7 (Month 5) .............................. 53 
8.2.4 
Visit 8 (Month 6) ................................................................................................. 54 
8.3 
Open-Label Treatment Period ...................................................................................... 54 
8.3.1 
Visit 9 (Month 7) and Visit 11 (Month 9) ........................................................... 54 
8.3.2 
Visit 10 (Month 8), Visit 12 (Month 10), and Visit 13 (Month 11) .................... 55 
8.3.3 
Visit 14 (Month 12) ............................................................................................. 55 
8.4 
Follow-Up Period......................................................................................................... 56 
8.4.1 
Visit 15 (Month 15) – End-of-Study Visit ........................................................... 56 
8.5 
Early Termination Visit ............................................................................................... 56 
8.6 
Unscheduled Visit ........................................................................................................ 57 
8.7 
Study conduct during coronavirus disease 2019 .......................................................... 57 
9 
ASSESSMENT OF PHARMACOKINETIC/PHARMACODYNAMIC VARIABLES 58 
9.1 
Assessment of pharmacokinetic variables ................................................................... 58 
9.2 
Assessment of pharmacodynamic variables ................................................................ 58 
10 ASSESSMENT OF EFFICACY ...................................................................................... 59 
10.1 
Bone mineral density measurements ........................................................................... 59 
11 ASSESSMENT OF SAFETY .......................................................................................... 60 
11.1 
Adverse events ............................................................................................................. 60 
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11.1.1 
Definitions ........................................................................................................... 60 
11.1.1.1 
Adverse event ............................................................................................ 60 
11.1.1.2 
Serious adverse event ................................................................................ 60 
11.1.1.3 
Adverse events of special interest ............................................................. 62 
11.1.1.4 
Adverse events of interest ......................................................................... 62 
11.1.2 
Procedures for reporting and recording adverse events ....................................... 63 
11.1.2.1 
Description of adverse events .................................................................... 63 
11.1.2.2 
Rule for repetition of an adverse event...................................................... 63 
11.1.2.3 
Additional procedures for reporting serious adverse events ..................... 63 
11.1.3 
Follow up of adverse events ................................................................................ 64 
11.2 
Pregnancy ..................................................................................................................... 64 
11.3 
Suspected transmission of an infectious agent............................................................. 65 
11.4 
Overdose of investigational medicinal product ........................................................... 65 
11.5 
Safety signal detection ................................................................................................. 65 
11.6 
Laboratory measurements ............................................................................................ 66 
11.6.1 
Evaluation of PDILI ............................................................................................ 67 
11.6.1.1 
Consultation with Medical Monitor and local hepatologist ...................... 71 
11.6.1.2 
Immediate action: determination of IMP discontinuation ......................... 71 
11.6.1.3 
Testing: identification/exclusion of alternative etiology ........................... 72 
11.6.1.4 
Follow-up evaluation ................................................................................. 73 
11.7 
Other safety measurements .......................................................................................... 73 
11.7.1 
Vital sign measurements ...................................................................................... 73 
11.7.2 
12-lead ECG recordings ...................................................................................... 74 
11.7.3 
Physical examination ........................................................................................... 74 
11.7.4 
Body weight and height ....................................................................................... 74 
11.7.5 
Antibodies to romosozumab ................................................................................ 74 
12 STUDY MANAGEMENT AND ADMINISTRATION ................................................. 75 
12.1 
Adherence to protocol .................................................................................................. 75 
12.2 
Monitoring ................................................................................................................... 75 
12.2.1 
Definition of source data ..................................................................................... 75 
12.2.2 
Source data verification ....................................................................................... 76 
12.3 
Data handling ............................................................................................................... 76 
12.3.1 
Case Report form completion .............................................................................. 76 
12.3.2 
Database entry and reconciliation ........................................................................ 76 
12.3.3 
Subject Screening and Enrollment log/Subject Identification Code list.............. 77 
12.4 
Termination of the study .............................................................................................. 77 
12.5 
Archiving and data retention ........................................................................................ 77 
12.6 
Audit and inspection .................................................................................................... 77 
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12.7 
Good Clinical Practice ................................................................................................. 78 
13 STATISTICS ................................................................................................................... 78 
13.1 
Definition of analysis sets ............................................................................................ 78 
13.2 
General statistical considerations ................................................................................. 79 
13.3 
Planned analyses .......................................................................................................... 79 
13.3.1 
6-month analysis .................................................................................................. 79 
13.3.2 
Final analysis ....................................................................................................... 80 
13.4 
Planned efficacy analysis ............................................................................................. 80 
13.4.1 
Analysis of the primary efficacy variable ............................................................ 80 
13.4.1.1 
Analysis of secondary variables ................................................................ 81 
13.4.2 
Planned pharmacokinetic and pharmacodynamic analyses ................................. 81 
13.4.2.1 
Planned pharmacokinetic analyses ............................................................ 81 
13.4.2.2 
Planned pharmacodynamic analyses ......................................................... 81 
13.4.3 
Planned safety and other analyses ....................................................................... 82 
13.4.3.1 
Safety analyses .......................................................................................... 82 
13.5 
Handling of protocol deviations................................................................................... 82 
13.6 
Handling of dropouts or missing data .......................................................................... 82 
13.7 
Planned interim analysis and data monitoring ............................................................. 83 
13.8 
Determination of sample size ....................................................................................... 84 
14 ETHICS AND REGULATORY REQUIREMENTS ...................................................... 85 
14.1 
Informed consent ......................................................................................................... 85 
14.2 
Subject identification cards .......................................................................................... 85 
14.3 
Institutional Review Boards and Independent Ethics Committees .............................. 85 
14.4 
Subject privacy............................................................................................................. 86 
14.5 
Protocol amendments ................................................................................................... 86 
15 FINANCE, INSURANCE, AND PUBLICATION ......................................................... 86 
16 REFERENCES (AVAILABLE UPON REQUEST) ....................................................... 87 
17 APPENDICES ................................................................................................................. 90 
17.1 
Protocol Amendment 1 ................................................................................................ 90 
17.2 
Protocol Amendment 2 ................................................................................................ 91 
17.3 
Protocol Amendment 3 .............................................................................................. 103 
18 DECLARATION AND SIGNATURE OF INVESTIGATOR ..................................... 107 
19 SPONSOR DECLARATION ........................................................................................ 108 
 
LIST OF TABLES 
Table 2‒1: 
Epidemiology data on osteoporosis in China................................................... 19 
Table 2‒2: 
Pharmacologic therapies for postmenopausal osteoporosis available in 
China, EU, and USA ........................................................................................ 22 
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OP0002 
 
 
 
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Table 5‒1: 
Schedule of study assessments......................................................................... 31 
Table 6‒1:  
Semiquantitive (SQ) grading scale .................................................................. 44 
Table 11‒1: 
Anticipated SAEs for osteoporotic population ................................................ 62 
Table 11‒2: 
Clinical laboratory measurements.................................................................... 66 
Table 11‒3: 
Required investigations and follow up for PDILI............................................ 69 
Table 11‒4: 
PDILI laboratory measurements ...................................................................... 72 
Table 11‒5: 
PDILI information to be collected ................................................................... 73 
 
LIST OF FIGURES 
Figure 5‒1: 
Overall study design for OP0002 ..................................................................... 35 
 
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OP0002 
 
 
 
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LIST OF ABBREVIATIONS  
AE 
adverse event 
AFF 
atypical femoral fracture 
ALN 
alendronate 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMD 
bone mineral density 
BP 
blood pressure 
BSAP 
bone-specific alkaline phosphatase 
BTM 
bone turnover marker 
BW 
body weight 
CDE 
Center of Drug Evaluation 
CDMS 
clinical data management system 
CI 
confidence interval 
COVID-19 
coronavirus disease 2019 
CPM 
Clinical Project Manager 
CPMP 
Committee for Proprietary Medicinal Products 
CRO 
contract research organization 
CSR 
Clinical Study Report 
CV 
cardiovascular 
DMC 
Data Monitoring Committee 
DXA 
dual-energy x-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
electronic Case Report form 
EOS 
End-of-Study  
ES 
Enrolled Set 
ET 
Early Termination 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
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Romosozumab 
OP0002 
 
 
 
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GMP 
Good Manufacturing Practice 
HDL 
high density lipoprotein 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IMP 
investigational medicinal product 
iPTH 
intact parathyroid hormone 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
iv 
intravenous(ly) 
L 
lumbar 
LDL 
low density lipoprotein 
LLOQ 
lower limit of quantification 
LS 
least squares  
MedDRA® 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
NHANES 
National Health and Nutritional Examination Survey 
OC 
osteocalcin 
OH 
hydroxy 
OL 
open-label 
ONJ 
osteonecrosis of the jaw 
P1NP 
procollagen type 1 N-telopeptide 
PD 
pharmacodynamic(s) 
PDILI 
potential drug-induced liver injury 
PD-PPS 
Pharmacodynamic Per-Protocol Set 
PFS 
prefilled syringe(s) 
PK 
pharmacokinetic(s) 
PK-PPS 
Pharmacokinetic Per-Protocol Set 
po 
orally 
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PPS 
Per-Protocol Set 
PS 
Patient Safety 
PT  
preferred term 
PTH 
parathyroid hormone 
QM  
every month 
QW 
every week 
RS 
Randomized Set 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
sc 
subcutaneous(ly) 
sCTX 
serum type I collagen C-telopeptide 
SD 
standard deviation 
SERM 
selective estrogen receptor modulator 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SQ0, SQ1, SQ2, 
SQ3 
visual semiquantitative grading scale for vertebral fractures on lateral 
spine x-rays: SQ0=no fracture; SQ1=mild fracture; SQ2=moderate 
fracture; SQ3=severe fracture (Genant et al, 1993) 
SS 
Safety Set 
T4 
thyroxine 
TEAE 
treatment-emergent adverse event 
TMF 
trial master file 
TPTD 
teriparatide 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
WHO 
World Health Organization 
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1 
SUMMARY 
OP0002 is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study followed 
by an Open-Label (OL) Treatment Period to evaluate the efficacy, safety and tolerability of 
romosozumab treatment in postmenopausal Chinese women with osteoporosis across 
approximately 30 study sites in mainland China. 
The study consists of 4 study periods: a Screening Period (Day -35 to Day -1); a 6-month 
Double-Blind, Placebo-Controlled Period; a 6-month OL Treatment Period; and a 3-month 
Follow-Up Period.  
Overall, approximately 300 postmenopausal Chinese women with osteoporosis are expected to 
be randomized in the study to meet the study objectives. Subject eligibility will be confirmed 
during the Screening Period.  
Eligible subjects will be randomized, stratified by age, in a 2:1 ratio to receive 
romosozumab 210mg subcutaneously (sc) every month (QM) or matched placebo sc QM in a 
blinded manner for 6 months. From Screening until the End-of-Study (EOS) Visit, subjects will 
be required to take daily calcium and vitamin D supplementation. 
Upon completion of the 6-month Double-Blind, Placebo-Controlled Period, all subjects will 
enter the OL Treatment Period and receive romosozumab 210mg sc QM for 6 months in an 
OL fashion. During this period, all subjects will receive active treatment (romosozumab) 
allowing for the collection of efficacy and safety data for an additional 6 months (a total of 
12 months for subjects initially randomized to romosozumab and 6 months for those initially 
randomized to placebo).  
Subjects can decide to discontinue investigational medicinal product (IMP) but continue 
participation in the study. However, subjects who withdraw early from the study should 
complete the Early Termination (ET) Visit. Subjects who withdraw from the study will not be 
replaced.  
After completing the OL Treatment Period, subjects will be followed up for an additional 
3 months and will complete the EOS Visit (Month 15). Subject participation in the study is 
concluded after the EOS Visit. Subjects who test positive for neutralizing antibodies to 
romosozumab at the EOS Visit or ET Visit will be asked to return for additional follow-up 
testing for up to 1 year after final administration of investigational medicinal product (IMP).  
No interim analysis is planned for the study. An independent Data Monitoring Committee 
(DMC) will be formed to monitor the safety of subjects during the study.  
The 6-month analysis of efficacy and safety will be performed using the data obtained from the 
6-month Double-Blind, Placebo-Controlled Period. The primary variable of the 6-month analysis 
is the evaluation of the effect of romosozumab treatment compared with placebo on the percent 
change in bone mineral density (BMD) at the lumbar spine, as assessed by dual-energy x-ray 
absorptiometry (DXA). In addition, analyses of secondary efficacy variables include evaluation 
of the effect of romosozumab treatment compared with placebo on the percent change in BMD at 
the total hip and femoral neck. The pharmacokinetic (PK) variable (serum concentrations of 
romosozumab), pharmacodynamic (PD) variables (bone turnover markers [BTMs]), and safety 
variables will be assessed. 
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The final analysis will be performed after all subjects have the opportunity to complete the 
Month 15 Visit. The remaining efficacy, PD, and safety analyses for Month 12 and the safety 
analyses for the overall study period, ie, the period from the start of double-blind treatment to the 
Month 15 Visit for each subject, will be evaluated. The serum concentrations of romosozumab 
after 12 months of treatment (continuing 6 months of romosozumab in subjects who are initially 
randomized to 6 months of romosozumab treatment) and 6 months of treatment (in subjects who 
are randomized to placebo for 6 months and transition to romosozumab for 6 months) will be 
assessed. 
2 
INTRODUCTION 
2.1 
Background of product 
Romosozumab is a humanized immunoglobulin G (IgG) monoclonal antibody that binds to and 
inhibits sclerostin (Poole et al, 2005; van Bezooijen et al, 2004; Winkler et al, 2003; Balemans et 
al, 2001; Brunkow et al, 2001). Romosozumab has a dual effect on bone, increasing bone 
formation and decreasing bone resorption (McClung et al, 2014; Ominsky et al, 2014; Padhi et 
al, 2011), leading to rapid and substantial gains in BMD, improved bone structure and strength, 
and fracture risk reduction.  
2.2 
Global clinical development program 
A comprehensive clinical program has been developed globally for romosozumab and comprises 
of approximately 14,000 subjects across 19 clinical studies conducted in North America, Europe, 
Asia (including Hong Kong, Taiwan, Korea, and Japan), and other regions and included healthy 
subjects, postmenopausal women with osteoporosis or low BMD, and men with osteoporosis.  
Population PK/PD analyses were performed, including development of a population PK model, 
a dose-response model (which described the relationship between dose and BMD gains at both 
lumbar spine and total hip), and a concentration-response model (which described the 
relationship between romosozumab concentrations, BTMs [procollagen type 1 N-telopeptide 
(P1NP) and serum type I collagen C-telopeptide (sCTX)], and BMD gains at the lumbar spine). 
The PK profile of romosozumab is typical for an IgG monoclonal antibody, showing nonlinear 
PK at low doses due to target-mediated drug disposition. Dose-proportional increases in 
exposure are observed for doses of 140mg and higher. The PK is linear over time. No dose 
adjustments are required on the basis of patient characteristics. Population PK analysis identified 
weight, age, gender, race (Japanese vs non-Japanese), and estimated glomerular filtration rate as 
having an impact on PK, with the effect of body weight (BW) having the greatest impact 
(decreasing BW resulting in increased exposure). However, PK/PD modelling demonstrated BW 
had minimal impact on BMD gain at 12 months (±15% compared to a typical subject). 
Two studies conducted in postmenopausal Japanese women, a single-dose Phase 1 study 
(20090378) and a Phase 2 efficacy and safety study (20101291), showed similarity in dose 
response in the Japanese population versus the global population of postmenopausal women. 
Based on the Phase 2 dose-ranging study results (20060326), 2 global Phase 3 fracture studies 
(20070337 [FRAME], and 20110142 [ARCH]) were conducted in postmenopausal women with 
osteoporosis using 210-mg QM dosing for 12 months followed by antiresorptive therapy to 
demonstrate reduction of fracture risk.  
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A 12-month romosozumab treatment duration in the global Phase 3 studies was supported by the 
following considerations: 
• Substantial increases in BMD were observed during 12 months of romosozumab 
administration in the Phase 2 dose-ranging study. At 12 months, the 210-mg QM dosing 
regimen resulted in a BMD increase from baseline of 11.3% at the lumbar spine and 4.1% at 
the total hip. The BMD increases were greater with the romosozumab dose of 210mg QM 
compared with alendronate (ALN), teriparatide (TPTD), and placebo. 
• Increases in bone formation as assessed with bone formation markers were not apparent 
beyond 12 months in the Phase 2 dose-ranging study. For the romosozumab 210-mg QM 
dosing regimen, the median P1NP was 10.2% below baseline 1 week after the Month 12 
dose; in contrast to an increase of 82.7% above baseline 1 week after the Day 1 dose. 
• Based on Month 18 data available for the 210-mg QM treatment group in the Phase 2 
dose-ranging study, beyond Month 12, the BMD appeared to increase more gradually, likely 
primarily due to the antiresorptive effect and due to attenuation of the bone-forming effect as 
mentioned above. 
The 210-mg romosozumab QM dosing regimen was selected for the global Phase 3 program 
based on the following data: 
• In the Phase 2 dose-ranging study, the romosozumab 210-mg QM dosing regimen resulted in 
a greater increase in BMD at the lumbar spine and total hip at 12 months compared with 
other romosozumab dosing groups. 
• The romosozumab 210-mg QM dosing regimen resulted in the largest and most prolonged 
increase in markers of bone formation, including bone-specific alkaline phosphatase (BSAP), 
P1NP, and osteocalcin (OC) in the Phase 2 dose-ranging study. Median P1NP and OC levels 
remained above baseline up to Months 6 and 9, respectively, and median BSAP levels 
remained above baseline up to Month 12. In comparison, the 140-mg QM dosing regimen 
increased markers of bone formation for 3 to 6 months. 
• The incidence of adverse events (AEs) in the Phase 2 dose-ranging study was not dose 
related, and the incidence of neutralizing antibodies against romosozumab was low (2%) and 
similar across QM doses. Thus, the safety profile of the 210-mg QM dosing regimen does not 
appear to be appreciably different from that of lower doses. 
The sequential treatment of romosozumab followed by an antiresorptive was selected for the 
Phase 3 program based on the following findings: 
• The Phase 2 findings provided early evidence that 12 months of romosozumab treatment at a 
dose of 210mg QM may lay the foundation of increased bone mass that translated into 
significant antifracture efficacy.  
• Because the BMD gains are reversible when treatment is discontinued, follow-on with an 
antiresorptive is recommended to preserve this benefit. This established the concept of the 
sequential therapy of romosozumab for 12 months followed by an antiresorptive therapy, 
which was used for the design of the Phase 3 studies. 
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The ability of romosozumab to reduce the risk of fracture in postmenopausal women with 
osteoporosis has been demonstrated in the 2 pivotal Phase 3 fracture studies: 
20070337 
This Phase 3, multicenter, parallel-group study in women with postmenopausal osteoporosis was 
designed to evaluate if romosozumab treatment for 12 months compared with placebo was 
effective in reducing the incidence of new vertebral fractures, and if romosozumab treatment for 
12 months followed by denosumab treatment for 12 months was effective in reducing the 
incidence of new vertebral fractures compared with 12 months of placebo followed by 
denosumab treatment for 12 months. The study met the coprimary endpoints by reducing the 
incidence of new vertebral fracture through Months 12 and 24 in postmenopausal women with 
osteoporosis treated with romosozumab. Subjects receiving sc injections of romosozumab 
210mg QM had a statistically significant 73% reduction in the relative risk of a vertebral fracture 
through 12 months compared with those receiving placebo (p <0.001). The effect size persisted 
after both groups were transitioned to denosumab through the second year of treatment. 
Specifically, through Month 24, romosozumab followed by denosumab reduced the relative risk 
of new vertebral fracture by a statistically significant 75% compared with placebo followed by 
denosumab (p <0.001). 
20110142 
In this Phase 3, multicenter, randomized, double-blind, ALN-controlled study, 
4093 postmenopausal women with osteoporosis were randomized in a 1:1 ratio to receive either 
romosozumab 210mg sc QM (2046 subjects) or ALN 70mg orally (po) every week (QW) 
(2047 subjects) for 12 months. After the initial 12-month study period, all subjects received ALN 
while remaining blinded to their initial treatment assignment. The Primary Analysis was 
performed when clinical fracture events (comprising of nonvertebral fracture or clinical vertebral 
fracture) were confirmed for at least 330 subjects and all subjects had the opportunity to 
complete the Month 24 study visit. 
The results at the time of the Primary Analysis (median observation time 33 months) 
demonstrated that treatment with romosozumab for 12 months followed by ALN significantly 
reduced the incidence of new vertebral fractures through 24 months (coprimary endpoint), 
clinical fractures (coprimary endpoint), and nonvertebral fractures (key secondary endpoint) in 
postmenopausal women with osteoporosis at high risk for fracture compared with ALN alone. At 
24 months, subjects in the romosozumab treatment group had a statistically significant 50% 
reduction in the relative risk of a new vertebral (spine) fracture compared with those receiving 
ALN alone. At the time of the Primary Analysis, subjects in the romosozumab treatment group 
had a 27% reduction in the relative risk of clinical fracture and a 19% reduction in nonvertebral 
fractures, compared with those receiving ALN alone. A nominally significant reduction in hip 
fractures was also observed in subjects in the romosozumab treatment group. 
Subject incidence of AEs and serious adverse events (SAEs) were generally well balanced 
between treatment groups in each study. In the 2 Phase 3 studies (20070337 and 20110142), the 
number of positively-adjudicated events of atypical femoral fracture (AFF) and osteonecrosis of 
the jaw (ONJ) was low. In 20110142, a numerical imbalance in the positively-adjudicated 
cardiovascular (CV) SAEs was observed between the romosozumab and ALN groups at 
12 months. This imbalance was observed specifically for serious cardiac ischemic and 
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cerebrovascular events, with a higher incidence in the romosozumab group compared with the 
ALN group (romosozumab: 0.8% for both events; ALN: 0.3% for both events). These findings 
were not observed at 12 months in the larger, placebo-controlled study in postmenopausal 
women with osteoporosis (20070337). A causal relationship between romosozumab and 
CV SAEs has not been established.  
Across the studies, the benefit-risk profile of romosozumab is considered favorable. Treatment 
with romosozumab has demonstrated fracture risk reduction within 12 months, ongoing fracture 
risk reduction maintained with follow-on antiresorptive therapy, and robust improvement in 
BMD at the spine and the hip (including in subjects previously treated with antiresorptive 
therapy). 
Further information on the studies mentioned above can be found in Section 5.4.  
Refer to the Investigator’s Brochure (IB) for more detailed information on romosozumab (eg, 
pharmacology, quality, nonclinical data, clinical data, and Reference Safety Information). 
2.3 
Osteoporosis  
2.3.1 
Prevalence of osteoporosis 
Osteoporosis is a condition caused by an imbalance of osteoblast and osteoclast activity resulting 
in progressive loss of bone density and strength, which can lead to fragility fractures and result in 
patient burden and increased mortality (Cummings and Melton, 2002; NIH Consensus 
Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy, 2001). 
The lifetime risk of osteoporotic fracture overall is 40% to 42% among women in Western 
Europe and Australia, and approximately 50% among white women aged 50 years and older in 
the US (National Osteoporosis Foundation, 2014; Office of the Surgeon General, 2004). 
Estimates from the USA, Europe, Australia, Canada, and Japan suggest that across these 
countries approximately 44 million women aged 50 years or older have postmenopausal 
osteoporosis (Wade et al, 2014; Hernlund et al, 2013) and approximately 4.5 million suffer 
osteoporotic fractures annually (Hernlund et al, 2013; Wade et al, 2012; Burge et al, 2007). The 
number of osteoporosis-related fractures is projected to increase substantially as the world’s 
population ages. While osteoporosis and osteoporotic fractures are most commonly associated 
with postmenopausal women, these are also observed in men. 
2.3.2 
Burden of the disease  
Osteoporosis and resulting fragility fractures are a costly burden to patients, payers, and society. 
In particular, fractures lead to significant impairment in mobility, which can have a long-lasting 
impact on social and physical functioning. In addition, fractures and associated functional losses 
lead to high levels of disability resulting in increased use of long-term institutional care and 
rehabilitation services. 
In postmenopausal women and in men, fragility fractures confer ongoing pain and discomfort, 
which impact physical function, emotional status, self-care, and usual activities, resulting in 
long-term health-related quality of life reductions similar to those seen with chronic diseases 
such as diabetes, arthritis, and lung disease. Moreover, fragility fractures, particularly those of 
the hip or spine, are associated with increased mortality, which may persist for several years. 
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This mortality risk increases even further with the occurrence of a second fracture (Bliuc et al, 
2009; Johnell et al, 2004). 
Prior fracture is among the strongest risk factors for subsequent fracture. Hip fractures result in a 
2.5-fold increased risk of subsequent fractures, and vertebral fractures result in a 5-fold increased 
risk for subsequent vertebral fracture and a 2- to 3-fold increased risk for fractures at other sites 
(National Osteoporosis Foundation, 2014; van Helden et al, 2006; Colón-Emeric et al, 2003). 
The incidence of a new vertebral fracture in the year after a previous fracture is about 19% 
(Lindsay et al, 2001). Van Geel and colleagues, in a population-based study of 
4140 postmenopausal women, found the risk of subsequent clinical fracture (which encompasses 
nonvertebral fractures and symptomatic vertebral fractures) was about double the risk of a first 
fracture (van Geel et al, 2009). Of all subsequent fractures, 23% occurred within 1 year after the 
first fracture and 54% occurred within 5 years. 
2.3.3 
Prevalence of osteoporosis in China 
Although limited, epidemiology data on osteoporosis are available for China as shown in 
Table 2‒1.  
Table 2‒1: 
Epidemiology data on osteoporosis in China 
 
Total population 
50 years and older 
General 
Male 
Female 
General 
Male 
Female 
2006 surveya 
NA 
4.2% 
12.8% 
15.7% 
8.8% 
30.8% 
2009 reviewb 
13% 
NA 
NA 
NA 
22.4% 
40.1% 
2016 meta-analysisc  
NA 
15.33% 
25.41% 
34.65% 
NA 
NA 
NA=not applicable 
a China Health Promotion Foundation. White Paper, 2008 
b Wang et al, 2009 
c Chen et al, 2016 
The prevalence rate of osteoporosis in China has increased in past decades. A 2016 
meta-analysis showed that the prevalence rate in 2003 to 2008, 2009 to 2011, 2012 to 2015 was 
14.94%, 23.65%, and 27.96%, respectively. Similar to the global population, in China the 
prevalence rates of osteoporosis increased with age. In the 2016 meta-analysis, the prevalence 
rate by age group (40 to 50, 50 to 60, 60 to 70, 70 to 80, and 80+ years) was 8.88%, 19.57%, 
35.1%, 43.48%, and 56.10%, respectively (Chen et al, 2016). This indicates that aging is one of 
the main risk factors of osteoporosis. China has a population of 1.4 billion, which is about 
18.9% of the world population. The population aged over 60 years had increased from 
130 million (10.97%) at the end of the twentieth century to 210 million (15.5%) in 2015 
(Osteoporosis and Bone Mineral Research Society of the Chinese Medical Association, 2017; 
Lin et al, 2015). The National Statistics Bureau data stated that in China in 2016 around 
418 million inhabitants were over 50 years of age, of whom, 150 million had osteoporosis. Due 
to the aging population in China, osteoporosis will gradually become a major public health 
problem. 
Osteoporotic fracture, one of the most severe complications of osteoporosis, is prevalent among 
the elderly population with osteoporosis. This is considered to be a fracture from low-energy 
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trauma that is defined as a fall from a standing height or less, or a trauma that would not give rise 
to fracture in a healthy individual. A cross-sectional and population-based study conducted in 
Shanghai showed that the prevalence of osteoporotic fractures in the elderly was 15.9% in 
females and 14.3% in males. A large national study in Beijing found that the prevalence of 
fractures in the elderly was 26.6% (Lin et al, 2015).  
Hip fracture can lead to devastating consequences, causing both significant morbidity and excess 
mortality. The average annual number of hip fractures in people older than 50 years, according to 
the Beijing Ministry of Health, increased from 479 to 2423 in women and from 441 to 1586 in 
men between 1990 and 2004. Meanwhile, from 2002 to 2006, the rates of hip fractures for those 
aged 50 years or older increased by 58% in women and 49% in men. Similar trends can also be 
seen in other areas of China including Taiwan, Chongqing, and Hefei. A patient who has 
survived a hip fracture usually exhibits decreased mobility, impaired quality of life, more 
dependence on family, and increased demand for medical caregivers and social services, as well 
as a substantial physical, mental, and financial burden. The rate of disability is up to 50% and the 
mortality is as high as 15% to 33% in the first year after the hip fracture. Worse still, about 
28% of females and 37.5% of males who suffer a hip fracture die by the second year. Similar to 
other countries, among all types of osteoporotic fractures, the cost of hip fractures is the highest 
(Lin et al, 2015). 
Despite being the most common complication of osteoporosis, accounting for almost 50% of all 
osteoporotic fractures, vertebral fractures have received less attention compared to hip fractures. 
The prevalence of vertebral fracture is increasing in association with aging. The prevalence of 
vertebral fractures is lower than 20% for people aged 50 to 69 years in Beijing, Chengdu, and 
Shanghai, and for people aged 70 to 79 years is 19%, 25.1%, and 25.42%, respectively. 
However, for people over 80 years of age, the prevalence of vertebral fractures is above 36% in 
all 3 cities (Lin et al, 2015).  
In China in 2015, 2.69 million major osteoporotic fractures (vertebral, hip, wrist fractures) 
occurred and cost 72 billion RMB, with estimates of osteoporotic fractures reaching 4.83 million 
in 2035 and 5.99 million in 2050. Meanwhile, the cost in 2035 and 2050 is estimated to be 
$19.92 billion and $25.43 billion, respectively (Si et al, 2015). Overall, beyond the burden to the 
patients and families, osteoporosis and associated fractures represents also a high financial 
burden to society. 
2.3.4 
Current treatments for osteoporosis and their limitations  
Despite there being a broad range of available therapies, there is an existing unmet medical need 
in osteoporosis, especially for patients who are at increased risk of fractures. The efficacy of 
antiresorptive therapies for the treatment of osteoporosis has been well documented. And yet, for 
patients with osteoporosis at increased risk of fracture, notably in those who have had a recent 
fracture, the time to onset of effect with current therapies may leave certain groups of patients 
insufficiently protected early in treatment. For some antiresorptive therapies (ALN, ibandronate, 
and bazedoxifene), studies have shown that it takes 3 years or longer to demonstrate a significant 
reduction in the risk of vertebral, nonvertebral, or clinical fracture. Given that patients with 
osteoporosis are most likely to suffer subsequent fractures in the 2-year period immediately 
following their previous (or first) fracture, there is an immediate need for treatments that lead to 
clinically meaningful improvements in BMD within this 2-year period. 
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In addition to efficacy concerns, nitrogen-containing bisphosphonates such as ALN, risedronate, 
and ibandronate have been associated with gastrointestinal side effects. Alendronate and oral 
ibandronate are contraindicated in patients with disorders involving delayed passage through the 
esophagus, such as esophageal stricture and achalasia (Boniva® package insert, 2016; Bonviva 
Summary of Product Characteristics [SmPC]; Fosamax® package insert, 2015; Fosavance 
SmPC). Furthermore, drugs of this class have to be administered with an adequate volume of 
water at the time of awakening every morning when taken po, and patients receiving this therapy 
are not permitted to lie down, to ingest anything else but water, nor to take other oral medication 
for at least 30 minutes after each dose. Because of these limitations, there are patients who 
cannot begin or continue to use this class of drugs or who cannot comply with the instructions 
for dosing, despite an increased risk of fracture.  
Although other antiresorptive therapies such as risedronate, raloxifene, and denosumab 
demonstrated significant reductions of 60% to 68% in the risk of vertebral fractures in their 
respective pivotal clinical studies within 1 year (Cummings et al, 2009; Maricic et al, 2002; 
Harris et al, 1999), bone-forming therapies can provide larger improvements in bone structure 
and strength; however, only 1 class of bone-forming therapies is available – parathyroid hormone 
(PTH) analogs.  
The PTH fragment, TPTD, is the only widely available bone-forming agent. Teriparatide has 
some limitations, such as the need for daily injections, a relatively small BMD increase at the hip 
(2.6% total hip in 19 months and even more limited in patients previously exposed to a 
bisphosphonate [Miller et al, 2008; Neer et al, 2001]), and a special warning of potential risk of 
osteosarcoma, limiting the treatment duration to 24 months in a lifetime. For TPTD, the time to 
onset of effect may leave patients relatively unprotected early in treatment. According to 1 study, 
about 12% of patients had a fracture in the 2 years following initiation of TPTD use, even in 
persistent users, and most of those fractures (64%) occurred during the first year on therapy 
(Bonafede et al, 2015). Furthermore, transitioning patients from a bisphosphonate to TPTD, 
which is more common than use of TPTD as first-line treatment, can lead to significantly 
reduced or delayed gains in BMD over the first year of treatment relative to treatment-naïve 
subjects, particularly at the hip (Miller et al, 2008; Obermayer-Pietsch et al, 2008; Ettinger et 
al,  2004). In the USA, another bone-building agent has been recently approved, abaloparatide 
(Tymlos™, Radius Health, Inc, MA, USA) for postmenopausal women with osteoporosis at high 
risk for fracture due to a history of osteoporotic fracture, multiple risk factors for fracture, or 
patients who have not responded to or are intolerant to other available osteoporosis therapy 
(Food and Drug Administration approval date: 28 Apr 2017). This product is not currently 
approved in EU or China, and like TPTD, abaloparatide is administered by daily injection. 
2.3.5 
Current treatment approach for osteoporosis in China 
In China, the updated guideline of diagnosis/treatment of osteoporosis has been published in 
2017 by the Osteoporosis And Bone Mineral Research Society of the Chinese Medical 
Association.  
The diagnosis of osteoporosis is based on BMD and history of fragility fracture. For BMD, DXA 
exam at the lumbar spine or proximal femur is the gold standard for diagnosis. The T-score 
evaluation is based on the World Health Organization (WHO) criteria (2007) and using database 
of healthy peak BMD. Other than BMD exams and fragility fractures, BTMs and blood tests are 
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used for supportive and differential diagnosis. The BMD assessments can be used as a surrogate 
for efficacy evaluation and fracture risk evaluation, consistent with Western countries. 
Besides the basic treatment including lifestyle change, calcium and vitamin D supplementation, 
pharmacologic therapies are indicated to manage osteoporosis patients. There are 3 categories of 
drugs available in China: i) antiresorptive agents, ii) bone-forming agents, and iii) others. The 
majority of available pharmacologic therapies belong in the category of antiresorptive agents, 
among which, bisphosphonates are the most widely used (Table 2‒2).Further information on the 
antiresorptive and bone-forming agents is presented in Section 2.3.4. In China, ALN has an 
indication of osteoporosis in males. Calcitonin has good efficacy on ostalgia, but has a limitation 
of 3 months continuous usage due to risk of malignancies.  
Overall, even though some treatment options available elsewhere are not yet available in China 
(eg, abaloparatide, bazedoxifene, denosumab), the basic treatment approach for osteoporosis in 
the elderly in China is basically similar to other countries. Thus, there remains an unmet medical 
need in China for a therapy that rapidly increases bone mass and bone strength and delivers 
fracture risk protection, which is particularly important in patients who have already suffered a 
fracture or are otherwise at increased risk for fracture in the near term. 
Table 2‒2: 
Pharmacologic therapies for postmenopausal osteoporosis 
available in China, EU, and USA 
Drug category 
Drug class 
Drug name 
China 
EU 
USA 
Antiresorptive 
Bisphosphonates 
Alendronate 
Yes 
Yes 
Yes 
Ibandronate 
Yes 
Yes 
Yes 
Risedronate 
Yes 
Yes 
Yes 
Zoledronic acid 
Yes 
Yes 
Yes 
Calcitonin 
Calcitonin 
Yes 
Yes 
Yes 
Hormone replacement 
therapy 
Estrogen 
Yes 
Yes 
Yes 
Selective estrogen 
receptor modulator  
Raloxifene 
Yes 
Yes 
Yes 
Bazedoxifene 
No 
Yes 
Yes 
RANK ligand inhibitor 
Denosumab 
Yes 
Yes 
Yes 
Bone-forming 
agent 
Parathyroid hormone 
Teriparatide 
Yes 
Yes 
Yes 
Parathyroid hormone-
related protein 
(PTHrP) 
Abaloparatide 
No 
No 
Yes 
 
Other 
Vitamin D analogous 
Yes 
Yes 
Yes 
Strontium 
Noa 
Noa 
No 
RANK=receptor activator of nuclear factor kappa-B 
a Servier (manufacturer of strontium ranelate) withdrew their brand medicine Protelos (strontium ranelate) in 2017. 
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2.4 
Rationale for the study 
UCB proposes to conduct a Phase 3 study to evaluate the efficacy and safety of romosozumab 
treatment in postmenopausal Chinese women with osteoporosis. The requirements for this study 
and the study design were discussed between the sponsor and Center of Drug Evaluation (CDE) 
at the Chinese Agency in 2018. 
3 
STUDY OBJECTIVES 
3.1 
Objectives for the Double-Blind, Placebo-Controlled Period 
3.1.1 
Primary objective  
The primary objective is to evaluate the effect of treatment with romosozumab for 6 months 
compared with placebo on the percent change in BMD at the lumbar spine in postmenopausal 
Chinese women with osteoporosis. 
3.1.2 
Secondary objective 
The secondary objective is to evaluate the effect of treatment with romosozumab for 6 months 
compared with placebo on the percent change in BMD at the total hip and femoral neck in 
postmenopausal Chinese women with osteoporosis.  
3.1.3 
Other objectives 
The other objectives are as follows: 
• To evaluate the effect of treatment with romosozumab for 3 months compared to placebo on 
the percent change in BMD at the lumbar spine, total hip, and femoral neck in 
postmenopausal Chinese women with osteoporosis. 
• To evaluate the effect of treatment with romosozumab at 1-, 3-, and 6-month time points 
compared with placebo on the percent changes in BTMs in postmenopausal Chinese women 
with osteoporosis. The BTMs include the bone formation marker P1NP and the bone 
resorption marker sCTX. 
• To characterize serum concentrations of romosozumab in postmenopausal Chinese women 
with osteoporosis who are randomized to romosozumab treatment. 
3.1.4 
Safety objective 
The safety objective is to characterize the safety and tolerability of romosozumab treatment for 
6 months compared with placebo in postmenopausal Chinese women with osteoporosis. 
3.2 
Objectives for the Open-Label Treatment Period 
3.2.1 
Secondary objective 
The secondary objective is to describe the percent change in BMD at the lumbar spine, total hip, 
and femoral neck in postmenopausal Chinese women with osteoporosis who are continuing with 
6 months of romosozumab treatment after initially being randomized to 6 months of 
romosozumab treatment in the Double-Blind, Placebo-Controlled Period (a total of 12 months of 
romosozumab treatment).  
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3.2.2 
Other objectives 
The other objectives are as follows: 
• To describe the percent change in BMD at the lumbar spine, total hip, and femoral neck in 
postmenopausal Chinese women with osteoporosis who transition to 6 months of 
romosozumab treatment after initially being randomized to placebo in the Double-Blind, 
Placebo-Controlled Period. 
• To describe the percent changes in BTMs in postmenopausal Chinese women with 
osteoporosis who are continuing with 6 months of romosozumab treatment after initially 
being randomized to 6 months of romosozumab treatment in the Double-Blind, 
Placebo-Controlled Period (for a total of 12 months of romosozumab treatment). The BTMs 
include bone formation marker P1NP and bone resorption marker sCTX. 
• To describe the percent changes in BTMs in postmenopausal Chinese women with 
osteoporosis who transition to 6 months of romosozumab treatment after initially being 
randomized to placebo in the Double-Blind, Placebo-Controlled Period. The BTMs include 
bone formation marker P1NP and bone resorption marker sCTX. 
• To describe area under the curve (AUC) for the entire 12-month treatment for P1NP in 
postmenopausal Chinese women with osteoporosis who are continuing with 6 months of 
romosozumab treatment after initially being randomized to 6 months of romosozumab 
treatment in the Double-Blind, Placebo-Controlled Period (for a total of 12 months of 
romosozumab treatment). 
• To characterize the serum concentrations of romosozumab in postmenopausal Chinese 
women with osteoporosis who are continuing with 6 months of romosozumab treatment after 
initially being randomized to 6 months of romosozumab treatment in the Double-Blind, 
Placebo-Controlled Period (for a total of 12 months of romosozumab treatment). 
• To characterize the serum concentrations of romosozumab in postmenopausal Chinese 
women with osteoporosis who are initially randomized to placebo in the Double-Blind, 
Placebo-controlled Period and transition to romosozumab treatment. 
3.2.3 
Safety objectives 
The safety objectives will be presented for the OL Treatment Period (up to Month 12) and for the 
overall study period that includes the 3-month Follow-Up Period (for a total of 15 months) as 
follows: 
• To characterize the safety and tolerability of romosozumab treatment in postmenopausal 
Chinese women with osteoporosis who are continuing with 6 months of romosozumab 
treatment after initially being randomized to 6 months of romosozumab treatment in the 
Double-Blind, Placebo-Controlled Period (for a total of 12 months of romosozumab 
treatment).  
• To characterize the safety and tolerability of romosozumab treatment in postmenopausal 
Chinese women with osteoporosis who are initially randomized to placebo in the 
Double-Blind, Placebo-Controlled Period and transition to romosozumab treatment. 
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4 
STUDY VARIABLES 
4.1 
Study variables for the Double-Blind, Placebo-Controlled Period 
4.1.1 
Efficacy variables 
4.1.1.1 
Primary efficacy variable  
The primary efficacy variable is percent change from baseline in BMD at the lumbar spine at the 
end of the Double-Blind, Placebo-Controlled Period (Month 6) as assessed by DXA. 
4.1.1.2 
Secondary efficacy variables 
The secondary efficacy variables are as follows: 
• Percent change from baseline in BMD at the total hip at the end of the Double-Blind, 
Placebo-Controlled Period (Month 6) as assessed by DXA. 
• Percent change from baseline in BMD at the femoral neck at the end of the Double-Blind, 
Placebo-Controlled Period (Month 6) as assessed by DXA. 
4.1.1.3 
Other efficacy variables 
The other efficacy variables are percent change from baseline in BMD at the lumbar spine, total 
hip, and femoral neck at Month 3 as assessed by DXA. 
4.1.2 
Pharmacokinetic and pharmacodynamic variables 
4.1.2.1 
Other pharmacokinetic variables 
The other PK variables are serum trough concentrations of romosozumab at Day 1 (baseline) and 
at Months 1, 3, and 6. 
4.1.2.2 
Other pharmacodynamic variables  
The other PD variables are percent changes from baseline in P1NP and sCTX at Months 1, 3, 
and 6. 
4.1.3 
Safety variables 
4.1.3.1 
Primary safety variable  
The primary safety variable is the overall incidence of treatment-emergent adverse events 
(TEAEs).  
4.1.3.2 
Other safety variables  
The other safety variables are as follows:  
• Changes from baseline in laboratory assessments (serum chemistry and hematology) and 
shifts from baseline to the worst value between baseline and Month 6. 
• Changes from baseline in vital signs. 
• Changes from baseline in ECG parameters. 
• Clinically significant physical examination findings from baseline through Month 6. 
• Incidence of subjects with antiromosozumab antibodies at Day 1 (baseline) and at Months 1, 
3, and 6. 
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4.2 
Study variables for the Open-Label Treatment Period 
4.2.1 
Efficacy variables 
4.2.1.1 
Secondary efficacy variables 
The secondary efficacy variables are as follows:  
• Percent change from baseline in BMD at the lumbar spine at the end of OL Treatment Period 
(Month 12) as assessed by DXA in subjects who are continuing with 6 months of 
romosozumab treatment after initially being randomized to 6 months of romosozumab 
treatment in the Double-Blind, Placebo-Controlled Period (for a total of 12 months of 
romosozumab treatment). 
• Percent change from baseline in BMD at the total hip at the end of OL Treatment Period 
(Month 12) as assessed by DXA in subjects who are continuing with 6 months of 
romosozumab treatment after initially being randomized to 6 months of romosozumab 
treatment in the Double-Blind, Placebo-Controlled Period (for a total of 12 months of 
romosozumab treatment). 
• Percent change from baseline in BMD at the femoral neck at the end of OL Treatment Period 
(Month 12) as assessed by DXA in subjects who are continuing with 6 months of 
romosozumab treatment after initially being randomized to 6 months of romosozumab 
treatment in the Double-Blind, Placebo-Controlled Period (for a total of 12 months of 
romosozumab treatment). 
4.2.1.2 
Other efficacy variables 
The other efficacy variables are percent change from baseline in BMD at the lumbar spine, total 
hip, and femoral neck at the end of OL Treatment Period (Month 12) as assessed by DXA in 
subjects who are initially randomized to placebo in the Double-Blind, Placebo-Controlled Period 
and transition to romosozumab treatment for 6 months. 
4.2.2 
Pharmacokinetic and pharmacodynamic variables  
4.2.2.1 
Other pharmacokinetic variables 
The other PK variables are as follows:  
• Serum trough concentrations of romosozumab at Months 7, 9, and 12 in subjects who are 
continuing with 6 months of romosozumab treatment after initially being randomized to 
6 months of romosozumab in the Double-Blind, Placebo-Controlled Period (a total of 
12 months of romosozumab treatment). 
• Serum trough concentrations of romosozumab at Months 7, 9, and 12 (1, 3, and 6 months of 
romosozumab exposure, respectively) in subjects who are initially randomized to placebo in 
the Double-Blind, Placebo-Controlled Period and transition to romosozumab treatment for 
6 months. 
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4.2.2.2 
Other pharmacodynamic variables  
The other PD variables are as follows: 
• Percent changes from baseline in P1NP and sCTX at Months 7, 9, and 12 in subjects who are 
continuing with 6 months of romosozumab treatment after initially being randomized to 
6 months of romosozumab treatment in the Double-Blind, Placebo-Controlled Period (a total 
of 12 months of romosozumab treatment). 
• Percent changes from baseline in P1NP and sCTX at Months 7, 9, and 12 (1, 3, and 6 months 
of romosozumab exposure, respectively) in subjects who are initially randomized to placebo 
in the Double-Blind, Placebo-Controlled Period and transition to romosozumab treatment for 
6 months. 
• AUC for the entire 12-month treatment period for P1NP in subjects who are continuing with 
6 months of romosozumab treatment after initially being randomized to 6 months of 
romosozumab treatment in the Double-Blind, Placebo-Controlled Period (for a total of 
12 months of romosozumab treatment). 
4.2.3 
Safety variables 
The safety variables listed below will be assessed during the OL Treatment Period, including 
some selected safety variables that will be followed up to Month 15, in subjects who are initially 
randomized to 6 months of romosozumab treatment in the Double-Blind, Placebo-Controlled 
Period and continue with romosozumab for 6 months (for a total of 12 months of romosozumab 
treatment) and in subjects who are initially randomized to placebo in the Double-Blind, 
Placebo-Controlled Period and transition to romosozumab treatment for 6 months.  
4.2.3.1 
Primary safety variable 
The primary safety variable is the overall incidence of TEAEs.  
4.2.3.2 
Other safety variables 
The other safety variables are as follows: 
• Changes from baseline in laboratory assessments (serum chemistry and hematology) and 
shifts from baseline to the worst value between baseline and Month 12. 
• Changes from baseline in vital signs. 
• Changes from baseline in ECG parameters. 
• Clinically significant physical examination findings from baseline through Month 12. 
• Incidence of subjects with antiromosozumab antibodies at Months 7, 9, and 12, and at the 
EOS Visit. 
5 
STUDY DESIGN 
5.1 
Study description 
OP0002 is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study followed 
by an OL Treatment Period to evaluate the efficacy, safety and tolerability of romosozumab 
treatment in postmenopausal Chinese women with osteoporosis. 
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The study consists of 4 study periods: a Screening Period (Day -35 to Day -1); a 6-month 
Double-Blind, Placebo-Controlled Period; a 6-month OL Treatment Period, and a 3-month 
Follow-Up Period. The overall study design including treatment assignments is depicted in 
Figure 5‒1. 
5.1.1 
Screening Period 
After the subject has been informed about the study and signed the Informed Consent form 
(ICF), the Screening procedures and assessments will be performed as described in Table 5‒1 
within a period of 35 days prior to IMP administration. To be eligible to participate in the study, 
subjects must be postmenopausal Chinese women, 55 to 90 years of age (inclusive), have a BMD 
T-score ≤-2.50 at the lumbar spine, total hip, or femoral neck and an independent risk factor for 
fracture at Screening, with at least 2 vertebrae in the lumbar (L)1 through L4 region and at least 
1 hip evaluable by DXA. After consent, subjects should undergo BMD by DXA and lateral spine 
x-rays to confirm they fulfill the BMD criteria before any other Screening evaluations are 
conducted. 
In addition, before enrolling subjects in the study, a careful individual assessment of the CV risk 
profile should be performed. For more information on the potential CV risk, see the results of 
20110142 in Section 2.2. 
Subjects who meet all the inclusion criteria and none of the exclusion criteria will be eligible to 
participate in the study. A complete list of the eligibility criteria is provided in Section 6. 
From Screening until the EOS Visit, subjects will be required to take daily calcium and 
vitamin D supplementation. Refer to Section 7.8.1.1 for further information on the dosing and 
management of these supplements. Subjects who fail the serum 25 hydroxy (OH) vitamin D 
eligibility criterion at Screening may be retested once following vitamin D repletion. 
5.1.2 
Double-Blind, Placebo-Controlled Period 
Approximately 300 subjects will be randomized, stratified by age (<75 years, ≥75 years), in a 
2:1 ratio to receive romosozumab 210mg sc QM (200 subjects) or matched placebo sc QM 
(100 subjects) in a blinded manner for 6 months to evaluate if romosozumab treatment compared 
with placebo is effective in increasing BMD, as assessed by DXA at the lumbar spine, total hip, 
and femoral neck.  
During this period, in addition to efficacy (BMD measurements) and safety assessments 
(eg, physical examinations, vital sign measurements, and ECG parameters) being performed, 
blood samples will be collected to analyze PK, immunogenicity, BTMs (P1NP and sCTX) and 
laboratory data (including intact parathyroid hormone [iPTH] and lipids) at the time points 
specified in the schedule of study assessments (Table 5‒1). Only Lunar or Hologic densitometers 
should be used to measure BMD during the study. 
The 6-month analysis, which will include the analyses of the primary and secondary efficacy 
variables, PK variables, PD variables, and safety variables will be performed using the data 
obtained from the 6-month, Double-Blind, Placebo-Controlled Period. 
5.1.3 
Open-Label Treatment Period 
Upon completion of the 6-month Double-Blind, Placebo-Controlled Period, subjects will enter 
the OL Treatment Period and receive romosozumab 210mg sc QM for 6 months in an 
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OL fashion. During this period, all subjects will receive active treatment (romosozumab) 
allowing for the collection of efficacy and safety data for an additional 6 months (a total of 
12 months for subjects randomized to romosozumab and 6 months for those randomized to 
placebo). Refer to the schedule of study assessments for the efficacy and safety assessments to be 
performed during this period (Table 5‒1).  
In addition to the efficacy and safety assessments, blood samples for BTM (P1NP and sCTX), 
PK, immunogenicity, and laboratory (including iPTH and lipids) testing will be collected at 
specified time points during the OL Treatment Period (see Table 5‒1).  
5.1.4 
Follow-Up Period 
After completing the OL Treatment Period (Month 12), subjects will be followed up for an 
additional 3 months and should complete the EOS Visit at Month 15. The assessments for this 
visit are specified in Table 5‒1. Subject participation in the study is concluded once the EOS 
procedures and assessments are completed. Subjects who test positive for neutralizing antibodies 
to romosozumab at the EOS Visit or ET Visit will be asked to return for additional follow-up 
testing for up to 1 year after final administration of IMP. Additional information on 
antiromosozumab antibody testing procedures is presented in Section 11.7.5. 
The final analysis will be performed after completion of the Follow-Up Period. The remaining 
efficacy, PK, PD, and safety analyses for Month 12 and the safety analysis for the overall study 
period, ie, the period from the start of double-blind treatment to the Month 15 Visit for each 
subject, will be evaluated.  
Subjects can decide to discontinue IMP but continue participation in the study. However, 
subjects who withdraw early from the study should return to the study to complete the ET Visit 
(see Section 8.5). Subjects who withdraw from the study will not be replaced. 
An independent DMC will monitor the safety of subjects in OP0002 on an ongoing basis. Further 
information on the DMC is provided in Section 13.7. 
No interim analysis is planned for this study. 
5.1.5 
Study duration per subject 
For each individual subject, the study will last approximately 16 months, as follows:  
• Screening Period – up to 35 days 
• Double-Blind, Placebo-Controlled Period – 6 months (final administration of IMP 
[romosozumab or placebo] at Month 5) 
• OL Treatment Period – 6 months (final administration of romosozumab at Month 11) 
• Follow-Up Period – 3 months with the EOS Visit at Month 15  
A subject’s participation in the study may be extended up to 1 year after the final IMP 
administration if the subject tests positive for neutralizing antibodies to romosozumab at the 
EOS Visit or ET Visit (see Section 11.7.5).  
The end of the study is defined as the date of the last visit of the last subject in the study. 
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5.1.6 
Planned number of subjects and sites 
Approximately 300 subjects are to be randomized in the study, ensuring approximately 
200 subjects in the romosozumab group and approximately 100 subjects in the placebo group. 
The planned number of study sites is approximately 30.  
5.1.7 
Anticipated regions and countries 
The study will be conducted in mainland China. 
5.2 
Schedule of study assessments 
The study procedures and assessments to be conducted at each visit are presented in the schedule 
of study assessments (Table 5‒1). 
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Table 5‒1: 
Schedule of study assessments 
Activity 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Period 
Open-Label Treatment Period 
 
Follow
-Up 
Period 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
ET 
15 
/EOS 
Day/montha 
Within 35 
days of 
D1b 
D1 
M1 M2 
M3 
M4 
M5 
M6 
M7 M8 M9 
M10 
M11 
M12 
-- 
M15 
Windows (days) 
-35 
-- 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
-- 
-14 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Withdrawal criteria  
 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical fracture history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discuss signs and 
symptoms of myocardial 
infarction and stroked 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lifestylee 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Height and weight  
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Vital signsf 
X 
 
X 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
ECGg 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Safety laboratory testsh  
X 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
X 
 
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Table 5‒1: 
Schedule of study assessments 
Activity 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Period 
Open-Label Treatment Period 
 
Follow
-Up 
Period 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
ET 
15 
/EOS 
Day/montha 
Within 35 
days of 
D1b 
D1 
M1 M2 
M3 
M4 
M5 
M6 
M7 M8 M9 
M10 
M11 
M12 
-- 
M15 
Windows (days) 
-35 
-- 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
-- 
-14 
Lipid profile 
 
Xi 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Serologyj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 25 (OH) vitamin D 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH, free T4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
iPTH 
X 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
X 
 
Blood sample for PK 
analysesk 
 
Xl 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
X 
 
Blood sample for 
antibodies to 
romosozumab 
 
Xl 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
Xm 
Xm 
Lateral spine x-rays 
(lumbar and thoracic) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone mineral scan (DXA 
lumbar spine, total hip, and 
femoral neck)n 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
P1NP 
 
Xl 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
X 
 
sCTXo 
 
Xl 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
X 
 
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Table 5‒1: 
Schedule of study assessments 
Activity 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Period 
Open-Label Treatment Period 
 
Follow
-Up 
Period 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
ET 
15 
/EOS 
Day/montha 
Within 35 
days of 
D1b 
D1 
M1 M2 
M3 
M4 
M5 
M6 
M7 M8 M9 
M10 
M11 
M12 
-- 
M15 
Windows (days) 
-35 
-- 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
-- 
-14 
Concomitant medications 
entire study period
Concomitant medical 
procedures 
entire study period 
Recording of AEs 
entire study period 
IMP administrationp 
(double-blind treatment) 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Romosozumab 
administrationp 
(OL treatment) 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Instructions on daily 
calcium and vitamin D 
supplementationq  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vitamin D loading dose (if 
required) 
 
Xr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Daily calcium and vitamin 
D supplementationq 
entire study period 
 
AE=adverse event; BMD=bone mineral density; BP=blood pressure; BTM=bone turnover marker; D=day; DXA=dual-energy x-ray absorptiometry; 
eCRF=electronic Case Report form; ECG=electrocardiogram; EOS=End-of-Study; ET=Early Termination; HBcAb=hepatitis B core antibody; 
HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HDL=high density lipoprotein; HIV=human immunodeficiency virus; IMP=investigational 
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medicinal product; iPTH=intact parathyroid hormone; LDL=low density lipoprotein; M=month; OH=hydroxy; OL=open-label; P1NP=procollagen type 1 
N-telopeptide; PK=pharmacokinetic(s); sCTX=serum type I collagen C-telopeptide; T4=thyroxine; TSH=thyroid-stimulating hormone 
a For the purpose of this study, a month is defined as 30 days.  
b After consent, subjects should undergo BMD by DXA and lateral spine x-rays to confirm they fulfill BMD criteria before any other Screening evaluations are 
conducted.  
c After randomization, confirm that the subject fulfills none of the withdrawal criteria.  
d Before enrolling subjects in the study, a careful individual assessment of the cardiovascular risk profile should be performed.  
e Lifestyle records subject’s alcohol use, tobacco use, and caffeinated beverage use. 
f Vital signs include BP, pulse rate, and temperature; vital signs are to be measured after the subject has been in a seated or semi-recumbent position for at least 
3 minutes. Vital signs should be measured prior to blood sampling and prior to IMP administration, where applicable. 
g A 12-lead ECG will be recorded after the subject has been in a seated or semi-recumbent position for at least 3 minutes. The ECG should be recorded prior to 
blood sampling and prior to IMP administration, where applicable. 
h Safety laboratory tests include hematology and serum chemistry. A complete list of the clinical laboratory parameters is provided in Table 11‒2. 
i A blood sample for lipid testing (total cholesterol, LDL, HDL, and triglycerides) will be collected with the subject in a fasted state. Fasting state is defined as 
overnight fasting, with a minimum of 8h of fasting required. 
j Subjects who have evidence of or test positive for any of the following are excluded from the study: HBsAg, HBcAb, HCV antibody, and HIV antibody.  
k PK samples will be analyzed to determine serum concentrations of romosozumab. 
l On D1, samples for PK, BTMs, and antibodies are to be collected prior to IMP administration.  
m Subjects who test positive for neutralizing antibodies to romosozumab at the EOS Visit or ET Visit will be asked to return for additional follow-up testing. This 
testing is to occur every 3 months starting from when the site has been notified of the positive results until 1) neutralizing antibodies are no longer detectable or 
2) the subject has been followed for a period of at least 1 year (±4 weeks) postadministration of romosozumab. 
n Only Lunar or Hologic densitometers should be used to measure BMD during the study. Previous BMD scans by DXA may be used for Screening if the criteria 
in Section 10.1 are met. 
o Blood samples for determination of sCTX must be collected from subjects in a fasted state and before noon. Fasting state is defined as overnight fasting, with a 
minimum of 8h of fasting required. 
p Administration of IMP must be the final procedure at each applicable visit. Injections are to be administered by trained study personnel at the study site. 
Open-label romosozumab administration at Month 6 is the first dose of the OL Treatment Period.  
q All subjects will be required to take daily calcium and vitamin D supplementation during the study. Details of the calcium and vitamin D supplementation are to 
be recorded in the subject’s eCRF (refer to Section 7.8.1.1). 
r If a loading dose of vitamin D is required, then this should be administered within 1 week of D1. However, if the vitamin D loading dose is missed in this 
timeframe, it should be given as soon as possible thereafter. 
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5.3 
Schematic diagram 
Figure 5‒1: Overall study design for OP0002 
 
 
D=day; IMP=investigational medicinal product; IU=international unit; M=month; N=number of subjects in each treatment arm; QM=every month; 
sc=subcutaneous(ly)  
Note: Final analysis will include the remaining efficacy and safety analyses for Month 12 and the safety analyses for the overall study period, ie, the period from 
the start of double-blind treatment to the Month 15 Visit for each subject will be evaluated. 
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5.4 
Rationale for study design and selection of dose 
A randomized double-blind, placebo-controlled treatment period followed by an OL design has 
been selected to demonstrate the efficacy and safety of romosozumab in postmenopausal Chinese 
women with osteoporosis. 
5.4.1 
Rationale for the dose selected for romosozumab 
The romosozumab 210-mg sc QM regimen was selected based on the following reasons: 
• The 210-mg sc QM dosing regimen resulted in rapid and greatest increases in BMD at the 
lumbar spine, total hip, and femoral neck compared with the other romosozumab dosing 
regimens tested (70 and 140mg QM) in the Phase 2 studies. Other evaluations such as BTMs, 
also support the use of 210mg sc QM as summarized in Section 2.2.  
• In the global Phase 3 program, the romosozumab 210-mg sc QM dosing regimen 
demonstrated fracture risk reduction, which persisted after transitioning to antiresorptive 
therapy, while for safety, the 210-mg sc QM regimen was well tolerated as described in 
Section 2.2. 
5.4.2 
Rationale for selecting the BMD endpoint 
The primary efficacy variable selected for this study is change from baseline in BMD by DXA at 
6 months at the lumbar spine based on the following: 
• BMD by DXA is a key predictor of future fracture and Chinese treatment guidelines 
recommend use of BMD for the diagnosis of osteoporosis (Osteoporosis and Bone Mineral 
Research Society of the Chinese Medical Association, 2017). 
• BMD by DXA is also used in clinical practice to monitor the effect of osteoporosis 
pharmacological treatment and for clinical research purposes. Lumbar spine and hip are the 
recommended regions for measuring BMD in routine clinical practice. 
• It is acknowledged that osteoporotic fractures most commonly occur at the spine and hip, so 
BMD measurements at these anatomical sites are predictors of fracture risk at these sites 
(Lofman et al, 2000; Faulkner, 1998; Nelson et al, 1998; Marshall et al, 1996). 
• BMD by DXA represents a reliable surrogate endpoint for romosozumab as BMD gains 
translate into efficacy by reducing fracture risk, and this has been confirmed in the global 
Phase 3 fracture studies (20070337 and 20110142) where fracture risk reduction was 
demonstrated together with BMD increases with romosozumab treatment. 
• To extrapolate the global fracture data to China, the BMD endpoint is considered to be the 
most suitable endpoint to support efficacy under the International Council for Harmonisation 
(ICH) bridging concept and to avoid unnecessary medical resources and patient burden in 
performing large-scale fracture studies in China. 
• There is already strong evidence of fracture risk reduction with romosozumab treatment from 
the clinical development program outside China and as recommended for consideration in 
osteoporosis clinical study design by CDE officers in 2011 (Zhang et al, 2011), BMD is 
proposed as an alternative primary efficacy variable for local studies in China to bridge the 
evidence of fracture protection. 
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• In the previous romosozumab studies, the greatest BMD gains were observed at the lumbar 
spine compared with other anatomical sites (total hip and femoral neck); therefore, BMD at 
the lumbar spine is selected as the primary efficacy measure. 
5.4.3 
Rationale for 6-month duration of Double-Blind Period as primary 
efficacy endpoint 
Onset of action is considered relatively early with romosozumab treatment. The following 
evidence supports a 6-month duration for the primary efficacy assessment, BMD: 
• Changes in BTMs were noted early with romosozumab treatment. In the clinical studies in 
postmenopausal women with osteoporosis, romosozumab 210mg sc QM showed that the 
bone formation marker (P1NP) increased from baseline immediately and achieved peak 
levels by Month 1, then decreased towards baseline levels by approximately Month 6 to 
Month 9. The bone resorption marker (sCTX) decreased within a month after the first dose 
and generally remained below placebo at Month 12, but above the sCTX levels of the 
antiresorptive therapy ALN in the active-controlled study (20110142). 
• BMD data showed that romosozumab 210mg sc QM resulted in rapid and robust increases in 
BMD from baseline compared with both placebo and ALN within 12 months. BMD 
increases were observed at the lumbar spine, total hip, and femoral neck (nominal p <0.001) 
in the 2 Phase 3 studies in postmenopausal women (20070337 and 20110142). Additionally, 
the significant and progressive increases from baseline in BMD were apparent at Month 6 of 
the 12-month treatment period in the global Phase 2 and 3 studies conducted so far. 
• In accordance with BTM and BMD changes, the efficacy of romosozumab in reducing 
fracture risk has been seen relatively early. In 20070337, romosozumab 210mg sc QM 
significantly reduced the risk of new vertebral fracture compared with placebo through 
Month 12 (odds ratio=0.27, p <0.001), with a relative risk reduction of 73% (95% confidence 
interval [CI]: 53%, 84%). Romosozumab significantly reduced the risk of clinical fracture 
compared with placebo through Month 12, with a relative risk reduction of 36% 
(95% CI:11%, 54%; p=0.008). In 20110142, a reduction in risk of new vertebral fracture for 
romosozumab 210mg sc QM vs ALN 70mg po QW was observed during the 12-month 
double-blind treatment period (odds ratio=0.63, p=0.008), with a relative risk reduction for 
new vertebral fracture of 36% (95% CI: 11%, 54%). There was also a reduction in the risk of 
clinical fracture compared with ALN through Month 12 in 20110142, with a relative risk 
reduction of 28% (95% CI: 4%, 46%; nominal p=0.027). In addition, in 20070337 further 
early onset of antifracture effect was seen. Through Month 6, 14 subjects (0.4%) in the 
romosozumab group and 26 subjects (0.8%) in the placebo group had a new vertebral 
fracture; the relative risk reduction for romosozumab compared with placebo was 46% 
(95% CI: -3%, 72%; odds ratio=0.54; nominal p=0.056). 
• Based on the data presented above, placebo use can be minimized to 6 months compared to 
the previous studies with much longer duration where new fracture remained a concern for 
placebo subjects. 
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5.4.4 
Rationale for placebo-controlled study with an Open-Label Treatment 
Period. 
The rationale for the choice of placebo as a comparator during the Double-Blind Period with an 
OL Treatment Period is as follows: 
• A placebo-controlled study was chosen because it permits a minimally confounded 
demonstration of efficacy and safety of romosozumab in the treatment of postmenopausal 
Chinese women with osteoporosis. 
• The use of a placebo control is also consistent with regulatory guidance, as recommended for 
consideration in osteoporosis clinical study design by CDE officers (Zhang et al, 2011). 
• To minimize subject exposure to placebo, a 6-month treatment duration has been selected. 
(see Section 5.4.3 for the rationale for 6-month duration) 
• The randomization ratio is 2:1 between active treatment and placebo which reduces placebo 
exposure while maintaining sufficient sensitivity in the study.  
• The most severe osteoporotic population with a history of hip fracture and severe or 
moderate vertebral fracture and those with a BMD T-score of ≤-3.50 at the total hip or 
femoral neck have been excluded by the inclusion/exclusion criteria. 
• In addition, to maintain the integrity of the bone, subjects will receive a loading dose of 
vitamin D (50,000IU) at the start of the study in the case of low serum vitamin D levels and 
all subjects will receive daily calcium and vitamin D supplements throughout the study. 
These supplements have been shown to have a protective effect on the skeleton. 
• Inclusion of the 6-month OL Treatment Period will provide an opportunity for those subjects 
who are randomized to placebo to receive active treatment. This extension will generate 
additional safety and efficacy data in postmenopausal Chinese women resulting in a more 
consistent and robust efficacy and safety profile. 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS 
6.1 
Inclusion criteria 
To be eligible to participate in this study, all of the following criteria must be met: 
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
ICF is signed and dated by the subject or legal representative prior to initiation of any 
study-specific activities/procedures. 
2. Subject is considered reliable and capable of adhering to the protocol, visit schedule, and 
medication intake according to the judgment of the investigator. 
3a. Subject is an ambulatory postmenopausal Chinese women, 55 to 90 years of age (inclusive) 
at the time of Screening. Postmenopause is defined as no spontaneous vaginal bleeding or 
spotting for 12 or more consecutive months prior to Screening. 
4. Subject has a BMD T-score ≤-2.50 at the lumbar spine, total hip, or femoral neck, as assessed 
by the central imaging vendor at the time of Screening based on DXA scans, and using data 
for Caucasian women from the National Health and Nutritional Examination Survey 
(NHANES, 1998). 
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5. Subject must have at least 1 of following independent risk factors for fracture: 
• History of fragility fracture (except hip fracture, a severe [SQ3] vertebral fracture or more 
than 2 moderate [SQ2] vertebral fractures [see exclusion criteria]); 
• Parental history of hip fracture; 
• Low body weight (body mass index ≤19kg/m2); 
• Elderly (age ≥65 years); 
• Current smoker 
6. Subject has at least 2 vertebrae in the L1 to L4 region and at least 1 hip that are evaluable by 
DXA, as assessed by the central imaging vendor. 
6.2 
Exclusion criteria 
Subjects are not permitted to enroll in the study if any of the following criteria is met: 
1. Subject has a BMD T-score of ≤-3.50 at the total hip or femoral neck, as assessed by the 
central imaging vendor at the time of Screening based on DXA scans, and using data for 
Caucasian women from NHANES 1998. 
2. Subject has a known history of hip fracture. 
3. Subject has any severe (SQ3) or more than 2 moderate (SQ2) vertebral fractures, as assessed 
by the central imaging vendor based on the lateral spine x-ray at Screening (Visit 1). 
4. Subject has a history of myocardial infarction (MI). 
5. Subject has a history of stroke. 
6. Subject has a vitamin D insufficiency, defined as 25 (OH) vitamin D levels <20ng/mL, as 
assessed by the central laboratory at Screening. Vitamin D repletion will be permitted and the 
subject may be retested once within the Screening Period.  
7. Subject has used oral bisphosphonates: 
− Any doses received within 3 months prior to randomization (Day 1). 
− More than 1 month of cumulative use between 3 and 12 months prior to randomization. 
− More than 3 years of cumulative use, unless the last dose was received ≥5 years prior to 
randomization. 
8. Subject has used intravenous (iv) bisphosphonates: 
− zoledronic acid 
◦ 
Any doses received within 3 years prior to randomization. 
◦ 
More than 1 dose received within 5 years prior to randomization. 
− iv ibandronate, iv pamidronate, or iv ALN 
◦ 
Any doses received within 12 months prior to randomization. 
◦ 
More than 3 years of cumulative use, unless the last dose was received ≥5 years prior 
to randomization. 
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9. Subject has used denosumab or any cathepsin K inhibitor:  
− Any doses received within 18 months prior to randomization.  
10. Subject has used tibolone, cinacalcet, or calcitonin: 
− Any doses received within 3 months prior to randomization.  
11. Subject has used TPTD or any PTH derivative: 
− Any doses received within 3 months prior to randomization. 
− More than 1 month of cumulative use between 3 and 12 months prior to randomization. 
12. Subject has used systemic oral or transdermal estrogen or selective estrogen receptor 
modulators (SERMs): 
− More than 1 month of cumulative use within 6 months prior to randomization. 
13. Subject has used strontium ranelate or fluoride: 
− More than 1 month of cumulative use within 5 years prior to randomization. 
14. Subject has used hormonal ablation therapy:  
− More than 1 month of cumulative use within 6 months prior to randomization. 
15. Subject has used systemic glucocorticosteroids:  
− ≥5mg prednisone equivalent per day for more than 14 days within 3 months prior to 
randomization. 
16. Subject has a history of metabolic or bone disease (except osteoporosis) that may interfere 
with the interpretation of the results, such as sclerosteosis, Paget’s disease, rheumatoid 
arthritis, osteomalacia, osteogenesis imperfecta, osteopetrosis, ankylosing spondylitis, 
Cushing’s disease, hyperprolactinemia, and malabsorption syndrome. 
17. Subject has a history of solid organ or bone marrow transplants. 
18. Subject has a history of ONJ or AFF. 
19. Subject has a confirmed diagnosis or under investigation for multiple myeloma or related 
lymphoproliferative disorder at the Screening Visit. 
20. Subject has evidence of any of the following: 
a. Current, uncontrolled hyper- or hypothyroidism. Uncontrolled hyperthyroidism is defined 
as thyroid-stimulating hormone (TSH) and thyroxine (T4) outside of the normal range. 
Uncontrolled hypothyroidism is defined as TSH >10. 
b. Current, uncontrolled hyperparathyroidism or history of hypoparathyroidism. 
Uncontrolled hyperparathyroidism is defined as PTH outside the normal range in subjects 
with concurrent hypercalcemia or PTH values >20% above upper limit of normal (ULN) 
in normocalcemic subjects. 
c. Current hypercalcemia or hypocalcemia, defined as albumin-adjusted serum calcium 
outside the normal range, as assessed by the central laboratory at the time of Screening. 
Albumin-adjusted serum calcium levels may be retested once in case of an elevated 
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albumin-adjusted serum calcium level within 1.1xULN of the laboratory’s reference 
ranges. 
d. Subject has ≥3xULN of any of the following: alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), or >ULN total bilirubin 
(≥1.5xULN total bilirubin if known Gilbert’s syndrome). If subject has elevations only in 
total bilirubin that are >ULN and <1.5xULN, fractionate bilirubin to identify possible 
undiagnosed Gilbert’s syndrome (ie, direct bilirubin <35%). 
For randomized subjects with a baseline result >ULN for ALT, AST, ALP, or total 
bilirubin, a baseline diagnosis and/or the cause of any clinically meaningful elevation 
must be understood and recorded in the electronic Case Report form (eCRF). 
If subject has >ULN ALT, AST, or ALP that does not meet the exclusion limit at 
Screening, repeat the tests, if possible, prior to dosing to ensure there is no further 
ongoing clinically relevant increase. In case of a clinically relevant increase, inclusion of 
the subject must be discussed with the Medical Monitor.  
21. Subject is currently receiving treatment in another investigational device or drug study, or 
less than 30 days or 5 half-lives (whichever is longer) since ending treatment on another 
investigational device or drug study(ies). 
22. Subject is undergoing other investigational procedures while participating in this study. 
23. Subject has previously entered this study or has previously participated in a study with a 
sclerostin antibody product. 
24. Subject has had a malignancy within the last 5 years, except nonmelanoma skin cancers, 
cervical or breast ductal carcinoma in situ. 
25. Subjects has a known hypersensitivity to any of the products to be administered during 
dosing (calcium supplements, vitamin D products, or mammalian cell derived products). 
26. Subject who is breastfeeding or plans to become pregnant or breastfeed during the study or 
within 12 weeks of the final dose of study drug.  
27. Subject has a history or evidence of any other clinically significant disorder, condition or 
disease (eg, untreated or unstable, with the exception of those outlined above) that, in the 
opinion of the investigator, if consulted, would pose a risk to subject safety or interfere with 
the study evaluation, procedures, or completion. 
28. Subject shows a positive result for human immunodeficiency virus (HIV), hepatitis C virus, 
or hepatitis B infection at Screening (Visit 1). 
29. Subject has an active tuberculosis infection within 6 months of signing the ICF. 
30. Subject has active pneumonia. 
31. Subject has a reported history of hearing loss associated with cranial nerve VIII compression 
due to excessive bone growth (eg, as seen in conditions such as Paget’s disease, sclerosteosis, 
and osteopetrosis). 
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6.3 
Withdrawal criteria 
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care. Subjects have the option to either discontinue IMP but continue participation in the study 
(withdrawal of IMP) or discontinue IMP and withdraw participation from the study (withdrawal 
from study). Investigators should contact the Medical Monitor, whenever possible, to discuss the 
withdrawal of a subject in advance. 
6.3.1 
Withdrawal of IMP 
Subjects can decide to discontinue IMP but continue participation in the study. If IMP is 
discontinued, the investigator should encourage the subject to continue participation by attending 
scheduled study visits to have procedures/assessments performed and data collected including 
endpoints and AEs. The investigator must document any changes to the scheduled visits and 
assessments (Table 5‒1) and the plan for follow up that is agreed by the subject.  
Subjects might have IMP withdrawn if any of the following events occur (but not limited to): 
• Subject request. 
• Decision of the sponsor or investigator. 
• Safety concern (eg, due to an AE, ineligibility determined, protocol deviation, 
noncompliance, requirement for alternative therapy, protocol-specified criteria). 
• Clinical fracture or BMD decrease from baseline of 7% or more at the lumbar spine, total 
hip, or femoral neck. 
In the event that a subject experiences a clinical fracture or a BMD decrease from baseline of 
7% or more at the lumbar spine, total hip or femoral neck at any time during the study, the 
investigator is required to discuss the subject’s individual fracture risk and alternative 
treatment options with the subject and to note the discussion in the subject’s records. If a 
decision is made to begin an alternative approved therapy, the subjects must discontinue IMP 
and every effort should be made to have the subject complete the remaining study visits and 
assessments. 
6.3.2 
Withdrawal from study  
Subjects can be withdrawn from the study if any of the following events occur: 
• Subject develops a serious illness that would interfere with her continued participation. 
• Subject is noncompliant with the study procedures or medications in the opinion of the 
investigator. 
• Subject withdraws her consent. 
• There is confirmation of a pregnancy during the study, as evidenced by a positive pregnancy 
test. 
• The sponsor or a regulatory agency requests withdrawal of the subject. 
Withdrawal of consent for a study means that the subject does not wish to continue in the study. 
Subject data up to withdrawal of consent will be included in the analysis of the study.  
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Subjects who withdraw from the study should complete the ET Visit. Refer to the schedule of 
assessments for the procedures to be performed at this visit (Table 5‒1). These subjects will be 
encouraged to return to the study site to complete the procedures and assessments for the 
EOS Visit, 4 months after the final administration of IMP. 
Investigators should attempt to obtain information on subjects in the case of withdrawal or 
discontinuation. For subjects considered as lost to follow up, the investigator should make an 
effort (at least 1 phone call and 1 written message to the subject), and document his/her effort 
(date and summary of the phone call and copy of the written message in the source documents), 
to complete the final evaluation. All results of these evaluations and observations, together with a 
narrative description of the reason(s) for removing the subject, must be recorded in the source 
documents. The eCRF must document the primary reason for withdrawal. 
Subjects who withdraw from the study will not be replaced. 
6.3.3 
Potential drug-induced liver injury IMP discontinuation criteria 
Subjects with potential drug-induced liver injury (PDILI) must be assessed to determine if IMP 
must be discontinued. In addition, all concomitant medications and herbal supplements that are 
not medically necessary should also be discontinued.  
The PDILI criteria below require immediate and permanent discontinuation of IMP:  
• Subjects with either of the following: 
− ALT or AST ≥8xULN 
− ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN  
The PDILI criterion below requires immediate discontinuation of IMP: 
• Subjects with ALT or AST ≥3xULN who exhibit temporally associated symptoms of 
hepatitis or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness. Hypersensitivity symptoms include fever (without clear 
alternative cause), rash, or eosinophilia (ie, >5%). 
If a nondrug-related cause for the symptoms can be confirmed, these subjects may resume IMP 
administration after discussion with the responsible UCB physician, but only when the 
requirements for rechallenge with IMP as provided in Section 11.6.1.2.1 are followed.  
The PDILI criterion below allows for subjects to continue on IMP at the discretion of the 
investigator.  
• Subjects with ALT or AST ≥3xULN (and ≥2x baseline) and <8xULN, total bilirubin 
<2xULN, and no eosinophilia (ie, ≤5%), with no fever, rash, or symptoms of hepatitis 
(eg, fatigue, nausea, vomiting, right upper quadrant pain or tenderness). 
Evaluation of PDILI must be initiated as described in Section 11.6.1. If subjects are unable to 
comply with the applicable monitoring schedule, IMP must be discontinued immediately. 
Investigators should attempt to obtain information on subjects in the case of IMP discontinuation 
to complete the final evaluation. Subjects with PDILI should not be withdrawn from the study 
until investigation and monitoring are complete. All results of these evaluations and 
observations, as well as the reason(s) for IMP discontinuation and subject withdrawal (if 
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applicable), must be recorded in the source documents. The eCRF must document the primary 
reason for IMP discontinuation. 
6.4 
Retesting 
During the Screening Period, any laboratory values can be retested once to determine subject’s 
eligibility for the study and to ensure that there is no further ongoing clinical relevance.  
All retests must be confirmed by the central laboratory and the subject must be randomized 
within the 35-day Screening Period.  
6.5 
Lateral spine x-ray at Screening 
The x-rays of the lateral thoracic and lumbar spine will be acquired according to specific 
instructions provided by the central imaging vendor.  
For assessment of prevalent vertebral fractures at Screening, which will be performed by a 
radiologist at the central imaging center, a visual semiquantitative grading scale as defined in 
Table 6‒1 will be used (Genant et al, 1993). 
Table 6‒1: Semiquantitive (SQ) grading scale 
Grade 
Fracture severity 
Definition 
0 
Normal 
Approximately less than 20% reduction in anterior, middle, and/or 
posterior height 
1 
Mild 
Approximately 20% to 25% reduction in anterior, middle, and/or 
posterior height 
2 
Moderate 
Approximately 25% to 40% reduction in anterior, middle, and/or 
posterior height 
3 
Severe 
Approximately 40% or greater reduction in anterior, middle, and/or 
posterior height 
7 
STUDY TREATMENT 
7.1 
Description of investigational medicinal product 
For this study, romosozumab and placebo are considered IMP. 
Subjects will be administered either romosozumab or placebo in a blinded manner for 6 months 
after which time, all subjects will receive active treatment (romosozumab) in an OL manner for 
6 months.  
Romosozumab will be supplied as a sterile, clear to opalescent, colorless to light yellow, 
preservative-free solution for sc injection in a single-use prefilled syringe (PFS). Each PFS 
contains 90mg/mL of romosozumab in 55mM acetate and 13mM calcium containing 
6.0% w/v sucrose and 0.006% w/v polysorbate 20 at pH 5.2, with a deliverable volume of 
1.17mL (105mg romosozumab solution for injection).  
Placebo is supplied in a 1.17-mL PFS identical in appearance to romosozumab. Placebo will be 
stored and packaged the same as romosozumab.  
Details of the IMP are provided in the IMP Handling Manual.  
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Subjects will be required to take daily calcium and vitamin D supplementation during the study; 
however, these protocol-required products are not considered IMP. Further information on the 
calcium and vitamin D supplementation is provided in Section 7.8.1.1. 
7.2 
Treatments to be administered 
Procedures for dose administration are provided in the IMP Handling Manual. All IMP will be 
administered to subjects at the study site by trained study personnel.  
The IMP (romosozumab or placebo) will be administered over 2 study periods: the 
Double-Blind, Placebo-Controlled Period immediately followed by the OL Treatment Period as 
detailed below. 
• Double-Blind, Placebo-Controlled Period 
− Approximately 300 subjects will be randomized, stratified by age (<75 years, ≥75 years), 
in a 2:1 ratio to receive romosozumab 210mg sc QM (approximately 200 subjects) or 
matched placebo sc QM (approximately 100 subjects) in a blinded manner for 6 months, 
with the final administration of double-blind IMP at Month 5.  
• OL Treatment Period 
− At Month 6, all subjects will receive romosozumab 210mg sc QM for 6 months in an 
OL fashion, with the final administration of OL romosozumab at Month 11.  
Subjects will receive 2 sc injections of romosozumab QM (ie, 2 injections of 105mg 
romosozumab for a total dose of 210mg) or 2 injections of matched placebo QM for 6 months 
during the Double-Blind, Placebo-Controlled Period. The 2 sc injections will be administered 
one immediately after the other. During the OL Treatment Period, all subjects will receive 2 sc 
injections of romosozumab QM (ie, 2 injections of 105mg romosozumab each administered one 
immediately after the other for a total dose of 210mg) for 6 months. A separate 1.17-mL PFS 
will be used for each injection. Thus, to administer the IMP at each dosing visit, 2 PFS 
(romosozumab or placebo) will be supplied in a single box.  
Injections will be administered sc into different sites on the subject’s anterior abdominal wall, 
upper thigh, or upper arm by an individual at the study site who has been trained in the injection 
technique. The injection should not be administered in the same arm from which blood is drawn. 
The IMP injections must be administered after all other study visit procedures have been 
completed. 
The first dose of IMP must be administered on the day of randomization (Day 1). Details of the 
IMP administered including the date and time are to be recorded on each subject’s eCRF. 
Over the course of the study, a physician must be available during administration of 
romosozumab or placebo. It is recommended that all subjects be closely observed for 
approximately 30 minutes after dosing. In the unlikely event of overdose, refer to Section 11.4 
for further information. 
7.3 
Packaging 
The IMP will be manufactured, packaged, and labeled according to Good Manufacturing 
Practice (GMP) guidelines and applicable laws or regulations. The IMP will be suitably 
packaged in such a way as to protect it from deterioration during transport and storage. 
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Romosozumab and placebo injections will be identical in appearance and will be presented in 
indistinguishable containers (PFS) and boxes during the Double-Blind, Placebo-Controlled 
Period. The 2 PFS required for each IMP administration will be supplied in a single box, as 
assigned by the interactive response technology (IRT) system. 
7.4 
Labeling 
Clinical drug supplies will be labeled in accordance with the current ICH guidelines and Good 
Clinical Practice (GCP) and GMP and will include any locally required statements. If necessary, 
labels will be translated into the local language. 
7.5 
Handling and storage requirements 
Refer to the IMP Handling Manual for the storage conditions of the IMP. 
The investigator (or designee) is responsible for the safe and proper storage of IMP at the site. 
Investigational medicinal product stored by the investigator is to be kept in a secured area with 
limited access according to the storage conditions mentioned on the label. 
Appropriate storage conditions must be ensured either by controlling the temperature (eg, room, 
refrigeration unit) or by completion of a temperature log in accordance with local requirements 
on a regular basis (eg, once a week), showing actual and minimum/maximum temperatures 
reached over the time interval. 
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the IMP Handling Manual. 
7.6 
Drug accountability  
A Drug Accountability form will be used to record IMP dispensing information on a by-subject 
basis and will serve as source documentation during the course of the study. Details of any IMP 
lost, damaged (due to breakage or wastage), not used, partially used, disposed of at the study site, 
or returned to the sponsor or designee must also be recorded on the appropriate forms. All 
supplies and pharmacy documentation must be made available throughout the study for UCB (or 
designee) to review. 
To administer the injections, study personnel must be appropriately trained and licensed (per 
country guidelines). 
The investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of IMP until returned or destroyed. 
The investigator may assign some of the investigator’s duties for drug accountability at the study 
site to an appropriate pharmacist/designee. 
The investigator must ensure that the IMP is used only in accordance with the protocol. 
After completion of the clinical phase of the study, all used (including empty 
containers)/partially used, unused, damaged, and/or expired IMP must be reconciled and either 
destroyed at the site according to local laws, regulations, and UCB Standard Operating 
Procedures (SOPs) or returned to UCB (or designee). Investigational medicinal product intended 
for the study cannot be used for any other purpose than that described in this protocol. 
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7.7 
Procedures for monitoring subject compliance 
The IMP will be administered at the study site by staff trained in the injection technique. Date 
and time of IMP administration will be recorded in the subject’s eCRF. Drug accountability must 
be recorded on the Drug Accountability form. 
7.8 
Concomitant medications/treatments 
Any treatment administered from the time of signing the ICF to the EOS Visit will be considered 
concomitant medication. This includes medications that were started before the study and are 
ongoing during the study. 
Any concomitant medication use reported by the subject during the study will be recorded in the 
eCRF.  
7.8.1 
Permitted concomitant treatments (medications and therapies) 
Throughout the study, the investigator may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care except for those listed in Section 7.8.2.  
Subjects taking concomitant Chinese herbal medication as indicated by the investigator for 
osteoporosis must be on a stable dose prior to study entry and continue on that dose throughout 
the study.  
7.8.1.1 
Calcium and vitamin D supplementation 
All subjects will be required to take daily calcium and vitamin D supplementation by the oral 
route during the study. Details of daily calcium and vitamin D supplementation are to be 
recorded in the subject’s eCRF. 
The calcium and vitamin D supplements are not considered IMP. The investigator will be 
responsible for ensuring that subjects have access to these protocol-required therapies. Where 
available, vitamin D3 preparations should be used; if vitamin D3 is not available, use of vitamin 
D2 preparations is acceptable. 
From Screening through the EOS Visit, subjects should be taking between 500 to 600mg of 
elemental calcium along with 800 to 1200IU of vitamin D daily. 
Subjects with a serum 25 (OH) vitamin D level of ≥20ng/mL and ≤40ng/mL at Screening will 
receive an initial loading dose of 50,000IU of vitamin D on Day 1 (or within 1 week of Day 1) 
by the oral route. Subjects with a serum 25 (OH) vitamin D level of >40ng/mL at Screening may 
also receive the vitamin D loading dose at the investigator’s discretion. Subjects whose serum 
25 (OH) vitamin D at Screening is <20ng/mL may be given vitamin D supplementation and 
retested once during the Screening Period to determine subject’s eligibility. 
If a subject develops hypercalcemia over the course of the study, the investigator may use his or 
her medical judgment and reduce the calcium and/or vitamin D supplementation to maintain 
serum calcium concentration within the normal range. If a subject develops hypocalcemia over 
the course of the study, appropriate additional supplementation should be instituted as deemed 
acceptable by local guidelines, to maintain serum calcium concentration within the normal range. 
If a subject is unable to tolerate the daily calcium or vitamin D supplementation, the formulation 
may be changed or the dosage lowered. The intolerance as well as the resolution (ie, change in 
formulation or dosage) should be documented in the subject’s chart. 
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7.8.2 
Prohibited concomitant treatments (medications and therapies) 
Chinese herbal medicine for treating osteoporosis must not be initiated at any time during the 
study. 
In addition, the following concomitant medications are prohibited until the end of the OL 
Treatment Period (Month 12 Visit) or until 1 month after the early termination of study 
medication: 
• Strontium (including strontium ranelate and over-the-counter strontium preparations) 
• Fluoride  
• Vitamin K and vitamin K analogs (for the treatment of osteoporosis) 
• Activated vitamin D (1,25-di[OH] vitamin D or 1 [OH] vitamin D) 
• iv bisphosphonates 
• Oral bisphosphonates (cumulative dosing regimens of ≤1 month are acceptable) 
• Denosumab 
• TPTD or any PTH analogs 
• Systemic oral or transdermal estrogen (cumulative dosing regimens of ≤1 month are 
acceptable; vaginal preparations and estrogen creams will be allowed at any time) 
• SERMs (cumulative dosing regimens of ≤1 month are acceptable) 
• Calcitonin (cumulative dosing regimens of ≤1 month are acceptable) 
• Tibolone 
• Prolonged (ie, >3 months) oral glucocorticoid therapy at a prednisone equivalent dose of 
≥5.0mg/day (tapering glucocorticoid courses of ≤1-month duration is permitted regardless of 
dose; inhaled or topical glucocorticoids are permitted) 
• Any cathepsin K inhibitor, such as odanacatib (MK-0822) 
• Hormonal ablation therapy 
• Cinacalcet 
7.8.3 
Rescue medication 
No alternative osteoporosis medication will be allowed during this study and no change in the 
dose and frequency of romosozumab administration is permitted. In the event that a subject 
experiences a clinical fracture during the study, the investigator may discuss alternative 
treatment options. If the decision is made to begin an alternative approved therapy, the subject 
must discontinue IMP. Every effort should be made to have the subject complete the remaining 
study visits and assessments.  
7.9 
Blinding 
This is a Phase 3 multicenter, randomized, 6-month double-blind, placebo-controlled study 
followed by a 6-month OL Treatment Period. Details on maintaining the blind during the 
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Double-Blind, Placebo-Controlled Period and minimizing any bias during the OL Treatment 
Period are provided in Section 7.9.1.1 and Section 7.9.1.2, respectively. 
7.9.1 
Procedures for maintaining and breaking the treatment blind 
7.9.1.1 
Double-Blind, Placebo-Controlled Period 
All IMP injections administered during the Double-Blind, Placebo-Controlled Period 
(romosozumab and placebo) will be identical in appearance, presented in identical containers 
(PFS), and stored and packaged in the same manner in order to maintain the blind.  
All sponsor, contract research organization (CRO), and investigator site personnel involved in 
the study will be blinded to the IMP assignment during the Double-Blind, Placebo-Controlled 
Period with the following exceptions: 
• Sponsor Patient Safety (PS) staff reporting SAEs to regulatory authorities 
• Bioanalytical laboratory staff (analyzing blood samples for PK, antibodies, and BTMs) 
• Unblinded CRO Randomization Biostatistician (to produce the randomization list) 
• Unblinded Medical Monitor (only when deemed necessary to provide appropriate medical 
care to a subject) 
7.9.1.2 
Open-Label Treatment Period 
After the last subject has completed the final visit in the Double-Blind, Placebo-Controlled 
Period, individuals at the sponsor and CRO who will be involved in the data management and 
data cleaning, statistical analysis of the 6-month double-blind data, and the writing of the 
associated Clinical Study Report (CSR), will be unblinded to initial IMP assignments. Upon 
finalization of the CSR (6-month analysis), investigators will be unblinded to subject level 
treatment assignments. Investigators are obliged not to disclose to subjects their initial IMP 
assignment so that subjects will remain blinded during both the Double-Blind, 
Placebo-Controlled and OL Treatment Periods of the study.  
7.9.1.3 
Maintenance of study treatment blind 
All subject treatment details (romosozumab and placebo) will be allocated and maintained by the 
IRT system.  
Under normal circumstances, the blinded treatment must not be revealed. In the case of a 
medical emergency, UCB or its representatives must be notified immediately if the blind is 
broken. 
7.9.1.4 
Breaking the treatment blind in an emergency situation 
The integrity of the clinical study must be maintained by observing the treatment blind. In the 
event of an emergency, it will be possible to determine to which treatment arm the subject has 
been allocated by contacting the IRT system. All sites will be provided with details of how to 
contact the system for code breaking at the start of the study. The Medical Monitor or equivalent 
should be consulted prior to unblinding, whenever possible. 
The Clinical Project Manager (CPM) will be informed immediately via the IRT system when a 
code is broken, but will remain blinded to specific treatment information. Any unblinding of the 
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IMP performed by the investigator must be recorded in the source documents and on the Study 
Termination eCRF page. 
7.10 
Randomization and numbering of subjects 
An IRT system will be used for assigning subjects to treatment based on a predetermined 
production randomization list provided by the CRO. A CRO Randomization Biostatistician who 
is not involved otherwise in the study will write the randomization code using a validated 
program and produce the randomization list. The randomized list will be retained at the CRO in a 
secure location until database lock. The CRO team and UCB team directly involved in the 
conduct of the study will not have access to the productive randomization list up to the 
unblinding of the study. Before the start of the study, copies of the randomization list will be sent 
in a secure fashion to the IRT system and to the unblinded personnel identified in 
Section 7.9.1.1. The IRT system will generate individual assignments for subject kits of IMP, as 
appropriate, according to the visit schedule. 
Subjects will be randomized, stratified by age (<75 years, ≥75 years), in a 2:1 ratio of 
romosozumab to placebo during the Double-Blind, Placebo-Controlled Period, after which, all 
subjects will receive romosozumab during the OL Treatment Period.  
At Screening (Visit 1), after signing the ICF, the investigator or designee will contact the IRT 
system to enter a subject in the study. Each subject will be assigned a 5-digit number via the IRT 
system that serves as the subject identifier throughout the study. The subject number will be 
required in all communication between the investigator or designee and the IRT system 
regarding a particular subject.  
To randomize a subject to treatment on Visit 2 (Day 1), the investigator or designee will contact 
the IRT system to obtain the subject’s randomization number. The randomization number must 
be incorporated into the subject’s eCRF. 
The IRT system will allocate kit numbers based on the subject number for both the 
Double-Blind, Placebo-Controlled Period and the OL Treatment Period. Subject number and kit 
numbers will be tracked via the IRT system. 
The investigator or designee will contact the IRT system when a subject discontinues IMP and/or 
discontinues the study. Subjects who withdraw from the study will not be replaced. 
8 
STUDY PROCEDURES BY VISIT  
A general overview of the study assessments is provided in Table 5‒1. An outline of the study 
procedures and assessments to be performed at each visit is provided below.  
Every effort should be made to keep subjects on the study schedule. However, when this is not 
feasible, romosozumab or placebo may be administered within ±7 days of the study-defined 
visits. Also, subjects can complete with EOS Visit up to 14 days prior to Month 15. 
For the purpose of this study, a month is defined as 30 days.  
8.1 
Screening Visit (Visit 1) (up to 35 days) 
The Screening Visit (Visit 1) should be completed within the 35-day period prior to the first 
administration of IMP. 
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Prior to any study specific activities, subjects will be asked to read, sign, and date an ICF that has 
been approved by the sponsor and an IEC/IRB and that complies with regulatory requirements. 
Subjects will be given adequate time to consider any information concerning the study given to 
them by the investigator or designee. As part of the informed consent procedure, subjects will be 
given the opportunity to ask the investigator any questions regarding potential risks and benefits 
of participation in the study.  
After written informed consent is obtained from the subject, the investigator or designee will 
contact the IRT system to enter the subject in the study. The following procedures and 
assessments will be performed/recorded at this visit. 
Investigator or designee is advised to perform the BMD by DXA and lateral spine x-rays (lumbar 
and thoracic) first and only subjects who fulfill BMD criteria should undergo the remaining 
Screening assessments. Calcium and vitamin D supplements should be prescribed after or at this 
visit. 
• Collect and record demographic data 
• Obtain a medical history 
• Collect and record medical fracture history 
• Collect and record prior medications 
• Complete the lifestyle questions 
• Perform a physical examination 
• Measure the subject’s height and weight  
• Measure vital signs (blood pressure [BP], pulse rate, and temperature)  
• Perform a 12-lead ECG 
• Obtain blood samples for the following:  
− Safety laboratory tests (hematology and serum chemistry) 
− Serology 
− Serum 25 (OH) vitamin D (can be retested once during the Screening Period) 
− TSH, free T4 (if required for confirmation of thyroid status) 
− iPTH 
• Perform lateral spine x-rays (lumbar and thoracic) (instructions are provided in Section 6.5) 
• Perform BMD DXA scans at the lumbar spine, total hip, and femoral neck 
• Recording of concomitant medications 
• Recording of concomitant medical procedures 
• Recording of AEs 
• Instruct the subject to start taking for study purposes daily calcium and vitamin D 
supplementation  
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• Record information on the subject’s daily calcium and vitamin D supplementation 
In addition, before enrolling subjects in the study, a careful individual assessment of the CV risk 
profile should be performed.  
Based on the results of the Screening assessments and procedures at Visit 1, eligible subjects are 
instructed to return to the study site on Visit 2 (Day 1) to be randomized to receive the first dose 
of IMP. 
8.2 
Double-Blind, Placebo-Controlled Period 
8.2.1 
Visit 2 (Day 1) 
The following procedures and assessments will be performed/recorded prior to administration of 
IMP:  
• Confirm that the subject fulfills all the inclusion criteria and none of the exclusion criteria 
• Obtain blood samples for the following: 
− Safety laboratory tests (hematology and serum chemistry) 
− Lipids (total cholesterol, high density lipoprotein [HDL], low density lipoprotein [LDL], 
and triglycerides) - sample should be collected under fasting conditions. Fasting state is 
defined as overnight fasting, with a minimum of 8h of fasting required. 
− Serum 25 (OH) vitamin D 
− iPTH 
− PK (serum romosozumab concentration) 
− Antiromosozumab antibodies 
− BTMs (P1NP and sCTX) - sample for sCTX must be collected from subjects in a fasting 
state and before noon. Fasting state is defined as overnight fasting, with a minimum of 8h 
of fasting required. 
• Recording of concomitant medications  
• Recording of concomitant medical procedures 
• Recording of AEs 
• Discuss signs and symptoms of MI and stroke 
• Record any change in the subject’s daily calcium and vitamin D supplementation 
• Loading dose of vitamin D, if required - should be administered within 1 week of Day 1 
In addition, before enrolling subjects in the study, a careful individual assessment of the CV risk 
profile should be performed. 
After completion of these procedures and assessments, the investigator or designee should 
contact the IRT system to obtain the subject’s randomization number and the IMP kit number 
assigned to the subject. The IMP will be administered by trained study personnel.  
After the subject has been randomized:  
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• Confirm that the subject fulfills none of the withdrawal criteria 
8.2.2 
Visit 3 (Month 1) and Visit 5 (Month 3) 
At these visits, the following procedures and assessments will be performed/recorded prior to 
administration of IMP:  
• Confirm that the subject fulfills none of the withdrawal criteria 
• Measure vital signs (BP, pulse rate, and temperature) (Visit 3 only)  
• Perform a 12-lead ECG  
• Obtain blood samples for the following: 
− Safety laboratory tests (hematology and serum chemistry) 
− iPTH 
− PK (serum romosozumab concentration) 
− Antiromosozumab antibodies 
− BTMs (P1NP and sCTX) - sample for sCTX must be collected from subjects in a fasting 
state and before noon. Fasting state is defined as overnight fasting, with a minimum of 8h 
of fasting required. 
• Perform BMD DXA scans at the lumbar spine, total hip, and femoral neck (Visit 5 only) 
• Recording of concomitant medications 
• Recording of concomitant medical procedures 
• Recording of AEs 
• Discuss signs and symptoms of MI and stroke 
• Record any change in the subject’s daily calcium and vitamin D supplementation 
After completion of these procedures and assessments at each visit, IMP will be administered by 
trained study personnel. 
8.2.3 
Visit 4 (Month 2), Visit 6 (Month 4), and Visit 7 (Month 5) 
At these visits, the following assessments will be performed prior to administration of IMP:  
• Confirm that the subject fulfills none of the withdrawal criteria 
• Recording of concomitant medications 
• Recording of concomitant medical procedures 
• Recording of AEs 
• Discuss signs and symptoms of MI and stroke 
• Record any change in the subject’s daily calcium and vitamin D supplementation 
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After completion of these assessments at each visit, IMP will be administered by trained study 
personnel. The final administration of IMP during the Double-Blind, Placebo-Controlled Period 
will occur at Visit 7 (Month 5).  
8.2.4 
Visit 8 (Month 6) 
The following procedures and assessments will be performed/recorded prior to the first 
administration of OL romosozumab to all subjects:  
• Confirm that the subject fulfills none of the withdrawal criteria 
• Perform a physical examination 
• Measure the subject’s height and weight  
• Measure vital signs (BP, pulse rate, and temperature)  
• Perform a 12-lead ECG 
• Obtain blood samples for the following: 
− Safety laboratory tests (hematology and serum chemistry) 
− Lipids (total cholesterol, HDL, LDL, and triglycerides) 
− iPTH 
− PK (serum romosozumab concentration) 
− Antiromosozumab antibodies 
− BTMs (P1NP and sCTX) - sample for sCTX must be collected from subjects in a fasting 
state and before noon. Fasting state is defined as overnight fasting, with a minimum of 8h 
of fasting required. 
• Perform BMD DXA scans at the lumbar spine, total hip, and femoral neck 
• Recording of concomitant medications 
• Recording of concomitant medical procedures 
• Recording of AEs 
• Discuss signs and symptoms of MI and stroke 
• Record any change in the subject’s daily calcium and vitamin D supplementation 
After completion of these procedures and assessments, all subjects will receive the first dose of 
OL romosozumab administered by trained study personnel and transition to the OL Treatment 
Period of the study. 
8.3 
Open-Label Treatment Period 
8.3.1 
Visit 9 (Month 7) and Visit 11 (Month 9) 
At these visits, the following procedures and assessments will be performed/recorded prior to 
administration of OL romosozumab: 
• Confirm that subject fulfills none of the withdrawal criteria 
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• Measure vital signs (BP, pulse rate, and temperature) (Visit 9 only) 
• Perform a 12-lead ECG (Visit 11 only) 
• Obtain blood samples for: 
− Safety laboratory tests (hematology and serum chemistry) 
− iPTH 
− PK (serum romosozumab concentration) 
− Antiromosozumab antibodies 
− BTMs (P1NP and sCTX) - sample for sCTX must be collected from subjects in a fasting 
state and before noon. Fasting state is defined as overnight fasting, with a minimum of 8h 
of fasting required. 
• Recording of concomitant medications 
• Recording of concomitant medical procedures 
• Recording of AEs 
• Discuss signs and symptoms of MI and stroke 
• Record any change in the subject’s daily calcium and vitamin D supplementation 
After completion of these procedures and assessments at each visit, OL romosozumab will be 
administered by trained study personnel. 
8.3.2 
Visit 10 (Month 8), Visit 12 (Month 10), and Visit 13 (Month 11) 
At these visits, the following assessments will be recorded prior to administration of 
OL romosozumab: 
• Confirm that the subject fulfills none of the withdrawal criteria 
• Recording of concomitant medications 
• Recording of concomitant medical procedures 
• Recording of AEs 
• Discuss signs and symptoms of MI and stroke 
• Record any change in the subject’s daily calcium and vitamin D supplementation 
After completion of these assessments at each visit, OL romosozumab will be administered by 
trained study personnel. The final administration of romosozumab during the OL Treatment 
Period will occur at Visit 13 (Month 11).  
8.3.3 
Visit 14 (Month 12) 
The following procedures and assessments will be performed/recorded: 
• Confirm that the subject fulfills none of the withdrawal criteria 
• Perform a physical examination 
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• Measure the subject’s height and weight 
• Measure vital signs (BP, pulse rate, and temperature)  
• Perform a 12-lead ECG 
• Obtain blood samples for the following:  
− Safety laboratory tests (hematology and serum chemistry) 
− Lipids (total cholesterol, HDL, LDL, and triglycerides) 
− iPTH 
− PK (serum romosozumab concentration) 
− Antiromosozumab antibodies 
− BTMs (P1NP and sCTX) - sample for sCTX must be collected from subjects in a fasting 
state and before noon. Fasting state is defined as overnight fasting, with a minimum of 8h 
of fasting required. 
• Perform BMD DXA scans at the lumbar spine, total hip, and femoral neck 
• Recording of concomitant medications 
• Recording of concomitant medical procedures 
• Recording of AEs 
• Discuss signs and symptoms of MI and stroke 
• Record any change in the subject’s daily calcium and vitamin D supplementation 
8.4 
Follow-Up Period 
8.4.1 
Visit 15 (Month 15) – End-of-Study Visit  
The EOS Visit will occur 4 months after the final administration of OL romosozumab (Visit 13) 
and 3 months after the final study visit (Visit 14) in the OL Treatment Period. At this visit, the 
following procedure and assessments will be performed/recorded: 
• Obtain a blood sample for antiromosozumab antibody testing 
• Recording of concomitant medications 
• Recording of concomitant medical procedures 
• Recording of AEs 
• Record any change in the subject’s daily calcium and vitamin D supplementation before 
instructing the subject for study purposes to stop taking the supplements 
8.5 
Early Termination Visit 
Subjects who withdraw from the study for any reason prior to the EOS Visit should complete the 
ET Visit. The procedures and assessments to be performed at this visit are the same as those 
listed for the final study visit (Visit 14) in the OL Treatment Period, with the exception of lipids 
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(see Section 8.3.3). These subjects will be encouraged to return to the study site for the 
EOS Visit (see Section 8.4.1). 
8.6 
Unscheduled Visit 
At the investigator’s discretion, an Unscheduled Visit may be completed at any time during the 
study but prior to the EOS Visit, if deemed necessary for the subject’s safety and well-being. 
Details of this visit should be recorded on the subject’s chart. 
At this visit, any of the following assessments may be performed, depending on the reason for 
the visit: 
• Confirm that the subject fulfills none of the withdrawal criteria 
• Perform a physical examination 
• Measure vital signs (BP, pulse rate, and temperature)  
• Perform a 12-lead ECG 
• Safety laboratory tests (hematology and serum chemistry) 
• Recording of AEs 
• Recording of concomitant medications 
• Any other assessments that the investigator deems necessary 
8.7 
Study conduct during coronavirus disease 2019 
The protocol mandated visit schedule should be followed to the closest extent possible, based on 
the judgment of the investigator. However, during the coronavirus disease 2019 (COVID-19) 
epidemic or under other exceptional circumstances, remote follow-up may be conducted and the 
subjects may be contacted by telephone/video to assess as many details as possible, according to 
the protocol scheduling, to verify that the subject is suitable for continuing study treatment. 
In-person follow-up at an alternative study site or a home visit is acceptable. Some procedures 
may be collected by other remote means, if feasible. Study sites should make efforts to inform 
the sponsor or the CRO in the event that protocol procedures cannot be completed due to 
COVID-19. 
In those situations when the subject cannot return to the study site, the investigators are to assess 
the subject’s safety by telephone/video contact.  
Ad hoc subject contact may be warranted to understand the current health status of the subjects, 
to follow up on AEs, and inform them of any protective measures taken by the clinical site as a 
result of the COVID-19 pandemic (eg, any measures that may limit access to the site or may 
require additional actions by the subject prior to entry to the site). 
If a subject visits another facility for a medical issue, the investigator should request a detailed 
explanation of the subject’s condition and her participation in the clinical study from the subject 
or caregiver. Subjects or caregivers shall be reminded to completely collect and keep records of 
this visit. 
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9 
ASSESSMENT OF 
PHARMACOKINETIC/PHARMACODYNAMIC VARIABLES 
9.1 
Assessment of pharmacokinetic variables 
Blood samples for the determination of serum concentrations of romosozumab will be collected 
at the time points specified in the schedule of study assessments (Table 5‒1).  
At the visits where IMP is administered, the PK samples will be drawn prior to dosing. For those 
visits where samples for PK testing are collected, vital signs are measured, and 12-lead ECG are 
recorded, the vital sign measurements and 12-lead ECG readings should be taken prior to the 
collection of the PK samples. 
The dates and times of IMP administration and PK collection will be recorded in the eCRF.  
A fully validated bioanalytical method will be utilized to determine concentration of 
romosozumab. Detailed information on sample analysis will be provided in a separate 
bioanalytical report. 
The PK samples will be processed and analyzed by the bioanalytical laboratory. 
Methods for collecting, processing, storing, and shipping of the PK samples are presented in 
further detail in the bioanalytical laboratory manual. 
The PK results will not be made available to the investigator and study-related site personnel at 
any time after the first administration of double-blind IMP to avoid any potential unblinding 
during the Double-Blind Placebo-Controlled Period and to minimize any bias being introduced 
during the OL Treatment Period, once the investigator is unblinded to individual treatment 
assignments. 
9.2 
Assessment of pharmacodynamic variables 
The PD assessment is the concentration of BTMs, the bone formation marker, P1NP and the 
bone resorption marker, sCTX. 
Blood samples for BTM analyses will be collected from subjects at the visits specified in 
Table 5‒1. Blood samples to determine sCTX should be collected from the subject in a fasting 
state and before noon. Fasting state is defined as overnight fasting, with a minimum of 8h of 
fasting required. Blood samples should not be drawn from the same arm where IMP is 
administered. 
Blood samples for BTMs will be processed and analyzed by a central laboratory. 
Methods for collecting, processing, storing, and shipping of the BTM samples are presented in 
further detail in the laboratory manual. 
At any time after the first administration of double-blind IMP, BTM results will not be reported 
to the investigator and study-related site personnel to avoid any potential unblinding during the 
Double-Blind Placebo-Controlled Period and to minimize any bias being introduced during the 
OL Treatment Period, once the investigator is unblinded to individual treatment assignments. 
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10 
 ASSESSMENT OF EFFICACY 
The efficacy assessment in this study is BMD as measured by DXA scan at the lumbar spine, 
total hip, and femoral neck.  
10.1 
Bone mineral density measurements 
Bone density measurements will be performed by DXA at the time points outlined in the 
schedule of study assessments (Table 5‒1). All DXA scans will be analyzed by the central 
imaging vendor. Only Lunar or Hologic densitometers will be allowed in the study. All DXA 
scan data will be submitted electronically to the central imaging laboratory for analysis. Sites 
unable to submit data electronically can submit a compact disc or other media as specified in the 
DXA procedural manual, but electronic submission is preferred. After analysis by the central 
imaging vendor, the study site may be asked to re-acquire a scan due to malpositioning or other 
technical reasons. The study site must comply with these requests. 
A separate DXA procedure manual provided by the central imaging vendor will give specific 
instructions for acquisition of scans as well as performance of Instrument Quality Control. 
Bone density will be measured at the lumbar spine, total hip, and proximal femur. The DXA 
scans of the lumbar spine will be performed in duplicate (ie, subjects will be removed from the 
table inbetween scans). Lumbar spine scans must include L1 through L4. For total hip and 
proximal femur DXA scans, the left side should be used for all scans at all visits. If the right side 
must be used (eg, due to implants) or is inadvertently used at baseline, then it must be used 
consistently throughout the study. If a subject fractures the hip that has been scanned during the 
study up to the time of fracture, no further scans will be obtained for the affected location. The 
same DXA machine must be used for a particular subject for the duration of the study. 
For Screening purposes, DXA scans of the lumbar spine and proximal femur taken up to 35 days 
prior to the beginning of the Screening Period may be used if the following criteria are met: 
• Images were obtained as part of the routine standard of care or following appropriate 
informed consent procedures  
• Images were obtained by a trained technician using the parameters specified by the imaging 
vendor (refer to the appropriate imaging manual provided by the imaging vendor  
• DXA images were obtained using the same DXA scanner that will be used for this study 
To determine subject’s eligibility based on BMD T-scores, lumbar spine and proximal femur 
DXA scans will be analyzed by the central imaging vendor. Subjects must have at least 
2 evaluable lumbar vertebrae (L1-L4) and at least 1 evaluable hip as assessed by the central 
imaging vendor.  
All BMD data will be analyzed by the central imaging vendor and these results will not be 
reported to the investigator and study-related site personnel at any time after the first 
administration of double-blind IMP to avoid any potential unblinding during the Double-Blind 
Placebo-Controlled Period and to minimize the introduction of any bias during the OL Treatment 
Period, once the investigator is unblinded to individual treatment assignments.  
Investigators will be alerted if a subject experiences a BMD decrease from baseline of 7% or 
more at the lumbar spine, total hip, or femoral neck at any time during the study. The 
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investigator is required to discuss the implications for individual fracture risk and alternative 
treatment options and this discussion should be documented in the subject’s records. If a decision 
is made to begin alternative treatment, the subject should discontinue IMP and every effort will 
be made for the subject to complete the remaining study visits and assessments (see 
Section 6.3.1).  
11 
ASSESSMENT OF SAFETY 
In this study, the safety variables include the number and incidence of TEAEs; vital sign 
measurements; 12-lead ECG parameters; laboratory test results (hematology and serum 
chemistry), physical examination findings, and incidence of antibodies to romosozumab. The 
assessments of the safety variables are described below. 
11.1 
Adverse events  
11.1.1 
Definitions 
11.1.1.1 
Adverse event  
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the ICF), including any pretreatment and posttreatment periods required by the 
protocol, must be reported in the eCRF even if no IMP was taken but specific study procedures 
were conducted. This includes all AEs not present prior to the initial visit and all AEs that 
recurred or worsened after the initial visit. 
Signs or symptoms of the condition/disease for which the IMP is being studied should be 
recorded as AEs only if their nature changes considerably or their frequency or intensity 
increases in a clinically significant manner as compared to the clinical profile known to the 
investigator from the subject’s history or the Baseline Period.  
11.1.1.2 
Serious adverse event  
Once it is determined that a subject experienced an AE, the seriousness of the AE must be 
determined. An SAE must meet 1 or more of the following criteria: 
• Death 
• Life-threatening 
(Life-threatening does not include a reaction that might have caused death had it occurred in 
a more severe form.) 
• Significant or persistent disability/incapacity 
• Congenital anomaly/birth defect (including that occurring in a fetus) 
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• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent 1 of the other 
outcomes listed in the definition of serious 
(Important medical events may include, but are not limited to, potential Hy’s Law [see 
Section 11.1.1.3], allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.) 
• Initial inpatient hospitalization or prolongation of hospitalization 
(A patient admitted to a hospital, even if she is released on the same day, meets the criteria 
for the initial inpatient hospitalization. An emergency room visit that results in admission to 
the hospital would also qualify for the initial inpatient hospitalization criteria. However, 
emergency room visits that do not result in admission to the hospital would not qualify for 
this criteria and, instead, should be evaluated for 1 of the other criteria in the definition of 
serious [eg, life-threatening adverse experience, important medical event]. 
Hospitalizations for reasons not associated with the occurrence of an AE [eg, preplanned 
surgery or elective surgery for a pre-existing condition that has not worsened or manifested 
in an unusual or uncharacteristic manner] do not qualify for reporting. For example, if a 
subject has a condition recorded on her medical history and later has a preplanned surgery for 
this condition, it is not appropriate to record the surgery or hospitalization as an SAE, since 
there is no AE upon which to assess the serious criteria. Please note that, if the pre-existing 
condition has worsened or manifested in an unusual or uncharacteristic manner, this would 
then qualify as an AE and, if necessary, the seriousness of the event would need to be 
determined.) 
11.1.1.2.1 
Anticipated serious adverse events 
The Anticipated SAEs in Table 11‒1 have been identified as these events are anticipated to occur 
in the osteoporotic population at some frequency that is independent of drug exposure.  
This list does not change the investigator’s obligation to report all SAEs (including Anticipated 
SAEs) as detailed in Section 11.1.2.3. 
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Table 11‒1: Anticipated SAEs for osteoporotic population  
Population 
Anticipated SAE 
Osteoporotic 
Pneumonia 
 
Osteoarthritis 
 
Femur fracture 
 
Chronic obstructive pulmonary disease 
 
Cholelithiasis 
 
Urinary tract infection 
 
Radius fracture 
 
Femoral neck fracture 
 
Lung neoplasm malignant 
ISS=Integrated Summary of Safety; SAE=serious adverse event  
Note: Anticipated SAEs are based on treatment-emergent SAEs with an exposure-adjusted incidence rate 
≥0.2/100 subject-years in the placebo arm of placebo-controlled studies, with the exception of study endpoints, 
cerebrovascular event, and death (Source: ISS 2017, Table 14-6.7.2). 
11.1.1.3 
Adverse events of special interest  
An AE of special interest is any AE that a regulatory authority has mandated be reported on an 
expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to the 
administration of a UCB product/compound.  
Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total bilirubin in 
the absence of ≥2xULN ALP, with no alternative explanation for the biochemical abnormality, 
must ALWAYS be reported to UCB as an AE of special interest (ie, without waiting for any 
additional etiologic investigations to have been concluded). Follow-up information should then 
be reported if an alternative etiology is identified during investigation and monitoring of the 
subject. 
11.1.1.4 
Adverse events of interest 
The following AEs have been prospectively identified as AEs of interest for romosozumab:  
• Injection site reactions  
• Events potentially related to hypersensitivity  
• Hypocalcemia  
• Hyperostosis  
• Osteoarthritis 
• Malignancy  
• Positively-adjudicated ONJ, AFF, and CV events 
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Details of the adjudication processes for ONJ, AFF, and CV events are provided in 
Section 13.4.3.1. 
11.1.2 
Procedures for reporting and recording adverse events  
The subject will be given the opportunity to report AEs spontaneously. A general prompt will 
also be given at each study visit to detect AEs. For example: 
“Did you notice anything unusual about your health (since your last visit)?” 
In addition, the investigator should review any self-assessment procedures (eg, diary cards) 
employed in the study. 
11.1.2.1 
Description of adverse events  
When recording an AE, the investigator should use the overall diagnosis or syndrome using 
standard medical terminology, rather than recording individual symptoms or signs. The eCRF 
and source documents should be consistent. Any discrepancies between the subject’s own words 
on her own records (eg, diary card) and the corresponding medical terminology should be 
clarified in the source documentation. 
Details for completion of the AE eCRF (including judgment of relationship to IMP) are 
described in the eCRF Completion Guidelines. 
11.1.2.2 
Rule for repetition of an adverse event  
An increase in the intensity of an AE should lead to the repetition of the AE being reported with: 
• The outcome date of the first AE that is not related to the natural course of the disease being 
the same as the start date of the repeated AE, and the outcome of “worsening” 
• The AE verbatim term being the same for the first and repeated AE, so that the repeated AE 
can be easily identified as the worsening of the first one 
11.1.2.3 
Additional procedures for reporting serious adverse events  
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information by 
the site (see contact information for SAE reporting listed in the SAE Reporting section at the 
front of the protocol). The investigator must forward to UCB (or its representative) a duly 
completed “Investigator SAE Report Form for Development Drug” (SAE Report form) provided 
by UCB, even if the data are incomplete, or if it is obvious that more data will be needed in order 
to draw any conclusions. Information recorded on this form will be entered into the global safety 
database. 
An Investigator SAE Report form will be provided to the investigator. The Investigator SAE 
Report form must be completed in English.  
It is important for the investigator, when completing the SAE Report form, to include the 
assessment as to a causal relationship between the SAE and the IMP administration. This insight 
from the investigator is very important for UCB to consider in assessing the safety of the IMP 
and in determining whether the SAE requires reporting to the regulatory authorities in an 
expedited manner. 
Additional information (eg, autopsy or laboratory reports) received by the investigator must be 
provided within 24 hours. All documents in the local language must be accompanied by a 
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translation in English, or the relevant information included in the same document must be 
summarized in the Investigator SAE Report form. 
The investigator is specifically requested to collect and report to UCB (or its representative) any 
SAEs (even if the investigator is certain that they are in no way associated with the IMP), up to 
30 days from the end of the study for each subject, and to also inform participating subjects of 
the need to inform the investigator of any SAE within this period. Serious AEs that the 
investigator thinks may be associated with the IMP must be reported to UCB regardless of the 
time between the event and the end of the study. 
Upon receipt of the SAE Report form, UCB will perform an assessment of expectedness of the 
reported SAE. The assessment of the expectedness of the SAE is based on the IB. 
11.1.3 
Follow up of adverse events  
An AE should be followed until it has resolved, has a stable sequelae, the investigator determines 
that it is no longer clinically significant, or the subject is lost to follow up. This follow-up 
requirement applies to AEs, SAEs, and AEs of special interest; further details regarding follow 
up of PDILI events is provided in Section 11.6.1.4.  
If an AE is ongoing at the end of the study for a subject, follow up should be provided until 
resolution/stable level of sequelae is achieved, or until the investigator no longer deems that it is 
clinically significant, or until the subject is lost to follow up. If no follow up is provided, the 
investigator must provide a justification. The follow up will usually be continued for 4 months 
after the subject has discontinued her IMP. 
Information on SAEs obtained after clinical database lock will be captured through the PS 
database without limitation of time. 
11.2 
Pregnancy 
Since the study population is postmenopausal women, it is not expected that any subject will 
become pregnant during the study. However, in the event that a pregnancy occurs, the 
procedures outlined in this section should be followed. 
If an investigator is notified that a subject has become pregnant after the first intake of any IMP, 
the investigator must immediately notify UCB’s PS department by providing the completed 
Pregnancy Report and Outcome form (for contact details see SAE reporting information at the 
beginning of this protocol). The subject should be withdrawn from the study as soon as 
pregnancy is known (by positive pregnancy test), and the following should be completed: 
• The subject should return for an ET Visit and have the ET assessments performed with the 
exception of the BMD measurement by DXA (which is not to be performed). 
• The investigator should immediately stop any further administration of the IMP at the 
ET Visit.  
• An EOS Visit should be scheduled 4 months after the subject’s final dose of IMP. 
The investigator must inform the subject of information currently known about potential risks 
and about available treatment alternatives. 
The pregnancy will be documented on the Pregnancy Report and Outcome form provided to the 
investigator. The progression of the pregnancy and the eventual birth (if applicable) must be 
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followed up using the Pregnancy Report and Outcome form in which the investigator has to 
report on the health of the mother and of the child. Every reasonable attempt should be made to 
follow the health of the child for 30 days after birth for any significant medical issues. In certain 
circumstances, UCB may request that follow up is continued for a period longer than 30 days. If 
the subject is lost to follow up and/or refuses to give information, written documentation of 
attempts to contact the subject needs to be provided by the investigator and filed at the site. 
UCB’s PS department is the primary contact for any questions related to the data collection for 
the pregnancy, eventual birth, and follow up. 
A pregnancy becomes an SAE in the following circumstances: miscarriage, abortion (elective or 
spontaneous), unintended pregnancy after hormonal contraceptive failure (if the hormonal 
contraceptive was correctly used), ectopic pregnancy, fetal demise, or any congenital 
anomaly/birth defect of the baby. Those SAEs must be additionally reported using the 
Investigator SAE Report form. 
11.3 
Suspected transmission of an infectious agent 
For the purposes of reporting, any suspected transmission of an infectious agent via a medicinal 
product should be considered as an SAE; such cases must be reported immediately, recorded in 
the AE module of the eCRF, and followed as any other SAE. Any organism, virus, or infectious 
particle (eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent. 
11.4 
Overdose of investigational medicinal product 
Overdose with this product has not been reported. The effects of overdose of this product are not 
known. An antidote to overdose of this product is not known. The maximum amount of 
romosozumab that can be safely administered in a single dose has not been determined, and there 
is currently insufficient information to draw any conclusions about the safety of doses higher 
than those studied in clinical studies. The highest single dose of romosozumab tested in clinical 
studies is 10mg/kg sc.  
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded in the eCRF. Any SAE or nonserious AE associated with excessive dosing must be 
followed as any other SAE or nonserious AE. These events are only considered AEs or SAEs if 
there are associated clinical signs and symptoms or if the act of taking the excess medicine itself 
is an AE or SAE (eg, suicide attempt). 
11.5 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the IMP so that investigators, clinical study subjects, regulatory 
authorities, and IRBs/IECs will be informed appropriately and as early as possible. 
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the PS representative. 
As appropriate for the stage of development and accumulated experience with the IMP, 
medically qualified personnel at UCB may identify additional safety measures (eg, AEs, vital 
signs, laboratory or ECG results) for which data will be periodically reviewed during the course 
of the study. 
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An independent DMC will be formed to monitor the ongoing safety of subjects in the study. 
Further details on the DMC is provided in Section 13.7.  
11.6 
Laboratory measurements 
Blood samples will be collected for laboratory assessments at the time points specified in the 
schedule of study assessments (Table 5‒1). Blood will be drawn by venipuncture before each 
IMP administration. The clinical laboratory parameters to be measured are presented in 
Table 11‒2.  
Serology (hepatitis/HIV) testing, laboratory tests (hematology and serum chemistry), an 
endocrine test (serum 25 [OH] vitamin D), and some hormone tests (iPTH, TSH, and T4) will be 
performed at Screening to determine the subject’s eligibility for the study. 
The central laboratory will be responsible for all clinical laboratory testing.  
Details on the collection, storage, preparation, and shipping of samples to the central laboratory 
will be presented in the laboratory manual provided separately. 
The following laboratory parameters will be measured: 
Table 11‒2: Clinical laboratory measurements 
Hematology 
RBC count, hemoglobin, hematocrit, platelet count, total WBC count and 
differentials consisting of absolute counts of the following leukocyte 
types: neutrophils, lymphocytes, monocytes, eosinophils, and basophils 
Serum chemistry 
Sodium, potassium, chloride, bicarbonate, total protein, albumin, calcium, 
albumin-adjusted calcium, magnesium, phosphorus, glucose, BUN, 
creatinine, total bilirubin, ALP, AST, and ALT 
Lipids 
Total cholesterol, LDL, HDL, and triglycerides 
Serologya 
HBsAg, HBcAb, HCV antibody, HIV 1 and 2 antibodies 
Hormone 
iPTH  
TSH and T4a  
Endocrineb 
Serum 25 (OH) vitamin D 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; HBcAb=hepatitis B core antibody; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; 
HDL=high density lipoprotein; HIV=human immunodeficiency virus; iPTH=intact parathyroid hormone; 
LDL=low density lipoprotein; OH=hydroxy; RBC=red blood cell; T4=thyroxine; TSH=thyroid-stimulating 
hormone; WBC=white blood cell 
a Testing will be performed only at Screening (Visit 1). 
b Testing will be performed at Screening (Visit 1) and Visit 2 (Day 1). 
The original printouts from the laboratory, signed or initialed by the investigator, will be kept at 
the study site. The laboratory data will be transferred electronically to UCB. 
Results of laboratory assessments for serum calcium, albumin-adjusted calcium, phosphorus, 
ALP, P1NP, CTX, iPTH, romosozumab levels, and antiromosozumab antibodies are considered 
potentially unblinding and will not be reported to any study-related personnel after Day 1 in 
order to maintain the integrity of the study blind.  However, in the event of an abnormal value of 
clinical relevance (panic value) for serum calcium, albumin-adjusted calcium, phosphorus, or 
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ALP, sites will be notified of the unblinded value by the central laboratory.  After such 
notification is issued, the sites may perform additional follow-up blood draws for local analysis 
as required to support subject medical care. 
All clinically significant abnormal laboratory tests occurring during the study will be repeated at 
appropriate intervals until they return to baseline or to a level deemed acceptable by the 
investigator and the sponsor, or until the abnormality is explained by an appropriate diagnosis. 
All clinically significant values will be reported as AEs. 
11.6.1 
Evaluation of PDILI 
The PDILI IMP discontinuation criteria for this study are provided in Section 6.3.3, with the 
accompanying required follow-up investigation and monitoring detailed below. All PDILI events 
must be reported as an AE and reported to the study site and sponsor within 24 hours of learning 
of their occurrence. Any PDILI event that meets the criterion for potential Hy’s Law must be 
reported as an AE of special interest (see Section 11.1.1.3), and, if applicable, also reported as an 
SAE (see Section 11.1.1.2).  
Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in 
Table 11‒3 (specific tests dependent on laboratory results and corresponding symptoms) and 
consultation with a local hepatologist (if applicable; discussed in Section 11.6.1.1). The local 
hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. Additional investigation and monitoring may be required and adapted based 
on the diagnosis after the cause of the liver injury/abnormality is confirmed (details in 
Section 11.6.1.4).  
The results of all monitoring, including laboratory testing and other testing, should be made 
available to the study site and sponsor. 
All initial tests resulting in abnormal hepatic laboratory values need to be repeated, but 
appropriate medical action must not be delayed waiting for the repeat result. 
If tests are done locally for more rapid results, a concurrent sample should also be sent to the 
central laboratory whenever possible. Medical care decisions are to be made initially using the 
most rapidly available results and a conservative approach must be taken if the results from the 
2 laboratory tests are significantly different. Data from the local and central laboratory are to be 
recorded on the applicable eCRF pages. 
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. In these cases, the investigator should also 
consider dose reduction for medically necessary concomitant medication and consider changing 
any medically required concomitant medication known to be hepatotoxic to a suitable 
alternative. 
When IMP is stopped due to PDILI (as described in Section 6.3.3), IMP must be permanently 
discontinued unless a subsequent alternative diagnosis fully explains the hepatic findings. If a 
subsequent alternative diagnosis fully explains the hepatic findings, and the requirements 
provided in Section 11.6.1.2.1 are met, rechallenge with IMP may be appropriate.  
Rechallenge with a substance potentially causing drug-induced liver injury is dangerous, may be 
fatal, and must not occur. 
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The table below (Table 11‒3) summarizes the approach to investigate PDILI. 
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Table 11‒3: Required investigations and follow up for PDILI 
Laboratory value 
 
Immediate 
Follow up 
ALT or 
AST 
Total 
bilirubin 
Symptomsa of 
hepatitis or 
hypersensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
≥3xULN 
≥2xULNb 
NA 
Hepatology consult.c 
Medical Monitor 
must be notified 
within 24 hours 
(eg, by laboratory 
alert) and subject 
discussed with 
Medical Monitor 
ASAP. 
Immediate, 
permanent IMP 
discontinuation. 
 
Essential: Must 
have repeat liver 
chemistry values 
and additional 
testing completed 
ASAP (see 
Section 11.6.1.3); 
recommended to 
occur at the site 
with HCP. 
Monitoring of liver chemistry 
values at least twice per week 
until values normalize, stabilize, 
or return to within baseline 
values.d 
 
≥8xULN 
NA 
NA 
≥3xULN 
NA 
Yes 
Immediate, 
temporary or 
permanent, IMP 
discontinuation. 
≥3xULN 
(and ≥2x 
baseline) 
and 
<5xULN 
<2xULN 
No 
Discussion with 
Medical Monitor 
required if the 
criterion that allows 
for IMP continuation 
is met. 
Further investigation 
– immediate IMP 
discontinuation not 
required (see 
Section 11.6.1.2). 
Not required 
unless otherwise 
medically 
indicated (at 
discretion of 
investigator). 
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Table 11‒3: Required investigations and follow up for PDILI 
Laboratory value 
 
Immediate 
Follow up 
ALT or 
AST 
Total 
bilirubin 
Symptomsa of 
hepatitis or 
hypersensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
≥5xULN 
(and ≥2x 
baseline) 
and 
<8xULN 
<2xULN 
No 
Hepatology consult if 
there is no evidence of 
resolution (see Follow 
up requirements).c 
 
Discussion with 
Medical Monitor 
required. 
IMP discontinuation 
required if any of the 
following occur: 
• Subject cannot 
comply with 
monitoring 
schedule.  
• Liver chemistry 
values continue to 
increase during 
2-week monitoring 
period. 
• Liver chemistry 
values remain 
≥5xULN (and 
≥2x baseline) after 
2-week monitoring 
period. 
Essential: Every 
attempt must be 
made to have 
repeat liver 
chemistry values 
and additional 
testing completed 
within 48 hours at 
the site with HCP 
(see 
Section 11.6.1.3). 
Monitoring of liver chemistry 
values at least twice per week for 
2 weeks.d 
• Immediate IMP discontinuation 
required if liver chemistry 
values continue to increase. 
After 2 weeks of monitoring liver 
chemistry values: 
• Discontinue IMP if levels 
remain ≥5xULN (and ≥2x 
baseline); monitor until values 
normalize, stabilize, or return to 
within baseline values. d 
• Continue IMP if levels are no 
longer ≥5xULN (and ≥2x 
baseline); continue to monitor 
at least twice per week until 
values normalize, stabilize, or 
return to within baseline 
values.d 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; ASAP=as soon as possible; AST=aspartate aminotransferase; HCP=healthcare practitioner; 
IMP=investigational medicinal product; NA=not applicable; PDILI=potential drug-induced liver injury; ULN=upper limit of normal  
a Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or tenderness; hypersensitivity symptoms include eosinophilia (>5%), 
rash, and fever (without clear alternative cause). 
b If the subject also has ≥2xULN ALP, the possibility of an indication of biliary obstruction should be discussed with the Medical Monitor. 
.c Details provided in Section 11.6.1.1. The local hepatologist is the expert usually consulted by the treating physician for assessment and management of 
potential hepatic disease. This would usually be a hepatologist, but may be a gastroenterologist. 
d Unless an alternative monitoring schedule is agreed by the investigator and UCB responsible physician. Determination of stabilization is at the discretion of the 
investigator in consultation with the hepatologist (as applicable) and UCB responsible physician, as needed. 
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11.6.1.1 
Consultation with Medical Monitor and local hepatologist  
Potential drug-induced liver injury events require notification of the Medical Monitor within 
24 hours (eg, by laboratory alert), and the subject must be discussed with the Medical Monitor as 
soon as possible. If required, the subject must also be discussed with the local hepatologist. The 
local hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. If determined necessary, this discussion should be followed by a full 
hepatology assessment (see Section 11.6.1.3) and SAE report (if applicable). 
11.6.1.2 
Immediate action: determination of IMP discontinuation 
All PDILI events require immediate action, testing, and monitoring.  
The immediate action is dependent on the laboratory values and symptoms of hepatitis or 
hypersensitivity and ranges from continuation of IMP (followed by immediate investigation) to 
immediate and permanent discontinuation (see Section 6.3.3 and Table 11‒3 for details). 
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. The investigator should also consider dose 
reduction for medically necessary concomitant medication and consider changing any medically 
required concomitant medication known to be hepatotoxic to a suitable alternative. 
11.6.1.2.1 
IMP restart/rechallenge (if applicable) 
Rechallenge in a subject in whom a potentially causing drug-induced liver injury event is 
suspected, is dangerous, may be fatal, and must not occur. 
Subjects who are immediately discontinued from IMP due to having met certain criteria for 
PDILI (as described in Section 6.3.1 and Table 11-3), but for whom an alternative diagnosis is 
confirmed, ie, drug-induced liver injury is excluded, can rarely restart IMP. Rechallenge with 
IMP can occur only if ALL of the following requirements are met: 
• The results of additional testing and monitoring described in Section 11.6.1.3 and 
Section 11.6.1.4 confirm a nondrug-related cause for the abnormal hepatic laboratory 
parameters and any associated symptoms (ie, a subsequent alternative diagnosis fully 
explains the hepatic findings).  
• No alternative treatment options are available to the subject. 
• The subject has shown clear therapeutic benefit from the IMP. 
• Subject’s ALT or AST elevations do not exceed ≥3xULN. 
• Subject’s total bilirubin is <1.5xULN. 
• Subject has no signs or symptoms of hypersensitivity.  
• The rechallenge is approved by the UCB responsible physician, DMC, and a hepatologist. 
The hepatologist must be external to UCB but may be a member of the DMC. It is 
recommended that the hepatologist be a local hepatology expert or the hepatologist treating 
the subject. 
• Subject agrees to the investigator-recommended monitoring plan and understands their 
individual benefit risk for restarting IMP and this is adequately documented.  
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11.6.1.3 
Testing: identification/exclusion of alternative etiology 
The measurements and additional information required for the assessment of PDILI events when 
there is a reasonable possibility that they may have been caused by the IMP are detailed in 
Table 11‒4 (laboratory measurements) and Table 11‒5 (additional information). Results of the 
laboratory measurements and information collected are to be submitted to the sponsor on the 
corresponding eCRF. If the medical history of the subject indicates a requirement for other 
assessments not included below, these additional assessments should be completed and 
submitted, as applicable. 
All blood samples should be stored, if possible. If tests are done locally for more rapid results, 
a concurrent sample must also be sent to the central laboratory. 
The following measurements are to be assessed: 
Table 11‒4: PDILI laboratory measurements 
Virology-
related 
Hepatitis A IgM antibody 
HBsAg 
Hepatitis E IgM antibody 
HBcAb-IgM 
Hepatitis C RNA 
Cytomegalovirus IgM antibody 
Epstein-Barr viral capsid antigen IgM antibody (if unavailable, obtain heterophile 
antibody or monospot testing) 
Immunology 
Anti-nuclear antibody (qualitative and quantitative) 
Anti-smooth muscle antibody (qualitative and quantitative) 
Type 1 anti-liver kidney microsomal antibodies (qualitative and quantitative) 
Hematology 
Eosinophil count 
Urinalysis 
Toxicology screen 
Chemistry 
Amylase 
If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % direct bilirubin 
Serum CPK and LDH to evaluate possible muscle injury causing transaminase elevation 
Additional 
Prothrombin time/INRa 
PK sample 
ALT=alanine aminotransferase; CPK=creatine phosphokinase; HBcAb-IgM=hepatitis B core antibody-IgM; HBsAg=hepatitis B 
surface antigen; IgM=immunoglobulin M; INR=international normalized ratio; LDH=lactate dehydrogenase; PDILI=potential 
drug-induced liver injury; PK=pharmacokinetic(s); RNA=ribonucleic acid; ULN=upper limit of normal 
a Measured only for subjects with ALT >8xULN, elevations in total bilirubin and symptoms of hepatitis or hypersensitivity. 
Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or tenderness; hypersensitivity symptoms 
include eosinophilia (>5%), rash, and fever (without clear alternative cause). 
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The following additional information is to be collected: 
Table 11‒5: PDILI information to be collected 
New or updated information 
Concomitant prescription and over-the-counter medications (eg, acetaminophen, herbal remedies, 
vitamins); dosages and dates should be included. 
Pertinent medical history, including the following: 
• 
History of liver disease (eg, autoimmune hepatitis, nonalcoholic steatohepatitis or other “fatty 
liver disease”) 
• 
Adverse reactions to drugs 
• 
Allergies 
• 
Relevant family history or inheritable disorders (eg, Gilbert’s syndrome, alpha-1 antitrypsin 
deficiency) 
• 
Recent travel  
• 
Progression of malignancy involving the liver (Note: Metastatic disease to the liver, by itself, 
should not be used as an explanation for significant AST and/or ALT elevations.) 
The appearance or worsening of clinical symptoms of hepatitis or hypersensitivity (eg, fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, decreased appetite, abdominal pain, jaundice, fever, or 
rash) 
Recent clinically significant hypotension or hypoxemia with compromised cardiopulmonary function 
Alcohol and illicit drug use 
Results of liver imaging or liver biopsy, if done 
Results of any specialist or hepatology consult, if done 
Any postmortem/pathology reports 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; PDILI=potential drug-induced liver injury 
11.6.1.4 
Follow-up evaluation 
Potential drug-induced liver injury events require follow-up monitoring as described in 
Table 11‒3. Monitoring should continue until liver chemistry values normalize, stabilize, or 
return to baseline. Determination of stabilization is at the discretion of the investigator in 
consultation with the hepatologist (as applicable) and UCB responsible physician, as needed. 
11.7 
Other safety measurements 
Other safety measurements will include vital signs, 12-lead ECG readings, physical examination 
findings, and the incidence of antibodies to romosozumab.  
11.7.1 
Vital sign measurements 
Vital signs (BP [systolic and diastolic], pulse rate, and body temperature [oral or otic]) should be 
measured at the time points specified in Table 5‒1. 
Vital sign measurements will be recorded after the subject is in a seated or semi-recumbent 
position for at least 3 minutes. The subject’s preferred position should remain consistent 
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throughout the study. The BP readings should be taken from the same arm by the same qualified 
individual throughout the study.  
The method used for measuring the subject’s body temperature should be consistent throughout 
the study and documented in the subject’s eCRF. 
11.7.2 
12-lead ECG recordings 
Standard 12-lead ECGs will be recorded at the time points specified in Table 5‒1. All ECGs will 
be recorded after the subject is in a seated or in a semi-recumbent position for at least 3 minutes.  
The ECGs will be read by a central reader. The PR, RR, QRS, QT, and corrected QT (QTc) 
intervals and heart rate will be assessed. 
At any time during the study, the investigator may consult with the cardiologist at the central 
ECG laboratory to confirm the presence of a clinically significant ECG abnormality. It remains 
the responsibility of the investigator to decide whether an ECG finding is of clinical significance 
on the basis of the complete clinical picture and whether this finding influences the subject’s 
participation in the study. 
11.7.3 
Physical examination 
Physical examinations will be performed at the time points specified in Table 5‒1. Findings 
considered as clinically significant changes since the physical examination at Screening (Visit 1) 
will be recorded as AEs. 
11.7.4 
Body weight and height 
Body weight (subject in underwear or light clothing, without shoes) and height (subject without 
shoes) will be recorded at the time points specified in the schedule of study assessments in 
Table 5‒1. The subject’s BW will be rounded to the nearest 0.1kg. The subject’s height will be 
rounded to the nearest 0.5cm. 
11.7.5 
Antibodies to romosozumab 
Blood samples for antiromosozumab antibody testing will be collected from subjects at the time 
points indicated in Table 5‒1. However, only samples from subjects who receive romosozumab 
will be analyzed for antiromosozumab binding antibodies. 
A fully validated bioanalytical method will be utilized to determine antibodies to romosozumab. 
Detailed information on sample analysis will be provided in a separate bioanalytical report. 
The investigator will be notified of any positive neutralizing antibody results to romosozumab 
detected at the EOS Visit or ET Visit. Subjects who test positive for neutralizing antibodies to 
romosozumab at the EOS Visit or ET Visit will be asked to return for additional follow-up 
testing. This testing should occur approximately every 3 months starting from when the site has 
been notified of the positive result, until: (1) neutralizing antibodies are no longer detectable or 
(2) the subject has been followed for a period of at least 1 year (±4 weeks) after IMP 
administration. All follow-up results both positive and negative will be communicated to the site. 
More frequent testing (eg, QM) or testing over a longer period may be requested in the event of 
safety-related concerns.  
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Subjects who test positive for binding, non-neutralizing antibodies and have clinical sequelae 
that are considered potentially related to an antiromosozumab antibody response may also be 
asked to return for additional follow-up testing.  
Blood samples for antibody determination will be processed and analyzed by the bioanalytical 
laboratory. 
Methods for collecting, processing, storing, and shipping of the samples are presented in further 
detail in the bioanalytical laboratory manual. 
No notifications of a positive antibody status will be sent to the investigator before the EOS Visit 
or ET Visit to avoid any potential unblinding during the Double-Blind Placebo-Controlled Period 
and to minimize any bias being introduced during the OL Treatment Period, once the 
investigator is unblinded to individual treatment assignments. 
12 
STUDY MANAGEMENT AND ADMINISTRATION  
12.1 
Adherence to protocol 
The investigator should not deviate from the protocol. However, the investigator should take any 
measure necessary in deviation from or not defined by the protocol in order to protect clinical 
study subjects from any immediate hazard to their health and safety. In this case, this action 
should be taken immediately, without prior notification of the regulatory authority, IRB/IEC, or 
sponsor. 
After implementation of such measure, the investigator must notify the CPM of the sponsor 
within 24 hours and follow any local regulatory requirements. 
12.2 
Monitoring 
Monitoring of the study will be delegated by UCB to a CRO. The CRO will monitor the study to 
meet the CRO’s monitoring SOPs, ICH-GCP guideline, and applicable regulatory requirements, 
and to ensure that study initiation, conduct, and closure are adequate.  
The investigator and his/her staff are expected to cooperate with UCB (or designee) and to be 
available during the monitoring visits to answer questions sufficiently and to provide any 
missing information. The investigator(s)/institution(s) will permit direct access to source 
data/documents for study-related monitoring, audits, IRB/IEC review, and regulatory 
inspection(s). 
The investigator will allow UCB (or designee) to periodically review all eCRFs and 
corresponding source documents (eg, hospital and laboratory records for each subject). 
Monitoring visits will provide UCB (or designee) with the opportunity to evaluate the progress 
of the study, verify the accuracy and completeness of eCRFs, ensure that all protocol 
requirements, applicable authorities regulations, and investigator’s obligations are being fulfilled, 
and resolve any inconsistencies in the study records. 
12.2.1 
Definition of source data  
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
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(such as removable self-stick notes). Photocopies and/or printouts of eCRFs are not considered 
acceptable source documents.  
Source documents are original records in which raw data are first recorded. These may include 
hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, printouts, 
pharmacy records, care records, ECG or other printouts, for example. Source documents should 
be kept in a secure, limited access area. 
Source documents that are computer generated and stored electronically must be printed for 
review by the monitor (eg, ECG reports). Once printed, these copies should be signed and dated 
by the investigator and become a permanent part of the subject’s source documents. The 
investigator will facilitate the process for enabling the monitor to compare the content of the 
printout and the data stored in the computer to ensure all data are consistent. 
Electronic data records, such as electroencephalogram records, must be saved and stored as 
instructed by UCB (or designee). 
12.2.2 
Source data verification 
Source data verification ensures accuracy and credibility of the data obtained. During monitoring 
visits, reported data are reviewed with regard to being accurate, complete, and verifiable from 
source documents (eg, subject files, recordings from automated instruments, tracings [ECG], 
x-ray films, laboratory notes).  
12.3 
Data handling 
12.3.1 
Case Report form completion 
The investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
eCRFs and in all required reports. 
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change. 
Corrections made after the investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the investigator. 
The investigator should maintain a list of personnel authorized to enter data into the eCRF. 
Detailed instructions will be provided in the eCRF Completion Guidelines. 
12.3.2 
Database entry and reconciliation 
External electronic data will be loaded into a validated electronic database using a clinical data 
management system (CDMS). Computerized data cleaning checks will be used in addition to 
manual review to check for discrepancies and to ensure consistency of the data. The data are 
entered into the eCRFs once and are subsequently verified if the study is performed using 
electronic data capture. 
An electronic audit trail system will be maintained within the CDMS to track all data changes in 
the database once the data have been saved initially into the system or electronically loaded. 
Regular backups of the electronic data will be performed. 
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12.3.3 
Subject Screening and Enrollment log/Subject Identification Code list 
The subject’s screening and enrollment will be recorded in the Subject Screening and Enrollment 
Log. 
The investigator will keep a Subject Identification Code list. This list remains with the 
investigator and is used for unambiguous identification of each subject. 
The subject’s consent and enrollment in the study must be recorded in the subject’s medical 
record. These data should identify the study and document the dates of the subject’s 
participation. 
12.4 
Termination of the study 
UCB reserves the right to temporarily suspend or prematurely discontinue this study either at a 
single site, multiple sites, or at all sites at any time for reasons including, but not limited to, 
safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity. 
If the study is prematurely terminated or suspended, UCB (or its representative) will inform the 
investigators/institutions and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension, in accordance with applicable regulatory 
requirement(s). The IRB/IEC should also be informed and provided with reason(s) for the 
termination or suspension by the sponsor or by the investigator/institution, as specified by the 
applicable regulatory requirement(s). In addition, arrangements will be made for the return of all 
unused IMP and other material in accordance with UCB procedures for the study. 
12.5 
Archiving and data retention 
The investigator will maintain adequate records for the study, including eCRFs, medical records, 
laboratory results, Informed Consent documents, drug dispensing and disposition records, safety 
reports, information regarding participants who discontinued, and other pertinent data. 
All essential documents are to be retained by the investigator for 5 years after the 
completion/discontinuation of the study, or at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the IMP (whichever is longest). These documents should be retained for 
a longer period, however, if required by the applicable regulatory requirement(s) or by an 
agreement with UCB (CPMP/ICH/135/95, 2002 [Section 4.9.5]). The investigator will contact 
UCB for authorization prior to the destruction of any study records or in the event of accidental 
loss or destruction of any study records. The investigator will also notify UCB should he/she 
relocate or move the study-related files to a location other than that specified in the sponsor’s 
trial master file (TMF). 
12.6 
Audit and inspection 
The investigator will permit study-related audits mandated by UCB, after reasonable notice, and 
inspections by domestic or foreign regulatory authorities. 
The main purposes of an audit or inspection are to confirm that the rights and well-being of the 
subjects enrolled have been protected, that enrolled subjects (ie, signing consent and undergoing 
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study procedures) are appropriate for the study, and that all data relevant for the evaluation of the 
IMP have been processed and reported in compliance with the planned arrangements, the 
protocol, investigational site, and IRB/IEC SOPs, ICH GCP, and applicable regulatory 
requirements. 
The investigator will provide direct access to all study documents, source records, and source 
data. If an inspection by a regulatory authority is announced, the investigator will immediately 
inform UCB (or designee). 
12.7 
Good Clinical Practice 
Noncompliance with the protocol, ICH-GCP, or local regulatory requirements by the 
investigator, institution, institution staff, or designees of the sponsor will lead to prompt action 
by UCB to secure compliance. Continued noncompliance may result in the termination of the 
site’s involvement in the study. 
13 
STATISTICS 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan (SAP). 
13.1 
Definition of analysis sets 
The following analysis sets are defined for this study: 
• Enrolled Set (ES) will consist of subjects who signed the ICF.  
• Randomized Set (RS) will consist of subjects who have been randomized. Disposition data 
are based on the ES and the RS. 
• Safety Set (SS) will consist of all randomized subjects who received at least 1 dose of IMP. 
These subjects will be analyzed according to the actual treatment received, where subjects 
who receive at least 1 dose of romosozumab will be analyzed in the romosozumab treatment 
group regardless of the randomized treatment. Data on safety and exposure will be based on 
the SS. 
• The Full Analysis Set (FAS) will consist of all randomized subjects who received at least 
1 dose of IMP and provided at least 1 baseline and post-baseline BMD measurement. In the 
case of dosing administration error, analyses of the FAS will be conducted according to 
randomized treatment. This will be the primary efficacy analysis set. The FAS will be used 
for demographics, disease characteristics, and BMD efficacy analysis. 
• The Per-Protocol Set (PPS) will consist of subjects in the FAS who have completed a 
minimal exposure of 6 months of a treatment regimen without any important protocol 
deviations that may influence the validity of the data for the primary efficacy variable. 
Post-baseline deviations will not necessarily lead to exclusion of a subject from PPS analysis 
but may lead to exclusion of data. The PPS will be used as sensitivity analyses for BMD 
efficacy analysis. 
• The Pharmacokinetic Per-Protocol Set (PK-PPS) will include all subjects in the SS who have 
at least 1 evaluable serum romosozumab concentration measurement with no further 
PK-related important protocol deviations. This analysis set will be used in the PK analyses. 
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• The Pharmacodynamic Per-Protocol Set (PD-PPS) will include all subjects in the SS who 
have at least 1 evaluable BTM measurement with no further PD-related important protocol 
deviations. This analysis set will be used in the analyses of BTMs. 
13.2 
General statistical considerations 
Statistical evaluation will be performed by the biostatistics department at UCB and/or CRO. All 
computations will be performed using SAS® version 9.4 or later (SAS Institute, NC, USA). 
Summary statistics will consist of frequency tables for categorical variables. For continuous 
variables, descriptive statistics (number of available observations, mean, standard deviation 
(SD), median, minimum and maximum, coefficient of variation) will be tabulated. Data may be 
summarized by treatment group, and in addition, may be summarized by time. 
If not otherwise stated, baseline will be the predose value or, if missing, the Screening value. 
Baseline characteristics (eg, gender, age, weight, height, body mass index) for the SS will be 
summarized descriptively. 
For addressing multiplicity issues, a hierarchical testing procedure will be implemented which 
consists of 3 steps: 
1. Lumbar spine BMD percent change from baseline at 6 months  
2. Total hip BMD percent change from baseline at 6 months  
3. Femoral neck BMD percent change from baseline at 6 months 
Step 2 will be executed in a confirmatory sense only if the statistical test in Step 1 was 
statistically significant using a 2-sided type I error rate of 0.05.  
Step 3 will be executed in a confirmatory sense only if the test in Step 1 and the test in Step 2 are 
statistically significant on a level of 0.05 (2-sided).  
Data listings will be prepared for subjects with available data (ES, RS, SS, FAS, PD-PPS, and 
PK-PPS), depending on the domain.  
13.3 
Planned analyses 
13.3.1 
6-month analysis 
The 6-month analysis of efficacy and safety will be performed after all subjects have completed 
the 6-month Double-Blind, Placebo-Controlled Period. After the last subject last visit of the 
6-month Double-Blind Placebo-Controlled Period and after data cleaning, a database snapshot 
will be taken for the 6-month analysis. Following the snapshot, the study will be unblinded to the 
individuals at the sponsor and CRO involved in conducting the statistical analysis and in the 
compilation of the statistical analysis report and the CSR. The investigators and sponsors initially 
remain blinded. After internal finalization of the CSR, the unblinding of the investigators is 
required to conduct the stamping process. However, the investigators are still obliged not to 
disclose the initial double-blind treatment assignment to the individual subjects as long as the 
subjects are included in the OL Treatment Period. Subjects will remain blinded to the 
Double-Blind, Placebo-Controlled Period treatment assignment throughout the study. 
The primary variable of the 6-month analysis is the evaluation of the effect of treatment with 
romosozumab compared with placebo on the percent change in BMD at the lumbar spine in 
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postmenopausal Chinese women with osteoporosis. Formal statistical testing will be performed 
(see Section 13.2). 
The secondary variables of the 6-month analysis are to evaluate the effects of treatment with 
romosozumab compared with placebo on the percent change in BMD at the total hip and femoral 
neck. For these endpoints, confirmatory testing will be performed as outlined in Section 13.2.  
Other variables of the 6-month analysis include the evaluation of the effect of treatment with 
romosozumab compared with placebo at 3 months on the percent change in BMD at the lumbar 
spine, total hip and femoral neck, the evaluation of the effect of treatment with romosozumab 
compared with placebo at 1-, 3-, and 6-month time points on the percent changes in BTMs, and 
to characterize serum concentrations of romosozumab in subjects who are randomized to 
romosozumab for 6 months. For the other variables, statistical testing will be performed in an 
exploratory manner.  
The safety analyses of the 6-month analysis will compare the safety of romosozumab treatment 
with placebo in postmenopausal Chinese women with osteoporosis. The safety analyses in the 
6-month analysis will include all available data collected up to the time of 6-month data 
snapshot. 
13.3.2 
Final analysis 
After all subjects have the opportunity to complete the Month 15 Visit, a further database 
snapshot or database lock will be executed. Based on these data, the remaining efficacy and 
safety analyses for Month 12 and the safety analyses for the overall study period, ie, the period 
from the start of double-blind treatment to the Month 15 Visit for each subject will be evaluated. 
13.4 
Planned efficacy analysis 
13.4.1 
Analysis of the primary efficacy variable 
The comparison of the percent change from baseline in lumbar spine DXA BMD at Month 6 
between treatment groups will be evaluated using an analysis of covariance (ANCOVA) model. 
The ANCOVA model will include treatment group, baseline BMD value, machine type at 
baseline, and interaction of baseline BMD value and machine type at baseline as independent 
variables. Summaries of the results will include least squares (LS) means point estimates of the 
percent change from baseline for each treatment arm. The 2-sided 95% CI and associated p-value 
will be provided for the difference between the LS means for romosozumab and placebo. 
A sensitivity analysis with a repeated measurements model will be fit with the percent change 
from baseline at Months 3 and 6 in BMD of the lumbar spine as the dependent variable, and 
baseline BMD, machine type, interaction of baseline BMD and machine type, visit (categorical), 
treatment (categorical), and interaction of treatment and visit as the independent variables. The 
variance structure will allow for heteroskedasticity of variance between treatment groups. Due to 
the sensitivity nature of this analysis, formal significance testing will not be conducted. 
A blinded data review process will be implemented in which the missingness of data, statistical 
assumptions, and eligibility of definition of categorical variables/thresholds will be assessed. If it 
turns out that the number of randomized subjects without baseline and/or without BMD 
measurement at an on-treatment visit is high, then a sensitivity analysis under blinded conditions 
will be executed using multiple imputation strategies under the “missing at random” assumption. 
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Furthermore, depending on the amount of missingness and on frequencies of treatment 
discontinuations, additional sensitivity analyses under “missing not at random” assumptions may 
be defined as well. If such analyses are needed, they will be prespecified in the SAP before 
unblinding and database lock. 
For these BMD analyses, the FAS will be used. The results from the central imaging vendor will 
be used in the BMD analyses.  
13.4.1.1 
Analysis of secondary variables 
For the secondary efficacy BMD endpoints (at total hip and femoral neck at Month 6), a percent 
change from baseline in DXA BMD will employ an ANCOVA model. The ANCOVA model 
will include treatment group, baseline value of BMD, machine type at baseline and interaction of 
baseline BMD value and machine type at baseline as independent variables. Summaries of the 
results will include LS means point estimates of the percent change from baseline for each 
treatment arm. The variance structure will allow for heterogeneity between treatments. The 
2-sided 95% CI and associated p-value will be provided for the difference between the LS means 
for romosozumab and placebo. The FAS will be used for these analyses.  
A sensitivity analysis with a repeated measurements model will be fit with the percent change 
from baseline at Months 3 and 6 in BMD of the corresponding skeletal location (ie, total hip or 
femoral neck) as the dependent variable and baseline BMD, machine type, interaction of baseline 
BMD and machine type, visit (categorical), treatment (categorical), and interaction of treatment 
and visit as the independent variables. The variance structure will allow for heteroskedasticity of 
variance between treatment groups. Due to the sensitivity nature of this analysis, formal 
significance testing will not be conducted. 
13.4.2 
Planned pharmacokinetic and pharmacodynamic analyses 
13.4.2.1 
Planned pharmacokinetic analyses 
The serum trough concentrations of romosozumab will be summarized using descriptive 
statistics for those subjects who continued with 6 months of romosozumab after initially being 
randomized to 6 months of romosozumab treatment and for those subjects who are initially 
randomized to placebo for 6 months and transition to romosozumab for 6 months. 
Geometric mean (geometric coefficient of variation) and mean (±SD) romosozumab serum 
concentration time profiles will be displayed graphically. 
Individual concentration-time profiles will be displayed graphically on a linear scale and 
semi-logarithmic scale.  
The PK-PPS will be used in this analysis.  
13.4.2.2 
Planned pharmacodynamic analyses 
For the BTMs (P1NP and sCTX), descriptive statistics will be presented by treatment group at 
selected time points for both the romosozumab and placebo group. Descriptive statistics (eg, 
mean, median) will be displayed for the actual values (ie, observed variables without further 
imputation), change from baseline, and the percent changes from baseline in BTMs at each time 
point. In addition, AUC through Month 12 in P1NP will be produced by treatment group. 
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Pharmacodynamic-time plots will be generated for each PD parameter at selected time points for 
both the romosozumab and placebo group and these plots will be displayed on the same figure. 
Pharmacodynamic-time plots will be generated for the percent change from baseline for each PD 
parameter at selected time points for both the romosozumab and placebo group and these plots 
will be displayed on the same figure.  
The PD-PPS will be used for these analyses. 
13.4.3 
Planned safety and other analyses 
13.4.3.1 
Safety analyses 
The number and incidence of TEAEs will be summarized by the Medical Dictionary for 
Regulatory Activities (MedDRA®) system organ class and preferred term (PT). The incidence of 
TEAEs will also be summarized by intensity and relationship to IMP. In accordance with routine 
pharmacovigilance activities for romosozumab, any serious CV, ONJ, or AFF events will be 
subject to independent adjudication. 
Three separate independent adjudication committees will review and adjudicate on potential ONJ 
events, potential AFF events, and potentially serious CV events, respectively. Each adjudication 
committee will comprise of experts in that specific field. All events of ONJ and AFF reported 
during the study and those potential events identified through a predefined search of MedDRA 
terms will be submitted for blind review and adjudication to the relevant adjudication committee. 
All deaths and SAEs deemed by the investigator to be of potential CV origin or etiology and 
SAEs with terms mapping to a predefined MedDRA PT list potentially indicative of CV etiology 
will be submitted to the CV committee for review and adjudication. 
Vital sign variables and ECG parameters and changes from baseline will be descriptively 
summarized by scheduled time points.  
Laboratory parameters (hematology and serum chemistry) and changes from baseline will be 
descriptively summarized at each time point. Shift tables from baseline to each post-baseline 
time point will be presented.  
The incidence and percentage of subjects who develop antiromosozumab antibodies (binding and 
neutralizing) at any time will be tabulated only for the romosozumab group. 
Physical examination abnormalities will be listed by treatment. 
13.5 
Handling of protocol deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on study conduct or on the primary efficacy (effectiveness), key safety, or 
PK/PD outcomes for an individual subject. The criteria for identifying important protocol 
deviations will be predefined within the appropriate protocol-specific document. Important 
protocol deviations will be reviewed as part of the ongoing data cleaning process and data 
evaluation. All important deviations will be identified and documented prior to unblinding to 
confirm exclusion of data from analyses and subjects from analysis sets.  
13.6 
Handling of dropouts or missing data 
In general, even if the study treatment is discontinued, the subjects will be encouraged to 
continue the study schedule up to the planned final visit. For all subjects, all available data will 
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be included in analysis, regardless of whether the data are collected before or after the subject 
discontinues study treatment or before or after the subject takes alternative or prohibited 
medication. Potentially, (few) deaths could occur under this study protocol. However, these 
events mostly likely will not be linked to the study indication so that data in all the missed 
assessments after occurrence of death will be seen as missing. 
Missing baseline BMD by DXA at any anatomical site will not be imputed and evaluated for the 
BMD analysis.  
Missing post-baseline BMD will be imputed using the LOCF approach (by carrying forward the 
last nonmissing post-baseline value prior to the missing value from the same anatomical site) in 
the 6-month analysis. For the OL Treatment Period variables, only the OL Treatment Period 
value will be used for imputation, the values in the Double-Blind, Placebo-Controlled Period will 
not be carried forward into the OL Treatment Period. To ensure that the imputation approach 
provides valid results, sensitivity analyses with varying imputation methods will be defined. 
Those will include repeated measurement model and multiple imputation strategies as needed. 
If a subject has BMD values from different DXA machine types (ie, Hologic and Lunar) only 
those BMD values that are collected from the same machine type as the baseline BMD will be 
used for analyses and imputation. For anatomical sites that can be measured on different body 
sides (ie, left and right), only those BMD values that are collected from the same body side as the 
baseline BMD will be used for analyses and imputation. 
Missing BTMs (either baseline or post-baseline values) or PK will not be imputed. Any values 
below the lower limit of quantification (LLOQ) will be imputed using the LLOQ/2 for analysis. 
The impact of COVID-19 and COVID-19 vaccination will be evaluated at the blinded data 
evaluation meetings and details of analysis will be provided in the SAP. 
13.7 
Planned interim analysis and data monitoring 
No interim analysis is planned for this study. 
An independent DMC will be formed to monitor the ongoing safety of subjects in the study. The 
DMC will periodically review study data for potential safety issues.  
At each DMC meeting, safety and tolerability data will be available. Other data eg, PK data, may 
be provided to the DMC, if requested. In the case the DMC needs information that requires 
unblinding of individuals, an independent unblinded analysis group will be established consisting 
of personnel not otherwise involved in the conduct of this study who have access to the critical 
data. The data that requires unblinding will be disclosed and discussed in the closed session to 
which no sponsor or CRO personnel will have access. The precautions to preserve the blinding 
will be detailed in the DMC charter. 
Data will be presented by individuals not otherwise involved in the conduct of the study. The 
deliberations and decisions of the DMC will be formally minuted/documented. 
Ad hoc DMC meetings can be held for other reasons if deemed appropriate by the sponsor or the 
DMC members. 
Details of the role, scope, composition, responsibilities, and operation of the DMC, as well as the 
identity of the DMC members, will be defined in a separate DMC Charter.  
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13.8 
Determination of sample size 
The sample size calculations were done using historical BMD data of all 3 anatomical sites taken 
into account from the romosozumab studies 20070337 and 20120156. 
• Assumptions for BMD of the lumbar spine: 
Postmenopausal women with osteoporosis in 20120156 showed a treatment difference of 
8.4 with 95% CI: 6.9 to 9.9 when compared with placebo BMD response at lumbar spine. 
Furthermore, postmenopausal women with osteoporosis in 20070337 showed a treatment 
difference of 9.4 (95% CI: 7.9 to 10.8). Taking the minimum of the lower confidence bound 
(conservative approach) results in an assumption of 6.9 for the treatment difference in percentage 
change from baseline at Month 6. 
For postmenopausal women with osteoporosis in 20120156, the upper bounds of the SDs were 
4.94 for the romosozumab group and 3.93 for the placebo group; in 20070337, the upper bounds 
of the SDs were 6.10 and 3.32, respectively. This indicates that SDs were differing between 
romosozumab and placebo necessitating a statistical test accounting for differing SDs. To merge 
the SDs of 20070337 and 20120156, the pooled common SDs were calculated separately for 
romosozumab and placebo taking the upper bound in each study and each arm (conservative 
approach). As a result, the assumptions for the SDs are 5.26 for the romosozumab arm and 
3.34 for the placebo arm. 
• Assumptions for BMD of the total hip 
Studies 20070337 and 20120156 showed a minimum treatment difference on total hip BMD of 
3.5 (95% CI: 2.5 to 4.4) when compared with placebo. The combined upper bounds of the SDs 
for 20070337 and 20120156 were 3.80 for the romosozumab group and 3.03 for the placebo 
group. 
• Assumptions for BMD of the femoral neck: 
Studies 20070337 and 20120156 showed a minimum treatment difference on femoral neck BMD 
of 3.2 (95% CI: 2.0 to 4.3) when compared with placebo. The combined upper bounds of the 
SDs for 20070337 and 20120156 were 4.39 for the romosozumab group and 4.10 for the placebo 
group. 
• Resulting sample size: 
For the sample size calculations, a 2-group Satterthwaite t-test will be assumed (2-sided on a 
5% significance level) which allows for unequal SDs and unequal sample size ratios. Taking into 
account the upper bounds pooled common SDs and the minimum effect size as assumptions 
(BMD of the femoral neck outlined above), the sample size of 146 subjects for romosozumab 
and 73 subjects for placebo would preserve at least 90% power for the percent change from 
baseline in BMD of the lumbar spine, total hip and femoral neck at Month 6.  
To give a reasonable chance to show significance, at least 90% power for all 3 anatomical sites, 
following a hierarchical testing procedure (see Section 13.2) with safety objectives and dropout 
taken into account, a total sample size of 300 subjects (ie, 200 subjects in the romosozumab 
group and 100 subjects in the placebo group) seemed appropriate. 
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14 
ETHICS AND REGULATORY REQUIREMENTS 
14.1 
Informed consent 
Subject’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki. 
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the subject in both oral and written form by the investigator (or 
designee). Each subject will have the opportunity to discuss the study and its alternatives with 
the investigator. 
Prior to participation in the study, the ICF should be signed and personally dated by the subject, 
or her legal representative, and by the person who conducted the informed consent discussion 
(investigator or designee). The subject or her legal representative must receive a copy of the 
signed and dated ICF. As part of the consent process, each subject must consent to direct access 
to her medical records for study-related monitoring, auditing, IRB/IEC review, and regulatory 
inspection. 
If the ICF is amended during the study, the investigator (or the sponsor, if applicable) must 
follow all applicable regulatory requirements pertaining to the approval of the amended ICF by 
the IRB/IEC and use of the amended form. 
The subject may withdraw her consent to participate in the study at any time. A subject is 
considered as enrolled in the study when she has signed the ICF. An eCRF must not be started, 
nor may any study specific procedure be performed for a given subject, without having obtained 
her written consent to participate in the study. 
14.2 
Subject identification cards 
Upon signing the Informed Consent and Assent form (as applicable), the subject or legal 
representative will be provided with a subject identification card in the language of the subject. 
The investigator will fill in the subject identifying information and medical emergency contact 
information. The investigator will instruct the subject to keep the card with her at all times. 
14.3 
Institutional Review Boards and Independent Ethics 
Committees 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki. 
The investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies with 
the requirements of the current ICH-GCP version or applicable country-specific regulations will 
be responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the investigator/UCB will forward copies of the protocol, ICF, IB, 
investigator’s curriculum vitae (if applicable), advertisement (if applicable), and all other 
subject-related documents to be used for the study to the IRB/IEC for its review and approval. 
Before initiating a study, the investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol. 
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The investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to human subjects or others, and any protocol deviations, 
to eliminate immediate hazards to subjects. 
The investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the subjects. For 
minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the investigator to obtain an expedited review by the IRB/IEC as 
allowed. 
As part of the IRB/IEC requirements for continuing review of approved studies, the investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of subject risk involved, but no less than 
once per year. The investigator should provide a final report to the IRB/IEC following study 
completion. 
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the investigator or the sponsor, as specified by 
the applicable regulatory requirements in each concerned country. Where applicable, 
investigators are to provide the sponsor (or its representative) with evidence of such IRB/IEC 
notification. 
14.4 
Subject privacy 
UCB staff (or designee) will affirm and uphold the subject’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the subject number 
assigned at Screening. 
The investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IRB/IEC, or representatives of regulatory authorities will be allowed to review that portion of the 
subject’s primary medical records that directly concerns this study (including, but not limited to, 
laboratory test result reports, ECG reports, admission/discharge summaries for hospital 
admissions occurring during a subject’s study participation, and autopsy reports for deaths 
occurring during the study). 
14.5 
Protocol amendments 
Protocol changes may affect the legal and ethical status of the study and may also affect the 
statistical evaluations of sample size and the likelihood of the study fulfilling its primary 
objective. 
Significant changes to the protocol will only be made as an amendment to the protocol and must 
be approved by UCB, the IRB/IEC, and the regulatory authorities (if required), prior to being 
implemented. 
15 
FINANCE, INSURANCE, AND PUBLICATION 
Insurance coverage will be handled according to local requirements. 
Finance, insurance, and publication rights are addressed in the investigator and/or CRO 
agreements, as applicable. 
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16 
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Brunkow ME, Gardner JC, Van Ness J, et al. Bone dysplasia sclerosteosis results from loss of 
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Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and 
nonvertebral fractures in women with postmenopausal osteoporosis – a randomized controlled 
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Marshall D, Johnell O,Wedel H. Meta-analysis of how well measures of bone mineral density 
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McClung MR, Grauer A, Boonen S, et al. Romosozumab in postmenopausal women with low 
bone mineral density. N Engl J Med. 2014;370(5):412-20. 
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Nelson DA, Molloy R, Kleerekoper M. Prevalence of osteoporosis in women referred for bone 
density testing: utility of multiple skeletal sites. J Clin Densitom. 1998;1(1):5-11.  
NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. 
Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001:285:785-95. 
Obermayer-Pietsch BM, Marin F, McCloskey EV, et al. Effects of two years of daily teriparatide 
treatment on BMD in postmenopausal women with severe osteoporosis with and without prior 
antiresorptive treatment. J Bone Miner Res. 2008;23(10):1591-1600. 
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785, a sclerostin monoclonal antibody. J Bone Miner Res. 2011;26(1):19-26. 
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van Geel TA, van Helden S, Geusens PP, et al. Clinical subsequent fractures cluster in time after 
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van Helden S, Cals J, Kessels F, et al. Risk of new clinical fractures within 2 years following a 
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Wade SW, Strader C, Fitzpatrick LA, Anthony MS. Sex- and age-specific incidence of 
non-traumatic fractures in selected industrialized countries. Arch Osteoporos. 2012;7:219-27. 
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Zhang J, Wang HY, Yang ZM. Points of considerations on clinical trials of drugs for treating 
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17 
APPENDICES 
17.1 
Protocol Amendment 1 
Rationale for this amendment 
In this amendment, the definition of “month” has been revised to ensure that the analysis 
windows defined for this study are similar to those utilized in the global clinical program. Minor 
inconsistencies have been corrected. This amendment is considered nonsubstantial as these 
changes do not impact the efficacy, safety, or the conduct of the study. 
 
Specific changes to the protocol 
Section 
Original text 
Revised text 
Reason for change 
Table 5-1, 
footnote a 
a For the purpose of this 
study, a month is defined as 
a 4-week period of 28 days. 
a For the purpose of this 
study, a month is defined as 
30 days. 
To be similar to the 
global clinical program 
Section 6.3.2 
These subjects will be 
encouraged to return to the 
study site to complete the 
procedures and assessments 
for the EOS Visit, 16 weeks 
after the final administration 
of IMP. 
These subjects will be 
encouraged to return to the 
study site to complete the 
procedures and assessments 
for the EOS Visit, 4 months 
after the final 
administration of IMP. 
Timing of EOS Visit or 
follow up after 
subject’s final 
administration of IMP 
to be consistent 
throughout the protocol 
Section 8 
For the purpose of this 
study, a month is defined as 
a 4-week period of 28 days. 
For the purpose of this 
study, a month is defined as 
30 days. 
To be similar to the 
global clinical program 
Section 11.1.3 
The follow up will usually 
be continued for 12 weeks 
after the subject has 
discontinued her IMP. 
The follow up will usually 
be continued for 4 months 
after the subject has 
discontinued her IMP. 
Timing of EOS Visit or 
follow up after 
subject’s final 
administration of IMP 
to be consistent 
throughout the protocol 
Section 11.2, 
3rd bullet 
• 
An EOS Visit should be 
scheduled 16 weeks 
after the subject’s final 
dose of IMP. 
 
• 
An EOS Visit should be 
scheduled 4 months 
after the subject’s final 
dose of IMP. 
Timing of EOS Visit or 
follow up after 
subject’s final 
administration of IMP 
to be consistent 
throughout the protocol 
 
 
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17.2 
Protocol Amendment 2 
Rationale for this amendment 
This amendment is considered substantial as the changes will impact the safety of the subjects in 
the study. In this context, specific inclusion and exclusion criteria have been added to affirm that 
the patient population in the study is osteoporosis in postmenopausal women with high risk of 
fracture, and to ensure that patients who are at the highest cardiovascular risk are excluded from 
the study. To be included in the study, patients must present with at least 1 independent risk 
factor for fracture and have no history of MI or stroke. In addition, a careful individual 
assessment of the patient’s CV risk profile must be completed by the investigator in accordance 
with their routine clinical practice, with discussion of the signs and symptoms of MI and stroke 
on an ongoing basis, thereafter.  
Other changes include removal of 1 of the PK variables (normalized serum trough concentration 
of romosozumab by BW) as this is already covered in the planned PK-PPS analysis; removal of 
serum protein electrophoresis testing as multiple myeloma or related lymphoproliferative 
disorder is no longer assessed at Screening; removal of serum pregnancy test to identify a PDILI 
event given that the study population is postmenopausal women and also planned pregnancy is 
exclusionary; clarification of the process in the event of a clinical significant (panic value) for 
selected laboratory results, and clarification of the model to be used in the sensitivity analyses.   
 
Specific changes  
Details are presented in the following table.  
 
 
 
 
 
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Section 
Original text 
Revised/new text 
Reason for change 
Title Page 
UCB Biopharma SPRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Company name legally changed 
Study Contact 
Information, Sponsor 
UCB Biopharma SPRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Company name legally changed 
List of Abbreviations   None 
MI     myocardial infarction  
Abbreviated in text 
Section 1, Summary 
Eligible subjects will be randomized, stratified by 
age and prevalent vertebral fracture, in a 2:1 ratio 
to receive romosozumab 210mg subcutaneously 
(sc) every month (QM) or matched placebo sc 
QM in a blinded manner for 6 months. 
Eligible subjects will be randomized, 
stratified by age, in a 2:1 ratio to receive 
romosozumab 210mg subcutaneously (sc) 
every month (QM) or matched placebo sc 
QM in a blinded manner for 6 months. 
Stratification by prevalent 
vertebral fracture no longer 
necessary due to the new 
inclusion criterion #5 
Section 4.1.2.1, Other 
pharmacokinetic 
variables 
The other PK variables are serum trough 
concentrations of romosozumab and normalized 
serum trough concentrations by BW at Day 1 
(baseline) and at Months 1, 3, and 6. 
The other PK variables are serum trough 
concentrations of romosozumab at Day 1 
(baseline) and at Months 1, 3, and 6. 
Variable considered unnecessary 
as the normalized serum trough 
concentration by BW will be 
accounted for in the planned 
PK-PPS analysis 
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Section 
Original text 
Revised/new text 
Reason for change 
Section 4.2.2.1, Other 
pharmacokinetic 
variables 
• Serum trough concentrations of romosozumab 
and normalized serum trough concentrations by 
BW at Months 7, 9, and 12 in subjects who are 
continuing with 6 months of romosozumab 
treatment after initially being randomized to 
6 months of romosozumab in the Double-Blind, 
Placebo-Controlled Period (a total of 12 months 
of romosozumab treatment). 
• Serum trough concentrations of romosozumab 
and normalized serum trough concentrations by 
BW at Months 7, 9, and 12 (1, 3, and 6 months 
of romosozumab exposure, respectively) in 
subjects who are initially randomized to 
placebo in the Double-Blind, 
Placebo-Controlled Period and transition to 
romosozumab treatment for 6 months. 
• Serum trough concentrations of 
romosozumab at Months 7, 9, and 12 in 
subjects who are continuing with 6 months 
of romosozumab treatment after initially 
being randomized to 6 months of 
romosozumab in the Double-Blind, 
Placebo-Controlled Period (a total of 
12 months of romosozumab treatment). 
• Serum trough concentrations of 
romosozumab at Months 7, 9, and 12 (1, 3, 
and 6 months of romosozumab exposure, 
respectively) in subjects who are initially 
randomized to placebo in the 
Double-Blind, Placebo-Controlled Period 
and transition to romosozumab treatment 
for 6 months. 
Variable considered unnecessary 
as the normalized serum trough 
concentration by BW will be 
accounted for in the planned 
PK-PPS analysis 
Section 5.1.1, 
Screening Period 
To be eligible to participate in the study, subjects 
must be postmenopausal Chinese women, 55 to 
90 years of age (inclusive), and have a BMD 
T-score ≤-2.50 at the lumbar spine, total hip, or 
femoral neck at Screening, with at least 
2 vertebrae in the lumbar (L)1 through L4 region 
and at least 1 hip evaluable by DXA. 
To be eligible to participate in the study, 
subjects must be postmenopausal Chinese 
women, 55 to 90 years of age (inclusive), 
have a BMD T-score ≤-2.50 at the lumbar 
spine, total hip, or femoral neck and an 
independent risk factor for fracture at 
Screening, with at least 2 vertebrae in the 
lumbar (L)1 through L4 region and at least 
1 hip evaluable by DXA. 
To affirm that the patient 
population in the study is 
osteoporosis in postmenopausal 
women with high risk of fracture 
Section 5.1.1, 
Screening Period 
In addition, before enrolling subjects in the study, 
a careful individual assessment of the CV risk 
profile should be performed (including evaluation 
of CV history, CV risk factors such as 
hypertension, hyperlipidemia, diabetes mellitus, 
smoking and severe renal impairment and other 
relevant results from the Screening investigations 
such as ECG). 
In addition, before enrolling subjects in the 
study, a careful individual assessment of the 
CV risk profile should be performed. 
Examples of CV risk provided 
were not exhaustive. Removal of 
these examples allows the 
investigator to conduct an 
individualized assessment in 
accordance with their routine 
clinical practice  
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Section 
Original text 
Revised/new text 
Reason for change 
Section 5.1.2, 
Double-Blind, 
Placebo-Controlled 
Period 
Approximately 300 subjects will be randomized, 
stratified by age (<75 years, ≥75 years) and 
prevalent vertebral fracture (yes, no), in a 2:1 
ratio to receive romosozumab 210mg sc QM 
(200 subjects) or matched placebo sc QM 
(100 subjects) in a blinded manner for 6 months 
to evaluate if romosozumab treatment compared 
with placebo is effective in increasing BMD, as 
assessed by DXA at the lumbar spine, total hip, 
and femoral neck. 
Approximately 300 subjects will be 
randomized, stratified by age (<75 years, 
≥75 years), in a 2:1 ratio to receive 
romosozumab 210mg sc QM (200 subjects) 
or matched placebo sc QM (100 subjects) in 
a blinded manner for 6 months to evaluate if 
romosozumab treatment compared with 
placebo is effective in increasing BMD, as 
assessed by DXA at the lumbar spine, total 
hip, and femoral neck. 
Stratification by prevalent 
vertebral fracture no longer 
necessary due to the new 
inclusion criterion #5 
Section 5.2, 
Table 5-1, Schedule 
of study assessments 
None 
Activity added: 
Discuss signs and symptoms of myocardial 
infarction and stroked  - at all visits except 
Screening (Visit 1) and Visit 15/EOS 
Patient assessment added to 
align with the risk minimization 
measures and warnings and 
precautions for use for 
romosozumab  
Section 5.2, 
Table 5-1, Schedule 
of study assessments 
Activity removed: 
Serum protein electrophoresisi 
None 
Serum protein electrophoresis 
has been removed since multiple 
myeloma or related 
lymphoproliferative disorder is 
no longer assessed at Screening 
(revised exclusion criterion #19)  
Section 5.2, 
Table 5-1, Schedule 
of study assessments 
Footnote d: 
Lifestyle records subject’s alcohol use, tobacco 
use, and caffeinated beverage use. (now 
footnote e) 
Footnote d: 
Before enrolling subjects in the study, a 
careful individual assessment of the 
cardiovascular risk profile should be 
performed. 
Patient assessment added to 
align with the risk minimization 
measures and warnings and 
precautions for use for 
romosozumab  
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Section 
Original text 
Revised/new text 
Reason for change 
Section 5.2, 
Table 5-1, Schedule 
of study assessments 
Footnote i:  
This test will be performed to exclude subjects 
with multiple myeloma or related 
lymphoproliferative disorder. Serum protein 
electrophoresis can be performed by the local 
laboratory in the case electrophoresis results are 
available within 6 months of signing ICF. If no 
serum protein electrophoresis data available 
within 6 months, serum protein electrophoresis 
should be performed by the central laboratory at 
the Screening Visit (removed). 
Footnote i: 
A blood sample for lipid testing (total 
cholesterol, LDL, HDL, and triglycerides) 
will be collected with the subject in a fasted 
state. Fasting state is defined as overnight 
fasting, with a minimum of 8h of fasting 
required. (previously footnote h) 
Serum protein electrophoresis 
has been removed since multiple 
myeloma or related 
lymphoproliferative disorder is 
no longer assessed at Screening 
(revised exclusion criterion #19) 
Section 6.1, Inclusion 
criteria (#5) 
5. Subject has at least 2 vertebrae in the L1 to L4 
region and at least 1 hip that are evaluable by 
DXA, as assessed by the central imaging vendor. 
(now inclusion criterion #6) 
 
 
 
 
 
 
 
 
New criterion: 
5. Subject must have at least 1 of following 
independent risk factors for fracture: 
• History of fragility fracture (except hip 
fracture, a severe [SQ3] vertebral fracture 
or more than 2 moderate [SQ2] vertebral 
fractures [see exclusion criteria]); 
• Parental history of hip fracture; 
• Low body weight (body mass index 
≤19kg/m2); 
• Elderly (age ≥65 years); 
• Current smoker 
To affirm that the patient 
population in the study is 
osteoporosis in postmenopausal 
women with high risk of fracture 
Section 6.2, 
Exclusion criteria 
(#4) 
4. Subject has used oral bisphosphonates: 
- Any doses received within 3 months prior to 
randomization (Day 1). 
- More than 1 month of cumulative use between 
3 and 12 months prior to randomization. 
 - More than 3 years of cumulative use, unless the 
last dose was received ≥5 years prior to 
randomization. (now exclusion criterion #7) 
New criterion:  
4. Subject has a history of myocardial 
infarction (MI). 
To exclude patients at highest 
risk of future MI events 
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Romosozumab 
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Page 96 of 108 
Section 
Original text 
Revised/new text 
Reason for change 
Section 6.2, 
Exclusion criteria 
(#5) 
5. Subject has used intravenous (iv) 
bisphosphonates: 
- zoledronic acid 
◦ Any doses received within 3 years prior to 
randomization. 
◦ More than 1 dose received within 5 years 
prior to randomization. 
- iv ibandronate, iv pamidronate, or iv ALN 
◦ Any doses received within 12 months prior to 
randomization. 
◦ More than 3 years of cumulative use, unless 
the last dose was received ≥5 years prior to 
randomization. (now exclusion criteria #8) 
New criterion:  
5. Subject has a history of stroke. 
To exclude patients at highest 
risk of future stroke events 
Section 6.2, 
Exclusion criteria 
(#6) 
6. Subject has used denosumab or any cathepsin 
K inhibitor:  
- Any doses received within 18 months prior to 
randomization. (now exclusion criterion #9) 
 
6. Subject has a vitamin D insufficiency, 
defined as 25 (OH) vitamin D levels 
<20ng/mL, as assessed by the central 
laboratory at Screening. Vitamin D repletion 
will be permitted and the subject may be 
retested once within the Screening Period. 
(previously exclusion criterion #18) 
Exclusion criterion was moved 
up from #18 to #6 to maximize 
the operationalization of 
Screening activities 
Section 6.2, 
Exclusion criteria 
(#10) 
Criterion removed:  
10. Subject has used activated vitamin D3 or 
vitamin K2: 
- More than 1 month of cumulative use within 
6 months prior to randomization. 
10. Subject has used tibolone, cinacalcet, or 
calcitonin: 
- Any doses received within 3 months prior 
to randomization. (previously exclusion 
criterion #7) 
Criterion determined as not 
necessary for regional study 
participation 
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Page 97 of 108 
Section 
Original text 
Revised/new text 
Reason for change 
Section 6.2, 
Exclusion criteria 
(#17) 
17. Subject has a possible diagnosis of multiple 
myeloma or related lymphoproliferative disorder, 
as assessed by serum protein electrophoresis 
(Serum protein electrophoresis can be performed 
by the local laboratory in the case electrophoresis 
results are available within 6 months of signing 
ICF. If no serum protein electrophoresis data are 
available within 6 months, serum protein 
electrophoresis should be performed by the 
central laboratory at the Screening Visit.) 
19. Subject has a confirmed diagnosis or 
under investigation for multiple myeloma or 
related lymphoproliferative disorder at the 
Screening Visit. 
Clarified that subjects with a 
confirmed diagnosis or under 
investigation for multiple 
myeloma or related 
lymphoproliferative disorder are 
excluded from the study. Disease 
activity is not being assessed at 
Screening  
 
Section 6.2, 
Exclusion criteria 
(#18) 
Criterion moved to #6: 
18. Subject has a vitamin D insufficiency, defined 
as 25 (OH) vitamin D levels <20ng/mL, as 
assessed by the central laboratory at Screening. 
Vitamin D repletion will be permitted and the 
subject may be retested once within the Screening 
Period. 
18. Subject has a history of ONJ or AFF. 
(previously exclusion criterion #16) 
 
Exclusion criterion was moved 
up from #18 to #6 to maximize 
the operationalization of 
Screening activities 
Section 7.2, 
Treatments to be 
administered 
• Double-Blind, Placebo-Controlled Period 
- Approximately 300 subjects will be 
randomized, stratified by age (<75 years, 
≥75 years) and prevalent vertebral fracture 
(yes, no), in a 2:1 ratio to receive 
romosozumab 210mg sc QM (approximately 
200 subjects) or matched placebo sc QM 
(approximately 100 subjects) in a blinded 
manner for 6 months, with the final 
administration of double-blind IMP at 
Month 5. 
• Double-Blind, Placebo-Controlled Period 
- Approximately 300 subjects will be 
randomized, stratified by age 
(<75 years, ≥75 years), in a 2:1 ratio to 
receive romosozumab 210mg sc QM 
(approximately 200 subjects) or 
matched placebo sc QM (approximately 
100 subjects) in a blinded manner for 
6 months, with the final administration 
of double-blind IMP at Month 5.  
 
Stratification by prevalent 
vertebral fracture no longer 
necessary due to the new 
inclusion criterion #5 
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Section 
Original text 
Revised/new text 
Reason for change 
Section 7.9.1.1, 
Double-Blind 
Placebo-Controlled 
Period  
In addition, to maintain the blind, BMD, BTM, 
PK, immunogenicity, and selected laboratory 
results (ie, serum calcium, albumin-adjusted 
calcium, phosphorus, ALP, and iPTH) will not be 
reported to the investigator and study-related site 
personnel during the Double-Blind, 
Placebo-Controlled Period. However, if there is a 
clinically significant laboratory value noted for 
the selected laboratory values, the investigator 
will be notified by the central laboratory in order 
to treat the subject appropriately. The investigator 
may perform additional follow-up blood draws 
for local analysis as required to support subject 
medical care.  
Notifications will be issued for subjects who test 
positive for neutralizing antiromosozumab 
antibodies at the EOS or ET Visit. 
None  
 
 
 
 
 
Text was removed as these 
processes are described 
adequately in their respective 
sections 
Section 7.9.1.2, 
Open-Label 
Treatment Period 
In an effort to avoid introducing any bias and to 
maintain the quality of the data during the 
OL Treatment Period, BMD, BTM, PK, 
immunogenicity, and selected laboratory results 
(ie, serum calcium, albumin-adjusted calcium, 
phosphorus, ALP, and iPTH) will not be reported 
to the investigator and study-related site 
personnel during the OL Treatment Period, using 
the same process as described for the Double-
Blind, Placebo-Controlled Period in 
Section 7.9.1.1. However, if there is a clinically 
significant laboratory value noted for the selected 
laboratory values, the investigator will be notified 
by the central laboratory in order to treat the 
subject appropriately. 
Notifications will be issued for subjects who test 
positive for neutralizing antiromosozumab 
antibodies at the EOS or ET Visit.  
None 
Text was removed as these 
processes are described 
adequately in their respective 
sections 
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Section 
Original text 
Revised/new text 
Reason for change 
Section 7.10, 
Randomization and 
numbering of 
subjects 
Subjects will be randomized, stratified by age 
(<75 years, ≥75 years) and prevalent vertebral 
fracture (yes, no), in a 2:1 ratio of romosozumab 
to placebo during the Double-Blind, 
Placebo-Controlled Period, after which, all 
subjects will receive romosozumab during the 
OL Treatment Period. 
Subjects will be randomized, stratified by 
age (<75 years, ≥75 years), in a 2:1 ratio of 
romosozumab to placebo during the 
Double-Blind, Placebo-Controlled Period, 
after which, all subjects will receive 
romosozumab during the OL Treatment 
Period. 
Stratification by prevalent 
vertebral fracture no longer 
necessary due to the new 
inclusion criterion #5 
Section 8.1, 
Screening Visit 
(Visit 1) (up to 
35 days) 
• Obtain blood samples for the following:  
- Safety laboratory tests (hematology and 
serum chemistry) 
- Serum protein electrophoresis – Serum 
protein electrophoresis can be performed by 
the local laboratory in the case 
electrophoresis results are available within 
6 months of signing ICF. If no serum 
protein electrophoresis data are available 
within 6 months, serum protein 
electrophoresis should be performed by the 
central laboratory. 
- Serology 
- Serum 25 (OH) vitamin D (can be retested 
once during the Screening Period) 
- TSH, free T4 (if required for confirmation 
of thyroid status) 
- FSH 
- iPTH 
• Obtain blood samples for the following:  
- Safety laboratory tests (hematology and 
serum chemistry) 
- Serology 
- Serum 25 (OH) vitamin D (can be 
retested once during the Screening 
Period) 
- TSH, free T4 (if required for 
confirmation of thyroid status) 
- FSH 
- iPTH 
Serum protein electrophoresis 
has been removed since multiple 
myeloma or related 
lymphoproliferative disorder is 
no longer assessed at Screening 
(revised exclusion criterion #19) 
Section 8.1, 
Screening Visit 
(Visit 1) (up to 
35 days) 
In addition, before enrolling subjects in the study, 
a careful individual assessment of the CV risk 
profile should be performed (including evaluation 
of CV history, CV risk factors such as 
hypertension, hyperlipidemia, diabetes mellitus, 
smoking and severe renal impairment and other 
relevant results from the Screening investigations 
such as ECG). 
In addition, before enrolling subjects in the 
study, a careful individual assessment of the 
CV risk profile should be performed.  
 
Examples of CV risk provided 
were not exhaustive. Removal of 
these examples allows the 
investigator to conduct an 
individualized assessment in 
accordance with their routine 
clinical practice 
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Page 100 of 108 
Section 
Original text 
Revised/new text 
Reason for change 
Section 8.2.1, Visit 2 
(Day 1) 
In addition, before enrolling subjects in the study, 
a careful individual assessment of the CV risk 
profile should be performed (including evaluation 
of CV history, CV risk factors such as 
hypertension, hyperlipidemia, diabetes mellitus, 
smoking and severe renal impairment and other 
relevant results from the Screening investigations 
such as ECG). 
In addition, before enrolling subjects in the 
study, a careful individual assessment of the 
CV risk profile should be performed.  
 
Examples of CV risk provided 
were not exhaustive. Removal of 
these examples allows the 
investigator to conduct an 
individualized assessment in 
accordance with their routine 
clinical practice 
Section 8.2.1, Visit 2 
(Day 1) through 
Section 8.3.3, 
Visit 14 (Month 12) 
None 
• Discuss signs and symptoms of MI and 
stroke 
Patient assessment added to 
align with the risk minimization 
measures and warnings and 
precautions for use for 
romosozumab 
Section 11.6, 
Laboratory 
measurements 
Serology (hepatitis/HIV) testing, laboratory tests 
(hematology and serum chemistry including 
serum protein electrophoresis), an endocrine test 
(serum 25 [OH] vitamin D), and some hormone 
tests (iPTH, FSH, TSH, and T4) will be 
performed at Screening to determine the subject’s 
eligibility for the study. 
Serology (hepatitis/HIV) testing, laboratory 
tests (hematology and serum chemistry), an 
endocrine test (serum 25 [OH] vitamin D), 
and some hormone tests (iPTH, FSH, TSH, 
and T4) will be performed at Screening to 
determine the subject’s eligibility for the 
study. 
Serum protein electrophoresis 
has been removed since multiple 
myeloma or related 
lymphoproliferative disorder is 
no longer assessed at Screening 
(revised exclusion criterion #19) 
Section 11.6, 
Table 11-2, Clinical 
laboratory 
measurements 
Serum chemistry: Serum protein electrophoresisa 
Removed 
Serum protein electrophoresis 
has been removed since multiple 
myeloma or related 
lymphoproliferative disorder is 
no longer assessed at Screening 
(revised exclusion criterion #19) 
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Page 101 of 108 
Section 
Original text 
Revised/new text 
Reason for change 
Section 11.6, 
Laboratory 
measurements 
Results of laboratory assessments for serum 
calcium, albumin-adjusted calcium, phosphorus, 
iPTH, and ALP will not be reported to the 
investigator and study-related site personnel at 
any time after the first administration of 
double-blind IMP to avoid any potentially 
unblinding during the Double-Blind, 
Placebo-Controlled Period and to minimize the 
introduction of any bias during the OL Treatment 
Period once the investigator is unblinded to 
individual treatment assignments. However, in 
the event of an abnormal value of clinical 
significance for serum calcium, albumin-adjusted 
calcium, phosphorus, iPTH, or ALP, the 
investigator or designee will be notified of the 
unblinded value by the central laboratory. 
Results of laboratory assessments for serum 
calcium, albumin-adjusted calcium, 
phosphorus, ALP, P1NP, CTX, iPTH, 
romosozumab levels, and antiromosozumab 
antibodies are considered potentially 
unblinding and will not be reported to any 
study-related personnel after Day 1 in order 
to maintain the integrity of the study 
blind.  However, in the event of an abnormal 
value of clinical relevance (panic value) for 
serum calcium, albumin-adjusted calcium, 
phosphorus, or ALP, sites will be notified of 
the unblinded value by the central 
laboratory.  After such notification is issued, 
the sites may perform additional follow-up 
blood draws for local analysis as required to 
support subject medical care. 
Clarification of the process in the 
event of an abnormal value of 
clinical relevance (panic value) 
for serum calcium, 
albumin-adjusted calcium, 
phosphorus, or ALP  
Section 11.6.1.3, 
Table 11-4, PDILI 
laboratory 
measurements 
Additional: 
Prothrombin time/INRa 
Serum pregnancy test 
PK sample 
Additional: 
Prothrombin time/INRa 
PK sample 
Removed serum pregnancy test 
since the study population is 
postmenopausal women and 
planned pregnancy is excluded 
(exclusion criterion #26)  
Section 13.4.1, 
Analysis of the 
primary efficacy 
variable 
A sensitivity analysis of repeated measures model 
will be fit with the percent change from baseline 
at Months 3 and 6 in BMD of the lumbar spine as 
the dependent variable, and baseline BMD, 
machine type, interaction of baseline BMD and 
machine type, visit (categorical), treatment 
(categorical), and interaction of treatment and 
visit as the independent variables.  
A sensitivity analysis with a repeated 
measurements model will be fit with the 
percent change from baseline at Months 3 
and 6 in BMD of the lumbar spine as the 
dependent variable, and baseline BMD, 
machine type, interaction of baseline BMD 
and machine type, visit (categorical), 
treatment (categorical), and interaction of 
treatment and visit as the independent 
variables.  
Clarification of model used for 
the sensitivity analysis 
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Clinical Study Protocol 
Romosozumab 
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Page 102 of 108 
Section 
Original text 
Revised/new text 
Reason for change 
Section 13.4.1.1, 
Analysis of 
secondary variables 
A sensitivity analysis of repeated measures model 
will be fit with the percent change from baseline 
at Months 3 and 6 in BMD of the corresponding 
skeletal location (ie, total hip or femoral neck) as 
the dependent variable and baseline BMD, 
machine type, interaction of baseline BMD and 
machine type, visit (categorical), treatment 
(categorical), and interaction of treatment and 
visit as the independent variables.  
A sensitivity analysis with a repeated 
measurements model will be fit with the 
percent change from baseline at Months 3 
and 6 in BMD of the corresponding skeletal 
location (ie, total hip or femoral neck) as the 
dependent variable and baseline BMD, 
machine type, interaction of baseline BMD 
and machine type, visit (categorical), 
treatment (categorical), and interaction of 
treatment and visit as the independent 
variables.  
Clarification of model used for 
the sensitivity analysis 
Section 13.4.2.1 
Planned 
pharmacokinetic 
analyses   
The serum trough concentrations and normalized 
serum trough concentrations of romosozumab by 
BW will be summarized using descriptive 
statistics for those subjects who continued with 
6 months of romosozumab after initially being 
randomized to 6 months of romosozumab 
treatment and for those subjects who are initially 
randomized to placebo for 6 months and 
transition to romosozumab for 6 months. 
The serum trough concentrations of 
romosozumab will be summarized using 
descriptive statistics for those subjects who 
continued with 6 months of romosozumab 
after initially being randomized to 6 months 
of romosozumab treatment and for those 
subjects who are initially randomized to 
placebo for 6 months and transition to 
romosozumab for 6 months. 
Variable considered unnecessary 
as the normalized serum trough 
concentration by BW will be 
accounted for in the planned 
PK-PPS analysis 
Section 19, Sponsor 
Declaration  
Clinical Trial Biostatistician  
Statistical Representative 
In compliance with Standard 
Operating Procedure and 
associated documents  
Note: In Table 5-2, the addition of the new footnote d shifted the footnotes accordingly from d through h (previous version: Protocol Amendment 1) to e 
through i only (Protocol Amendment 2).  
Note: The numbering of the inclusion and exclusion criteria has changed from Protocol Amendment 1. With the addition of an inclusion criterion, the 
inclusion criteria are now numbered 1 through 6 (previously 1 through 5). With additions, deletions, and revisions to the exclusion criteria, the exclusion 
criteria are now numbered 1 through 31 (previously 1 through 30). 
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OP0002 
 
 
 
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Page 103 of 108 
17.3 
Protocol Amendment 3 
Rationale for this amendment 
This amendment is considered substantial. The main purpose for this amendment is to clarify 
Inclusion Criterion #3. In line with Chinese and international guidelines (eg, Menopause Group, 
2018), the diagnosis of menopause is to be made by clinical assessment, ie, without taking into 
acount the follicle-stimulating hormone (FSH) value. Following this, the subcriterion on the FSH 
value has been deleted. In addition, there is a new paragraph concerning the study conduct in 
case of restrictions imposed during exceptional circumstances (eg, COVID-19). 
 
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Romosozumab 
OP0002 
 
 
 
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Page 104 of 108 
Specific changes to the protocol 
Section 
Original text 
Revised text 
Reason for change 
Study Contact 
Information 
Study Physician, Clinical Project Manager, and 
Clinical Trial Biostatistician were changed. 
Lead Clinical Development Representative role 
was added. 
To update the study team. 
Section 1, 
Section 5.1.6 
OP0002 is a Phase 3, multicenter, randomized, 
double-blind, placebo-controlled study followed 
by an Open-Label (OL) Treatment Period to 
evaluate the efficacy, safety and tolerability of 
romosozumab treatment in postmenopausal 
Chinese women with osteoporosis across 
approximately 20 study sites in mainland China. 
The planned number of study sites is 
approximately 20. 
OP0002 is a Phase 3, multicenter, randomized, 
double-blind, placebo-controlled study followed 
by an Open-Label (OL) Treatment Period to 
evaluate the efficacy, safety and tolerability of 
romosozumab treatment in postmenopausal 
Chinese women with osteoporosis across 
approximately 30 study sites in mainland China. 
The planned number of study sites is 
approximately 30. 
To update the anticipated 
number of study sites. 
Section 2.3.5, 
Table 2.2 
Denosomab approval status listed as “No” in 
China. 
Denosomab approval status listed as “Yes” in 
China. 
Update to reflect current 
available therapies in 
China. 
Section 5.2, 
Table 5-1, 
Section 8.1 
FSH sample collected at the Screening Visit. 
FSH sample removed from the Screening Visit. 
Reference to FSH has been 
removed throughout the 
protocol. 
Section 6.1 
3. Subject is an ambulatory postmenopausal 
Chinese women, 55 to 90 years of age 
(inclusive) at the time of Screening. 
Postmenopause is defined as no spontaneous 
vaginal bleeding or spotting for 12 or more 
consecutive months prior to Screening, verified 
by a serum follicle stimulating hormone (FSH) 
level >40mUI/mL at Screening (Visit 1).  
3a. Subject is an ambulatory postmenopausal 
Chinese women, 55 to 90 years of age 
(inclusive) at the time of Screening. 
Postmenopause is defined as no spontaneous 
vaginal bleeding or spotting for 12 or more 
consecutive months prior to Screening. 
In line with Chinese and 
international guidelines 
(Menopause Group, 2018), 
the diagnosis of 
menopause is to be made 
by clinical assessment, ie, 
without taking into acount 
the FSH value. Reference 
to FSH has been removed 
throughout the protocol. 
Section 8.6 
None. 
• 
Any other assessments that the investigator 
deems necessary 
To allow for any 
additional assessments at 
the discretion of the 
investigator. 
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Page 105 of 108 
Section 
Original text 
Revised text 
Reason for change 
Section 8.7 
None. 
The protocol mandated visit schedule should be 
followed to the closest extent possible, based on 
the judgment of the investigator. However, during 
the coronavirus disease 2019 (COVID-19) 
epidemic or under other exceptional 
circumstances, remote follow-up may be 
conducted and the subjects may be contacted by 
telephone/video contact to assess as many details 
as possible, according to the protocol scheduling, 
to verify that the subject is suitable for continuing 
study treatment. In-person follow-up at an 
alternative study site or a home visit is acceptable. 
Some procedures may be collected by other 
remote means if feasible. Study sites should make 
efforts to inform the sponsor or the CRO in the 
event that protocol procedures cannot be 
completed due to COVID-19.  
In those situations when the subject cannot return 
to the study site, the investigators will assess the 
subject’s safety by telephone/video contact.  
Ad hoc subject contact may be warranted to 
understand the current health status of the 
subjects, to follow up on AEs, and inform them of 
any protective measures taken by the clinical site 
as a result of the COVID 19 pandemic (eg, any 
measures that may limit access to the site or may 
require additional actions by the subject prior to 
entry to the site).  
If a subject visits another facility for a medical 
issue, the investigator should request a detailed 
explanation of the subject’s condition and his/her 
participation in the clinical study from the subject 
or caregiver. Subjects or caregivers shall be 
reminded to completely collect and keep records 
of this visit. 
To clarify study conduct 
during COVID-19. 
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OP0002 
 
 
 
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Page 106 of 108 
Section 
Original text 
Revised text 
Reason for change 
Section 11.6, 
Table 11-2 
FSH included in clinical laboratory 
measurements. 
FSH removed from clinical laboratory 
measurements. 
Reference to FSH has been 
removed throughout the 
protocol. 
Section 13.3.1 
The safety objective of the 6-month analysis will 
compare the safety of romozosumab treatment 
with placebo in postmenopausal Chinese women 
with osteoporosis. The safety variables to be 
analyzed in the 6-month analysis are presented in 
Section 4.1.3. 
The safety analyses of the 6-month analysis will 
compare the safety of romozosumab treatment 
with placebo in postmenopausal Chinese women 
with osteoporosis. The safety analyses in the 
6-month analysis will include all available data 
collected up to the time of 6-month data snapshot. 
Clarification of the data to 
be included in the 6-month 
analysis safety analyses. 
Section 13.6 
None. 
The impact of COVID-19 and COVID-19 
vaccination will be evaluated at the blinded data 
evaluation meetings and details of analysis will be 
provided in the SAP. 
To clarify that details of 
any analyses of the impact 
of COVID-19 will be 
provided in the SAP. 
Section 16 
None. 
Menopause Group in the Chinese Society of 
Obstetrics and Gynecology. Chinese guideline 
(2018) on menopausal management and 
menopausal hormone therapy [J]. Chinese Journal 
of Obstetrics and Gynecology. 2018,53:729-739. 
New reference added. 
 
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Page 107 of 108 
18 
DECLARATION AND SIGNATURE OF INVESTIGATOR 
I confirm that I have carefully read and understood this protocol and agree to conduct this 
clinical study as outlined in this protocol, according to current Good Clinical Practice and local 
laws and requirements. 
I will ensure that all subinvestigators and other staff members read and understand all aspects of 
this protocol. 
I have received and read all study-related information provided to me. 
The objectives and content of this protocol as well as the results deriving from it will be treated 
confidentially, and will not be made available to third parties without prior authorization by 
UCB. 
All rights of publication of the results reside with UCB, unless other agreements were made in a 
separate contract. 
Investigator: 
 
 
 
 
Printed name  
 
Date/Signature 
 
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19 
SPONSOR DECLARATION 
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to current Good Clinical Practice. 
 
 
 
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SAP_001.pdf: 
UCB 
 
03 Mar 2023 
Statistical Analysis Plan 
Romosozumab 
OP0002 
 
 
 
Confidential 
Page 1 of 89 
 
STATISTICAL ANALYSIS PLAN  
 
Study: OP0002 
Product: Romosozumab 
A MULTICENTER RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO EVALUATE EFFICACY 
AND SAFETY AND TOLERABILITY OF ROMOSOZUMAB 
TREATMENT IN POSTMENOPAUSAL CHINESE WOMEN WITH 
OSTEOPOROSIS  
SAP/Amendment Number Date 
Final SAP 
28 May 2019 
SAP Amendment 1 
04 Aug 2020 
SAP Amendment 2 
03 Mar 2023 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
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Page 2 of 89 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 6 
1 
INTRODUCTION ............................................................................................................. 9 
2 
PROTOCOL SUMMARY ................................................................................................. 9 
2.1 
Objectives for the Double-Blind, Placebo-Controlled Period ....................................... 9 
2.1.1 
Primary objective ................................................................................................... 9 
2.1.2 
Secondary objective ............................................................................................... 9 
2.1.3 
Other objectives ..................................................................................................... 9 
2.1.4 
Safety objective ..................................................................................................... 9 
2.2 
Objectives for the Open-Label Treatment Period .......................................................... 9 
2.2.1 
Secondary objective ............................................................................................... 9 
2.2.2 
Other objectives ................................................................................................... 10 
2.2.3 
Safety objectives .................................................................................................. 10 
2.3 
Study variables for the Double-Blind, Placebo-Controlled Period .............................. 11 
2.3.1 
Efficacy variables ................................................................................................ 11 
2.3.1.1 
Primary efficacy variable .......................................................................... 11 
2.3.1.2 
Secondary efficacy variables ..................................................................... 11 
2.3.1.3 
Other efficacy variables ............................................................................. 11 
2.3.2 
Pharmacokinetic and pharmacodynamic variables .............................................. 11 
2.3.2.1 
Other pharmacokinetic variables ............................................................... 11 
2.3.2.2 
Other pharmacodynamic variables ............................................................ 11 
2.3.3 
Safety variables .................................................................................................... 11 
2.3.3.1 
Primary safety variable .............................................................................. 11 
2.3.3.2 
Other safety variables ................................................................................ 11 
2.4 
Study variables for the Open-Label Treatment Period ................................................ 12 
2.4.1 
Efficacy variables ................................................................................................ 12 
2.4.1.1 
Secondary efficacy variables ..................................................................... 12 
2.4.1.2 
Other efficacy variables ............................................................................. 12 
2.4.2 
Pharmacokinetic and pharmacodynamic variables .............................................. 12 
2.4.2.1 
Other pharmacokinetic variables ............................................................... 12 
2.4.2.2 
Other pharmacodynamic variables ............................................................ 13 
2.4.3 
Safety variables .................................................................................................... 13 
2.4.3.1 
Primary safety variable .............................................................................. 13 
2.4.3.2 
Other safety variables ................................................................................ 13 
2.5 
Study design and conduct ............................................................................................ 13 
2.6 
Determination of sample size ....................................................................................... 15 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 16 
3.1 
General presentation of summaries and analyses ........................................................ 16 
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3.2 
General study level definitions .................................................................................... 17 
3.2.1 
Analysis time points ............................................................................................ 17 
3.2.1.1 
6-month analysis ........................................................................................ 17 
3.2.1.2 
Final analysis ............................................................................................. 18 
3.2.2 
Relative day ......................................................................................................... 18 
3.2.3 
Analysis visit windows ........................................................................................ 19 
3.2.4 
Timing of analysis cut-offs .................................................................................. 20 
3.2.4.1 
End of study date ....................................................................................... 20 
3.2.4.2 
End of DBPC Period date .......................................................................... 21 
3.2.4.3 
Start of Open-Label Period ........................................................................ 21 
3.2.4.4 
End of Open-Label Treatment Period date ................................................ 21 
3.2.4.5 
End of Follow-Up Period date ................................................................... 21 
3.3 
Definition of Baseline values ....................................................................................... 21 
3.4 
Protocol deviations....................................................................................................... 22 
3.5 
Analysis sets................................................................................................................. 22 
3.5.1 
Enrolled Set ......................................................................................................... 22 
3.5.2 
Randomized Set ................................................................................................... 22 
3.5.3 
Safety Set ............................................................................................................. 22 
3.5.4 
Full Analysis Set .................................................................................................. 22 
3.5.5 
Per-Protocol Set ................................................................................................... 22 
3.5.6 
Pharmacokinetic Per-Protocol Set ....................................................................... 23 
3.5.7 
Pharmacodynamic Per-Protocol Set .................................................................... 23 
3.6 
Treatment assignment and treatment groups ............................................................... 23 
3.7 
Center pooling strategy ................................................................................................ 23 
3.8 
Coding dictionaries ...................................................................................................... 23 
3.9 
Changes to protocol-defined analyses ......................................................................... 23 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 24 
4.1 
Adjustments for covariates .......................................................................................... 24 
4.2 
Handling of dropouts or missing data .......................................................................... 24 
4.2.1 
Dates .................................................................................................................... 25 
4.3 
Interim analyses and data monitoring .......................................................................... 26 
4.4 
Multicenter studies ....................................................................................................... 26 
4.5 
Multiple comparisons/multiplicity ............................................................................... 26 
4.6 
Examination of subgroups ........................................................................................... 26 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 27 
5.1 
Subject disposition ....................................................................................................... 27 
5.2 
Protocol deviations....................................................................................................... 27 
5.3 
Impact of COVID-19 ................................................................................................... 27 
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6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 27 
6.1 
Demographics .............................................................................................................. 27 
6.2 
Other Baseline disease characteristics ......................................................................... 28 
6.2.1 
Cardiovascular risk factors: ................................................................................. 29 
6.3 
Medical history and concomitant diseases ................................................................... 29 
6.3.1 
Prevalent vertebral fracture .................................................................................. 30 
6.3.2 
Any historical fracture ......................................................................................... 30 
6.3.3 
Historical osteoporotic fracture ........................................................................... 30 
6.3.4 
Historical nonvertebral fracture ........................................................................... 30 
6.3.5 
Historical major nonvertebral fracture ................................................................. 30 
6.4 
Prior and concomitant medications .............................................................................. 30 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 31 
8 
EFFICACY ANALYSES ................................................................................................ 31 
8.1 
Statistical analysis of the primary efficacy variable .................................................... 31 
8.1.1 
Primary analysis of primary efficacy variable ..................................................... 31 
8.1.2 
Sensitivity and Supplementary analyses of the primary efficacy variable(s) ...... 33 
8.2 
Statistical analysis of the secondary efficacy variables ............................................... 35 
8.2.1 
Secondary efficacy variables - DBPC Period ...................................................... 35 
8.2.2 
Secondary efficacy variables - OL Treatment Period .......................................... 36 
8.3 
Statistical analysis of other efficacy variable............................................................... 36 
9 
PHARMACOKINETICS AND PHARMACODYNAMICS .......................................... 36 
9.1 
Pharmacokinetics ......................................................................................................... 37 
9.2 
Pharmacodynamics ...................................................................................................... 37 
10 SAFETY ANALYSES ..................................................................................................... 38 
10.1 
Extent of exposure ....................................................................................................... 38 
10.2 
Adverse events ............................................................................................................. 38 
10.2.1 
Time at risk of exposure ...................................................................................... 39 
10.2.2 
Exposure adjusted incidence rate (EAIR) and exposure adjusted event rate 
(EAER) ................................................................................................................ 39 
10.2.3 
Standard AE summaries ...................................................................................... 40 
10.2.4 
Adverse events of interest .................................................................................... 41 
10.2.4.1 
Osteonecrosis of the jaw adjudication ....................................................... 41 
10.2.4.2 
Atypical femoral fracture adjudication ...................................................... 41 
10.2.4.3 
Adjudicated positive cardiovascular events .............................................. 42 
10.2.5 
Adverse events of special interest ........................................................................ 42 
10.3 
Clinical laboratory evaluations .................................................................................... 42 
10.3.1 
Potential drug-induced liver injury and potential Hy’s Law evaluation .............. 42 
10.4 
Vital signs, physical findings, and other observations related to safety ...................... 43 
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10.4.1 
Vital signs ............................................................................................................ 43 
10.4.2 
Physical examinations ......................................................................................... 43 
10.4.3 
Height and Weight ............................................................................................... 43 
10.4.4 
Electrocardiograms .............................................................................................. 43 
10.4.5 
Immunogenicity Analysis .................................................................................... 43 
11 OTHER ANALYSES ...................................................................................................... 44 
12 REFERENCES ................................................................................................................ 45 
13 APPENDICES ................................................................................................................. 46 
13.1 
Alternative osteoporosis therapy (licensed drugs only) ............................................... 46 
13.2 
Definitions of adjusted p-values for BMD endpoints .................................................. 47 
13.3 
Fracture Risk Assessment Tool: 10-year Probability of Major Osteoporotic Fracture 
(FRAX) ........................................................................................................................ 48 
13.4 
Multiple Imputations for BMD endpoints ................................................................... 49 
13.5 
Adverse Event of Interest............................................................................................. 53 
13.6 
Adverse Event of Special Interest (PDILI) .................................................................. 56 
13.7 
Lipid-Type of Adverse Event ...................................................................................... 61 
13.8 
Immunogenicity Analysis ............................................................................................ 63 
13.9 
Region and Site Information ........................................................................................ 67 
13.10 Statistical Analysis Plan Amendment 1 ....................................................................... 69 
13.11 Statistical Analysis Plan Amendment 2 ....................................................................... 82 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ..................................................... 89 
 
 
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LIST OF ABBREVIATIONS  
ADA 
antidrug antibody 
AE 
adverse event 
AFF 
atypical femoral fracture 
ALP 
 
alkaline phosphatase 
ANCOVA 
analysis of covariance 
AUC 
area under the curve 
BMD 
bone mineral density 
BP 
blood pressure 
BTM 
bone turnover marker 
BW 
body weight 
CCBR 
Chinese Conference on Biometric Recognition 
CI 
confidence interval (s) 
CV 
Coefficient of variance 
CRO 
contract research organization 
DBPC 
Double-Blind, Placebo-Controlled 
DCM 
Data cleaning meeting 
DEM 
Data evaluation meeting 
DMC 
Data Monitoring Committee 
DXA 
dual-energy x-ray absorptiometry 
EAER 
exposure adjusted event rate 
EAIR 
exposure adjusted incidence rate 
ECG 
electrocardiogram 
eCRF 
electronic Case Report form 
EOS 
End of Study  
ES 
Enrolled Set 
ET 
Early Termination 
FSH 
follicle-stimulating hormone 
FU 
Follow-up 
ICE 
intercurrent events 
ICF 
Informed Consent form 
ICH 
International Council for Harmonisation 
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IMP 
investigational medicinal product 
iPTH 
intact parathyroid hormone 
iv 
intravenous(ly) 
LLOQ 
lower limit of quantification 
LS 
least squares  
MedDRA® 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed effects model with repeated measures 
MSR 
minimum significant ratio 
NAb 
neutralizing antibodies 
OH 
hydroxy 
OL 
open-label  
ONJ 
osteonecrosis of the jaw 
P1NP 
procollagen type 1 N-telopeptide 
PD 
pharmacodynamic(s) 
PD-PPS 
Pharmacodynamic Per Protocol Set 
PDF 
Portable Document Format 
PDILI 
potential drug-induced liver injury 
PK 
pharmacokinetic(s) 
PK-PPS 
Pharmacokinetic Per Protocol Set 
PT 
preferred term 
PTH 
parathyroid hormone 
QM  
every month 
RS 
Randomized Set 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
sc 
subcutaneous(ly) 
sCTX 
type I collagen C-telopeptide 
SD 
standard deviation(s) 
SOC 
system organ class 
SQ0, SQ1, SQ2, 
SQ3 
visual semiquantitative grading scale for vertebral fractures on lateral 
spine x-rays: SQ0=no fracture; SQ1=mild fracture; SQ2=moderate 
fracture; SQ3=severe fracture (Genant et al, 1993) 
SS 
Safety Set 
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T4 
thyroxine 
TEAE 
treatment-emergent adverse event 
TFLs 
Tables, Figures and Listings 
TPTD 
teriparatide 
TSH 
thyroid-stimulating hormone 
WHO 
World Health Organization 
 
 
 
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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide details of the statistical analyses 
that have been outlined within the protocol for romosozumab study OP0002 dated 23 Mar 2022. 
The scope of this SAP includes all analyses that are planned and will be conducted by the 
Biostatistics department or designee unless otherwise specified.  
Changes in the statistical methodology will be documented in a SAP amendment. Amendments 
to this document will be finalized prior to database lock. 
This SAP has been written in consideration of the guidelines International Council for 
Harmonisation (ICH) E9. 
2 
PROTOCOL SUMMARY 
2.1 
Objectives for the Double-Blind, Placebo-Controlled Period 
2.1.1 
Primary objective 
The primary objective is to evaluate the effect of treatment with romosozumab for 6 months 
compared with placebo on the percent change in BMD at the lumbar spine in postmenopausal 
Chinese women with osteoporosis. 
2.1.2 
Secondary objective 
The secondary objective is to evaluate the effect of treatment with romosozumab for 6 months 
compared with placebo on the percent change in BMD at the total hip and femoral neck in 
postmenopausal Chinese women with osteoporosis. 
2.1.3 
Other objectives 
The other objectives are as follows: 
• To evaluate the effect of treatment with romosozumab for 3 months compared to placebo on 
the percent change in BMD at the lumbar spine, total hip, and femoral neck in 
postmenopausal Chinese women with osteoporosis. 
• To evaluate the effect of treatment with romosozumab at 1-, 3-, and 6-month time points 
compared with placebo on the percent changes in BTMs in postmenopausal Chinese women 
with osteoporosis. The BTMs include the bone formation marker P1NP and the bone 
resorption marker sCTX. 
• To characterize serum concentrations of romosozumab in postmenopausal Chinese women 
with osteoporosis who are randomized to romosozumab treatment.  
2.1.4 
Safety objective 
The safety objective is to characterize the safety and tolerability of romosozumab treatment for 
6 months compared with placebo in postmenopausal Chinese women with osteoporosis. 
2.2 
Objectives for the Open-Label Treatment Period 
2.2.1 
Secondary objective 
The secondary objective is to describe the percent change in BMD at the lumbar spine, total hip, 
and femoral neck in postmenopausal Chinese women with osteoporosis who are continuing with 
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6 months of romosozumab treatment after initially being randomized to 6 months of 
romosozumab treatment in the Double-Blind, Placebo-Controlled (DBPC) Period (a total of 12 
months of romosozumab treatment).   
2.2.2 
Other objectives 
The other objectives are as follows: 
• To describe the percent change in BMD at the lumbar spine, total hip, and femoral neck in 
postmenopausal Chinese women with osteoporosis who transition to 6 months of 
romosozumab treatment after initially being randomized to placebo in the DBPC Period. 
• To describe the percent changes in BTMs in postmenopausal Chinese women with 
osteoporosis who are continuing with 6 months of romosozumab treatment after initially 
being randomized to 6 months of romosozumab treatment in the DBPC Period (for a total of 
12 months of romosozumab treatment). The BTMs include bone formation marker P1NP and 
bone resorption marker sCTX. 
• To describe the percent changes in BTMs in postmenopausal Chinese women with 
osteoporosis who transition to 6 months of romosozumab treatment after initially being 
randomized to placebo in the DBPC Period. The BTMs include bone formation marker P1NP 
and bone resorption marker sCTX. 
• To describe area under the curve (AUC) for the entire 12-month treatment for P1NP in 
postmenopausal Chinese women with osteoporosis who are continuing with 6 months of 
romosozumab treatment after initially being randomized to 6 months of romosozumab 
treatment in the DBPC Period (for a total of 12 months of romosozumab treatment). 
• To characterize the serum concentrations of romosozumab in postmenopausal Chinese 
women with osteoporosis who are continuing with 6 months of romosozumab treatment after 
initially being randomized to 6 months of romosozumab treatment in the DBPC Period (for a 
total of 12 months of romosozumab treatment). 
• To characterize the serum concentrations of romosozumab in postmenopausal Chinese 
women with osteoporosis who are initially randomized to placebo in the DBPC Period and 
transition to romosozumab treatment. 
2.2.3 
Safety objectives 
The safety objectives will be presented for the Open-Label (OL) Treatment Period (up to Month 
12) and for the overall study period that includes the 3-month Follow-Up (FU) Period (for a total 
of 15 months) as follows: 
• To characterize the safety and tolerability of romosozumab treatment in postmenopausal 
Chinese women with osteoporosis who are continuing with 6 months of romosozumab 
treatment after initially being randomized to 6 months of romosozumab treatment in the 
DBPC Period (for a total of 12 months of romosozumab treatment).  
• To characterize the safety and tolerability of romosozumab treatment in postmenopausal 
Chinese women with osteoporosis who are initially randomized to placebo in the DBPC 
Period and transition to romosozumab treatment. 
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2.3 
Study variables for the Double-Blind, Placebo-Controlled Period 
2.3.1 
Efficacy variables 
2.3.1.1 
Primary efficacy variable  
The primary efficacy variable is percent change from baseline in BMD at the lumbar spine at the 
end of the DBPC Period (Month 6) as assessed by DXA. 
2.3.1.2 
Secondary efficacy variables 
The secondary efficacy variables are as follows: 
• Percent change from baseline in BMD at the total hip at the end of the DBPC Period (Month 
6) as assessed by DXA. 
• Percent change from baseline in BMD at the femoral neck at the end of the DBPC Period 
(Month 6) as assessed by DXA. 
2.3.1.3 
Other efficacy variables 
The other efficacy variables are percent change from baseline in BMD at the lumbar spine, total 
hip, and femoral neck at Month 3 as assessed by DXA. 
2.3.2 
Pharmacokinetic and pharmacodynamic variables 
2.3.2.1 
Other pharmacokinetic variables 
The other PK variables are serum trough concentrations of romosozumab at Day 1 (baseline) and 
at Months 1, 3, and 6. 
2.3.2.2 
Other pharmacodynamic variables  
The other PD variables are percent changes from baseline in P1NP and sCTX at Months 1, 3, 
and 6. 
2.3.3 
Safety variables 
2.3.3.1 
Primary safety variable  
The primary safety variable is the overall incidence of treatment-emergent adverse events 
(TEAEs)  
2.3.3.2 
Other safety variables  
The other safety variables are as follows:  
• Changes from baseline in laboratory assessments (serum chemistry and hematology) and 
shifts from baseline to the worst value between baseline and Month 6. 
• Changes from baseline in vital signs. 
• Changes from baseline in electrocardiogram (ECG) parameters. 
• Clinically significant physical examination findings from baseline through Month 6. 
• Incidence of subjects with antiromosozumab antibodies at Day 1 (baseline) and at Months 1, 
3, and 6. 
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2.4 
Study variables for the Open-Label Treatment Period 
2.4.1 
Efficacy variables 
2.4.1.1 
Secondary efficacy variables 
The secondary efficacy variables are as follows:  
• Percent change from baseline in BMD at the lumbar spine at the end of OL Treatment Period 
(Month 12) as assessed by DXA in subjects who are continuing with 6 months of 
romosozumab treatment after initially being randomized to 6 months of romosozumab 
treatment in the DBPC Period (for a total of 12 months of romosozumab treatment). 
• Percent change from baseline in BMD at the total hip at the end of OL Treatment Period 
(Month 12) as assessed by DXA in subjects who are continuing with 6 months of 
romosozumab treatment after initially being randomized to 6 months of romosozumab 
treatment in the DBPC Period (for a total of 12 months of romosozumab treatment). 
• Percent change from baseline in BMD at the femoral neck at the end of OL Treatment Period 
(Month 12) as assessed by DXA in subjects who are continuing with 6 months of 
romosozumab treatment after initially being randomized to 6 months of romosozumab 
treatment in the DBPC Period (for a total of 12 months of romosozumab treatment). 
2.4.1.2 
Other efficacy variables 
The other efficacy variables are percent change from baseline in BMD at the lumbar spine, total 
hip, and femoral neck at the end of OL Treatment Period (Month 12) as assessed by DXA in 
subjects who are initially randomized to placebo in the DBPC Period and transition to 
romosozumab treatment for 6 months. 
2.4.2 
Pharmacokinetic and pharmacodynamic variables  
2.4.2.1 
Other pharmacokinetic variables 
The other PK variables are as follows:  
• Serum trough concentrations of romosozumab at Months 7, 9, and 12 in subjects who are 
continuing with 6 months of romosozumab treatment after initially being randomized to 
6 months of romosozumab in the DBPC Period (a total of 12 months of romosozumab 
treatment). 
• Serum trough concentrations of romosozumab at Months 7, 9, and 12 (1, 3, and 6 months of 
romosozumab exposure, respectively) in subjects who are initially randomized to placebo in 
the DBPC Period and transition to romosozumab treatment for 6 months. 
 
 
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2.4.2.2 
Other pharmacodynamic variables  
The other PD variables are as follows: 
• Percent changes from baseline in P1NP and sCTX at Months 7, 9, and 12 in subjects who are 
continuing with 6 months of romosozumab treatment after initially being randomized to 
6 months of romosozumab treatment in the DBPC (a total of 12 months of romosozumab 
treatment). 
• Percent changes from baseline in P1NP and sCTX at Months 7, 9, and 12 (1, 3, and 6 months 
of romosozumab exposure, respectively) in subjects who are initially randomized to placebo 
in the DBPC Period and transition to romosozumab treatment for 6 months. 
• AUC for the entire 12-month treatment period for P1NP in subjects who are continuing with 
6 months of romosozumab treatment after initially being randomized to 6 months of 
romosozumab treatment in the DBPC Period (for a total of 12 months of romosozumab 
treatment). 
2.4.3 
Safety variables 
The safety variables listed below will be assessed during the OL Treatment Period, including 
some selected safety variables that will be followed up to Month 15, in subjects who are initially 
randomized to 6 months of romosozumab treatment in the DBPC Period and continue with 
romosozumab for 6 months (for a total of 12 months of romosozumab treatment) and in subjects 
who are initially randomized to placebo in the DBPC Period and transition to romosozumab 
treatment for 6 months.  
2.4.3.1 
Primary safety variable 
The primary safety variable is the overall incidence of TEAEs.  
2.4.3.2 
Other safety variables 
The other safety variables are as follows: 
• Changes from baseline in laboratory assessments (serum chemistry and hematology) and 
shifts from baseline to the worst value between baseline and Month 12. 
• Changes from baseline in vital signs. 
• Changes from baseline in ECG parameters. 
• Clinically significant physical examination findings from baseline through Month 12. 
• Incidence of subjects with antiromosozumab antibodies at Months 7, 9, and 12, and at the 
EOS Visit. 
2.5 
Study design and conduct 
This is a Phase 3 multicenter randomized, DBPC study followed by OL Treatment Period in 
postmenopausal Chinese women with osteoporosis to evaluate the efficacy, safety and 
tolerability of romosozumab treatment. The study consists of 4 study periods: Screening Period 
(Day -35 to Day -1), 6-month DBPC period, 6-month OL Treatment Period, and 3-month FU 
Period. The overall study design including treatment assignments is depicted in the schematic 
diagram in Figure 1. For each individual subject, the study will last approximately 16 months. A 
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subject’s participation in the study may be extended up to 1 year after the final IMP 
administration if the subject tests positive for neutralizing antibodies to romosozumab at the 
EOS Visit or ET Visit. 
In the DBPC Period, after screening, approximately 300 subjects will be randomized, stratified 
by age (<75 years, ≥75 years) , in a 2:1 ratio to receive either 210 mg romosozumab 
subcutaneous (sc) treatment every month (QM) (200 subjects) or matched placebo sc QM (100 
subjects) in a blinded manner for 6 months to evaluate if romosozumab treatment for 6 months, 
compared with placebo, is effective in increasing BMD, as assessed by DXA, at the lumbar 
spine, total hip, and femoral neck. The primary analysis will be performed using the data 
obtained from the DBPC Period.   
Upon completion of the 6-month DBPC Period, subjects will enter the 6-month OL Treatment 
Period and receive 210mg romosozumab sc QM for 6 months in an open-label fashion. During 
this period, all subjects will receive active treatment (romosozumab), 12 months exposure for 
subjects randomised to romosozumab and 6 months exposure for those randomized to placebo. 
After completing the OL Treatment period, subjects will be followed up for an additional 3 
months (FU Period) and will complete the EOS Visit (Month 15). Subject participation in the 
study is concluded after the EOS Visit. Subjects who test positive for neutralizing antibodies to 
romosozumab at the EOS Visit or ET Visit will be asked to return for additional follow-up 
testing for up to 1 year after final administration of investigational medicinal product (IMP).  
BMD will be measured by DXA using same machine at screening, at 3 months, at the end of 
DBPC period (6 month), and at the end of 6 months OL Treatment Period (12 month). Only 
Lunar or Hologic densitometers will be allowed in the study. All DXA scans will be submitted to 
and analyzed by the central imaging vendor. To maintain the blind, all BMD data will be 
analyzed by the central imaging vendor and these results will not be reported to the investigator 
and study-related personnel after the first administration of IMP in the DBPC period, and to 
minimize the introduction of any bias during the OL Treatment Period, once the investigator is 
unblinded to individual treatment assignments. 
The end of the study is defined as the date of the last visit of the last subject in the study. 
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Figure 1: 
Overall study design for OP0002 
 
D=day; IMP=investigational medicinal product; IU=international unit; M=month; N=number of subjects in each 
treatment arm; QM=every month; sc=subcutaneous(ly)  
Note: Final analysis will include the remaining efficacy and safety analyses for Month 12 and the safety analyses for 
the overall study period, ie, the period from the start of double-blind treatment to the Month 15 Visit for each 
subject will be evaluated.   
 
2.6 
Determination of sample size 
The sample size calculations were done using historical BMD data of all 3 anatomical sites taken 
into account from the romosozumab studies 20070337 and 20120156. 
• Assumptions for BMD of the lumbar spine: 
Postmenopausal women with osteoporosis in 20120156 showed a treatment difference of 
8.4 with 95% CI: 6.9 to 9.9 when compared with placebo BMD response at lumbar spine. 
Furthermore, postmenopausal women with osteoporosis in 20070337 showed a treatment 
difference of 9.4 (95% CI: 7.9 to 10.8). Taking the minimum of the lower confidence bound 
(conservative approach) results in an assumption of 6.9 for the treatment difference in percentage 
change from baseline at Month 6. 
For postmenopausal women with osteoporosis in 20120156, the upper bounds of the SDs were 
4.94 for the romosozumab group and 3.93 for the placebo group; in 20070337, the upper bounds 
of the SDs were 6.10 and 3.32, respectively. This indicates that SDs were differing between 
romosozumab and placebo necessitating a statistical test accounting for differing SDs. To merge 
the SDs of 20070337 and 20120156, the pooled common SDs were calculated separately for 
romosozumab and placebo taking the upper bound in each study and each arm (conservative 
approach). As a result, the assumptions for the SDs are 5.26 for the romosozumab arm and 
3.34 for the placebo arm. 
• Assumptions for BMD of the total hip 
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Studies 20070337 and 20120156 showed a minimum treatment difference on total hip BMD of 
3.5 (95% CI: 2.5 to 4.4) when compared with placebo. The combined upper bounds of the SDs 
for 20070337 and 20120156 were 3.80 for the romosozumab group and 3.03 for the placebo 
group. 
• Assumptions for BMD of the femoral neck: 
Studies 20070337 and 20120156 showed a minimum treatment difference on femoral neck BMD 
of 3.2 (95% CI: 2.0 to 4.3) when compared with placebo. The combined upper bounds of the 
SDs for 20070337 and 20120156 were 4.39 for the romosozumab group and 4.10 for the placebo 
group. 
• Resulting sample size: 
For the sample size calculations, a 2-group Satterthwaite t-test will be assumed (2-sided on a 
5% significance level) which allows for unequal SDs and unequal sample size ratios. Taking into 
account the upper bounds pooled common SDs and the minimum effect size as assumptions 
(BMD of the femoral neck outlined above), the sample size of 146 subjects for romosozumab 
and 73 subjects for placebo would preserve at least 90% power for the percent change from 
baseline in BMD of the lumbar spine, total hip and femoral neck at Month 6.  
To give a reasonable chance to show significance, at least 90% power for all 3 anatomical sites, 
following a hierarchical testing procedure (see Section 4.5) with safety objectives and dropout 
taken into account, a total sample size of 300 subjects (ie, 200 subjects in the romosozumab 
group and 100 subjects in the placebo group) seemed appropriate. 
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General presentation of summaries and analyses 
Statistical evaluation will be performed by the biostatistics department at UCB and/or Parexel. 
All computations will be performed using SAS® version 9.4 or later (SAS Institute, NC, USA). 
Summary statistics will consist of frequency tables for categorical variables. For continuous 
variables, descriptive statistics (number of available observations, mean, median, SD, minimum 
and maximum, coefficient of variance (CV) [where applicable]) will be tabulated. Data may be 
summarized by treatment group and in addition, may be summarized by time (using defined 
analysis visit windows, referring to section 3.2.3). 
Unless otherwise noted, all summaries will be displayed by randomized treatment group 
(placebo, romosozumab 210mg sc QM) regardless of the treatment individual subjects actually 
received. A summary with all treatment groups combined (ie, total column) will be presented for 
the demographic and Baseline characteristics, for the prior medications, as well as for the 
medical, procedure history and risk factors. 
Decimal places for descriptive statistics will always apply the following rules: 
• “n” or “N” will be an integer. 
• Percentage values will be presented with 1 decimal place. No percentage will be 
displayed for zero counts and no decimal will be displayed when percentage is 100%. 
• Mean, SD, and median will use 1 additional decimal place compared to the original data. 
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• CV (%) will be presented with 1 decimal place. 
• Minimum and maximum will have the same number of decimal places as the original 
value. 
• Categorical missing data will be summarized in a separate category. 
Statistical tests of efficacy variables will be presented as 2-sided p-values rounded to 3 decimal 
places. P-values less than 0.001 will be presented as “<0.001” and p-values greater than 0.999 
will be presented as “>0.999.” The multiple testing issues for the primary and secondary efficacy 
analyses are handled with a fixed sequence testing procedure as described in Section 4.5.  
The SAS outputs supportive of any statistical model (ie. all excluding the descriptive analyses) 
will be provided as a separate Portable Document Format (PDF) document in addition to Tables, 
Figures and Listings (TFLs). These outputs will be included in the “Documentation of Statistical 
Methods” section of the clinical study report. 
The order of treatment groups to be presented in tables from left to right will be: 
Outputs including only data of the DBPC Period for 6-Month Analysis: 
• Placebo 
• Romosozumab 210mg 
Outputs including also data of the OLE Treatment Period and FU Period for Final Analysis: 
• Placebo / Romosozumab 210mg (subjects receive Placebo during 6-month DBPC Period and 
then receive Romosozumab during OLE Period) 
• Romosozumab 210mg / Romosozumab 210mg (subjects receive Romosozumab during 6-
month DBPC Period and then receive Romosozumab during OLE Period) 
Data listings will be prepared for subjects with available data including the calculated data 
[Enrolled Set (ES), Randomized Set (RS), Safety Set (SS), Full Analysis set (FAS), Per-Protocol 
Set (PPS), Pharmacokinetic Per-Protocol Set (PK-PPS) and Pharmacodynamic Per-Protocol Set 
(PD-PPS)], depending on the domain.  
3.2 
General study level definitions 
3.2.1 
Analysis time points 
3.2.1.1 
6-month analysis 
The 6-month analysis of efficacy and safety will be performed after all subjects have completed 
the 6-month DBPC Period. After the last subject last visit of the 6-month DBPC Period and after 
data cleaning, a database snapshot will be taken for the 6-month analysis. Following the 
snapshot, the study will be unblinded to the individuals of the dedicated team from sponsor and 
CRO involved in conducting the statistical analysis and in the compilation of the statistical 
analysis report and the CSR. The names of members of the dedicated team will be documented 
before the database snapshot. The investigators and other sponsor staff initially remain blinded. 
Upon finalization of the CSR (6-month analysis), investigators will remain blinded to treatment 
assignments for study participants in their sites. The leading Principal Investigator (PI) involved 
in the sign-off of the CSR (6-month analysis) will be unblinded at the aggregate level (tables and 
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figures) but will remain blinded to treatment assignment for individual study participants. Other 
investigators will remain blinded at the aggregate level to the 6-month results until the final 
analysis of the data. Note this is a change from the protocol as regulatory requirements now only 
require the leading PI to sign-off the CSR. Subjects will remain blinded to the DBPC Period 
treatment assignment throughout the study. 
The primary variable of the 6-month analysis is the evaluation of the effect of treatment with 
romosozumab compared with placebo on the percent change in BMD at the lumbar spine in 
postmenopausal Chinese women with osteoporosis. Formal statistical testing will be performed 
(see Section 4.5). 
The secondary variables of the 6-month analysis are to evaluate the effects of treatment with 
romosozumab compared with placebo on the percent change in BMD at the total hip and femoral 
neck. For these endpoints, confirmatory testing will be performed as outlined in Section 4.5. 
Other variables of the 6-month analysis include the evaluation of the effect of treatment with 
romosozumab compared with placebo at 3 months on the percent change in BMD at the lumbar 
spine, total hip and femoral neck, the evaluation of the effect of treatment with romosozumab 
compared with placebo at 1-, 3-, and 6-month time points on the percent changes in BTMs, and 
to characterize serum concentrations of romosozumab in subjects who are randomized to 
romosozumab for 6 months. For the other variables, statistical testing will be performed in an 
exploratory manner.  
The safety analyses of the 6-month analysis will compare the safety of romosozumab treatment 
with placebo in postmenopausal Chinese women with osteoporosis. The safety analyses in the 6-
month analysis will include all available data collected up to the time of 6-month data snapshot. 
The safety variables to be analyzed in the 6-month analysis are presented in Section 2.3.3.  
3.2.1.2 
Final analysis 
After all subjects have the opportunity to complete the Month 15 Visit, the database lock will be 
executed. Based on these data, the remaining efficacy and safety analyses for Month 12 and the 
safety analyses for the overall study period (treatment start through Month 15) will be 
performed.   
3.2.2 
Relative day 
Days on or after the day of first dose of IMP and prior to or on the day of last IMP:  
Relative day will be calculated as the current date minus the date of first dose of IMP + 1 (eg. the 
day of first dose will be Day 1).  
Days prior to the first dose of IMP: 
Relative day will be calculated as date of first dose of study drug minus the current date (the day 
prior to first dose will be Day -1).  
Days after the last dose of IMP: 
Relative day will be calculated as the current date minus the date of last dose of study drug 
including a “+” to denote posttreatment days (eg, the day after the last dose will be Day +1). 
Relative day will not be calculated for partial dates. 
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3.2.3 
Analysis visit windows 
For the Baseline assessment and definition, please refer to Section 3.3 for details. For the post-
baseline assessment, if more than 1 visit measurement falls within the defined visit window, the 
result from the visit closest to the target day will be used for analysis and summarization. If 2 
evaluations are of the same distance from the target day, the result from the later visit will be 
used.  Scheduled and unscheduled visits/measurements are considered for this purpose. To allow 
for variations in scheduling, the following visit windows will be used to assign evaluations to a 
most appropriate nominal visit for analysis and summarization. Furthermore, there will be no 
gaps between visit windows in order to include as many data points as possible for 
summarization. 
DXA Scans 
Nominal visit 
Target study 
day 
Window Definition (Study Day) 
Baseline 
1 
Last evaluation prior to first dose of IMP 
Month 3 
90 
Day 2 – 135 
Month 6 
180 
Day 136 - End of DBPC period + 14 days  
Month 12 
360 
≥ Day End of DBPC period + 15 
 
BTMs (serum CTX and P1NP), PK samples, antibodies samples and laboratory tests 
Nominal visit 
Target study 
day 
Window Definition (Study Day) 
Baseline 
1 
Last evaluation prior to or on Study Day 1 and prior to the 
first IMP 
Month 1 
30 
Day 2 – 60 
Month 3 
90 
Day 61 – 135 
Month 6 
180 
Day 136 – End of DBPC period (note: M6 IMP will belong 
to OL) 
Month 7 
210 
Day End of DBPC period + 1 – 240 
Month 9  
270 
Day 241-315 
Month 12 
360 
≥ Day 316 
 
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Vital signs 
Nominal visit 
Target study day 
Window Definition (Study Day) 
Baseline 
1 
Last evaluation prior to or on Study Day 1 prior to 
the first IMP 
Month 1 
30 
Day 2 – 105 
Month 6 
180 
Day 106 – End of DBPC period  
Month 7 
210 
Day End of DBPC period + 1 – 285 
Month 12 
360 
≥ Day 286 
 
ECG 
Nominal visit 
Target study day 
Window Definition (Study Day) 
Baseline 
1 
Last evaluation prior to or on Study Day 1 prior to 
the first IMP 
Month 1 
30 
Day 2 – 60 
Month 3 
90 
Day 61 – 135 
Month 6 
180 
Day 136 – End of DBPC period  
Month 9 
270 
Day End of DBPC period + 1 - 315 
Month 12 
360 
≥ Day 316 
The definition for End of Study, End of DBPC period, End of OL Period and End of Follow-Up 
Period are specified in Section 3.2.4. 
3.2.4 
Timing of analysis cut-offs 
3.2.4.1 
End of study date 
End of study (EOS) date is defined as the date of the last contact; or the date of the last 
assessment for the early termination (ET) visit for subjects who discontinued the study if no last 
contact date in EDC CRF form.  
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3.2.4.2 
End of DBPC Period date 
End of DBPC Period date is defined as the last date of the assessments of the Month 6 visit or 
start date of OL visits if Month 6 visit is missed. For subjects who discontinued from the study 
before completing Month 6, the ET date is used for the end of DBPC period date.   204g4 
3.2.4.3 
Start of Open-Label Period 
For subjects entering in the open-label period, the end of double-blind period date is the 
beginning of the open-label period date.  All scheduled assessments occurring on this date are 
attributed to the double-blind period.  The month 6 dose of ROMO is considered as occurring in 
the open-label period.  
3.2.4.4 
End of Open-Label Treatment Period date 
End of OL Treatment Period date is defined as the date of the last assessment of the Month 12 
visit. For subjects who discontinued from the study before completing Month 12, the ET date is 
used for the end of 12-month OL Treatment Period date. For those subjects who remained on 
study but missed the month 12 visit, last OL Treatment + 30 days will be used as the end of 12-
month treatment period date.  
3.2.4.5 
End of Follow-Up Period date 
End of FU Period date is defined as the date of the last assessment of the FU visit. For subjects 
who discontinued from the study before completing FU visit, the last contact date is used for the 
end of FU period date. For those subjects who remained on study but missed the FU, the final 
visit + 3 month or final administration of IMP + 4 month will be used as the end of FU period 
date. 
3.3 
Definition of Baseline values 
A Baseline value for a subject is defined as the latest measurement for that subject up to and 
including the day of administration of first IMP, unless otherwise stated. If there is evidence that 
measurements taken on the same day as administration of first study medication were actually 
taken after this administration, then only values strictly prior to that date should be considered 
for that subject for baseline.  If multiple measurements within the baseline period were done, the 
record that is the closest to and prior to or on the date of first IMP administration will be 
considered as the Baseline value.  If a Baseline measurement is missing or not collected, and a 
Screening value (within 35 days prior to day 1) is available, the Screening value will be utilized 
as Baseline instead.  
For computation of change from Baseline BMD of lumbar spine endpoint, Baseline will be 
identified as the average number of values (averaging is dedicated to the duplicate BMD values 
taken on the same day) obtained prior to the first dose of IMP (assuming that any observation on 
the same day as the first dose is prior to dosing, unless evidence stated). For computation of 
change from Baseline BMD of femoral neck and total hip, also other change from Baseline 
endpoints, the Baseline will be identified as the last observation prior to the first dose of IMP 
(assuming that any observation on the same day as the first dose is prior to dosing, unless 
evidence stated).The randomization date will be used as reference for subjects who did not 
receive any dose of IMP but who had non-missing observations on study.   
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3.4 
Protocol deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on study conduct or on the primary efficacy (effectiveness), key safety, or 
PK/PD outcomes for an individual subject. The criteria for identifying important protocol 
deviations will be pre-defined within the appropriate protocol-specific document. Important 
protocol deviations will be reviewed as part of the ongoing data cleaning process and data 
evaluation. All important deviations will be identified and documented prior to unblinding to 
confirm exclusion of subjects from analysis sets.  
Since the PPS will be used for a sensitivity analysis of the primary endpoint which is assessed at 
Month 6, the exclusion from PPS is limited to the double-blind period, ie only study participants 
with IPD prior to Month 6 can be excluded from the PPS. Study participants with IPD after 
Month 6 will not be excluded from the PPS, but might be excluded from PK-PPS and PD-PPS 
during OLE Period. 
3.5 
Analysis sets 
3.5.1 
Enrolled Set 
Enrolled Set (ES) will consist of subjects who signed the Informed Consent form (ICF).  
3.5.2 
Randomized Set 
Randomized Set (RS) will consist of subjects who have been randomized. Disposition data are 
based on the ES and the RS. 
3.5.3 
Safety Set 
Safety Set (SS) will consist of all randomized subjects who received at least 1 dose of IMP. 
These subjects will be analyzed according to the actual treatment received, where subjects who 
receive at least 1 dose of romosozumab will be analyzed in the romosozumab treatment group 
regardless of the randomized treatment.   
Data on safety and exposure will be based on the SS. 
3.5.4 
Full Analysis Set 
The Full Analysis Set (FAS) will consist of all randomized subjects who received at least 1 dose 
of IMP and provided at least 1 Baseline and post-baseline BMD measurement. In the case of 
dosing administration error, analyses of the FAS will be conducted according to randomized 
treatment. This will be the primary efficacy analysis set. 
The FAS will be used for demographics, disease characteristics and BMD efficacy analysis. 
3.5.5 
Per-Protocol Set 
The Per-Protocol Set (PPS) will consist of subjects in the FAS who have completed a minimal 
exposure of 6 months of a treatment regimen without any important protocol deviations that may 
influence the validity of the data for the primary and selected secondary BMD efficacy variables. 
Post-baseline deviations will not necessarily lead to exclusion of a subject from PPS analysis but 
may lead to exclusion of data.  
The PPS will be used as supportive analyses for BMD efficacy analysis. 
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3.5.6 
Pharmacokinetic Per-Protocol Set 
The Pharmacokinetic Per-Protocol Set (PK-PPS) will include all subjects in the SS who have at 
least one evaluable serum romosozumab concentration measurement with no further PK related 
important protocol deviations. This analysis set will be used in the PK analyses. 
3.5.7 
Pharmacodynamic Per-Protocol Set 
The Pharmacodynamic Per-Protocol Set (PD-PPS) will include all subjects in the SS who have at 
least 1 evaluable BTM measurement with no further PD-related important protocol deviations.  
This analysis set will be used in the analyses of the BTMs. 
3.6 
Treatment assignment and treatment groups 
It is expected that subjects will receive treatment as randomized; hence safety analyses will be 
based on the SS as randomized. However, if after unblinding it is determined that subjects 
received treatment other than what they were randomized to, then for safety analyses purposes 
subjects will be allocated to the actual treatment they received. 
Treatment assignment for all other analysis sets will be according to randomization and not 
actual treatment received. 
3.7 
Center pooling strategy 
Based on the clusters of the sites with considerations of geographical and climate differences, the 
pooling strategy will consider the following 3 regions: North, East and South. The detail of site 
and corresponding region is listed in Appendix 13.9. 
3.8 
Coding dictionaries 
The latest version of Medical Dictionary for Regulatory Activities (MedDRA®) will be used to 
code all adverse events, medical histories, and concomitant diseases to a SOC and a PT. 
World Health Organization (WHO) Drug dictionary will be used to code and classify all Prior / 
Concomitant Medications at the Anatomical Therapeutic Chemical Classification (ATC) level 
according to their indication and/or formulation. 
3.9 
Changes to protocol-defined analyses 
 Section 13.6 of the protocol amendment 3 describes the primary and secondary analysis to be 
used in this study. More specifically, the protocol describes primary analysis using last 
observation carried forward (LOCF) as the method for handling missing data. This SAP has been 
modified such that the missing or out of window data due to COVID-19 impact will be imputed 
by multiple imputation and other missing data (rather than due to COVID-19 impact) will be 
imputed by LOCF. The original LOCF method will be also applied in sensitivity analysis. The 
modification is provided in this SAP. 
Section 3.2.2 and Section 4.2.2.2 of the protocol amendment 3 describe the area under the curve 
through Month 12 in P1NP will be produced by treatment group (AUC). This SAP has removed 
AUC for other objectives. 
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4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
All model-based analyses will include treatment, age strata group (stratification factor), Baseline 
DXA BMD value, baseline machine type (Hologic or Lunar), region, the baseline machine type-
by-baseline DXA BMD value interaction as independent variables, if applicable. 
4.2 
Handling of dropouts or missing data 
In general, even if the IMP is discontinued, the subjects will be encouraged to continue the study 
schedule up to the planned final visit. For all subjects, all available data will be included in 
analyses, regardless of whether the data are collected before or after the subject discontinues 
IMP or before or after the subject takes alternative osteoporosis therapy (licensed drugs only) 
(see Appendix 13.1) or prohibited medication. This principle is as close as possible to the 
Intention to treat (ITT) principle and is currently accepted from a regulatory perspective as a 
conservative approach. Since this approach reflects effectiveness and real-world application 
rather than efficacy, it is in line with the late development stage of romosozumab within the 
clinical program.  
If not otherwise specified, any missing data will not be imputed. 
Supplementary analyses will be performed on the primary and secondary efficacy endpoints to 
assess the treatment effect of romosozumab when considering any subsequent or concomitant 
prohibited and/or alternative osteoporosis therapy (licensed drugs only).   
Potentially, deaths could occur during this study. However, these events most likely will not be 
linked to the study indication of postmenopausal osteoporosis in China so that data which would 
have been collected after date of death will not be imputed.  
In the data evaluation meetings (DEM), the following blinded overall incidences will be 
monitored since they have the potential to affect the interpretation or the existence of the BMD 
measurements: 
• Incidence of subjects who discontinued IMP 
• Incidence of subjects who discontinued IMP by reasons 
• Incidence of subjects who received prohibited medication during ongoing IMP 
treatment 
•  Incidence of subjects who received alternative osteoporosis therapy during ongoing 
IMP treatment 
• Incidence of subjects who received alternative osteoporosis therapy after early 
termination of IMP 
• Incidence of subjects who died 
For those sites which show strong deviations from the average of all sites during the DEM, 
appropriate measures such as re-training, following-up with corrective actions etc. would be 
considered. Further analyses including time to various discontinuation events (Kaplan-Meier 
plots), events by Baseline characteristics and events by efficacy endpoints may be conducted to 
explore the cause and impact of the discontinuations.   
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All the missing visit or missing data related to COVID-19 will be listed.  Additional listings will 
be provided for the patients’ assessments with COVID-19 impact.  Additional summary and 
sensitivity analyses will be provided if deems necessary.   
 
4.2.1 
Dates  
For analyses of AEs and concomitant medication usage, a complete date must be established in 
order to correctly identify the AE or medication as occurring during treatment in the study or not. 
For the purposes of imputing missing date or missing components of partially-reported start and 
stop dates for AEs and for medication use, the algorithms listed below will be followed. Start and 
stop dates of AEs or concomitant medication will be displayed as reported in the subject data 
listings (ie, no imputed values will be displayed in data listings). 
• Missing start day, but month and year present: 
If study start date (Day 1) occurred in the same month and year as the occurrence of the 
AE/medication, the start day of the event/medication will be assigned to the day of study start 
day. 
Otherwise the start day will be set to the 1st day of the month. 
• Missing start day and month, but year present: 
If the study start date (Day1) occurred in the same year as the occurrence of the 
AE/medication, the start day and month will be assigned to the date of study start day. 
Otherwise the start day and month will be set to 01 Jan. 
• Missing end day, but month and year present: 
If the date of last contact occurred in the same year and month as the occurrence of the 
AE/medication, the end day will be assigned to the date of the last contact.  
Otherwise the end day will be set to the last day of the month. 
• Missing end day and month, but year present: 
If the day of last contact occurred in the same year as the occurrence of the AE/medication, 
the end day and month will be assigned to the date of last contact. 
• Completely missing start date: 
An AE will be considered as occurring during treatment. 
Medications with an unknown stop date or a stop date after the date of the first IMP 
application will be considered as concomitant medication but not as prior medication. 
Medications with a stop date prior to first IMP application will be considered as prior 
medication but not as concomitant medication.  
• Completely missing stop date: 
Adverse events with a completely missing stop date will be considered ongoing. 
Medications with a completely missing stop date will be considered as concomitant 
medications. 
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4.3 
Interim analyses and data monitoring 
No interim analysis is planned for this study. 
An external, independent Data Monitoring Committee (DMC) will monitor unblinded safety and 
efficacy data on an ongoing basis throughout the study. DMC members will have access to 
treatment assignments if knowledge of treatment assignment at the individual level is essential to 
evaluate safety. To minimize the potential introduction of bias, these individuals will not have 
direct contact with the study site personnel or subjects. An independent statistical service 
provider will generate unblinded reports for review by the DMC.  If at any time there are safety 
concerns, the DMC will communicate the concerns to a representative from UCB senior 
management. The actual dates and the conduct of the DMC meetings are outlined in the DMC 
Charter. 
4.4 
Multicenter studies 
For the purpose of the summaries and analyses, the term ‘Site’ will be used to define each center. 
The primary efficacy variable will be presented by treatment groups and region to explore 
interactions between treatment and regions according to Section 3.7.  
4.5 
Multiple comparisons/multiplicity 
 For addressing multiplicity issues, a hierarchical testing procedure will be implemented which 
consists of 3 steps. 
(1) Lumbar spine BMD percent change from Baseline at 6 months 
(2) Total hip BMD percent change from Baseline at 6 months  
(3) Femoral neck BMD percent change from Baseline at 6 months 
The statistical test of the treatment effects in the second step will be made in a confirmatory 
manner only when the treatment effect on the primary efficacy endpoint is statistically 
significant using a 2-sided type I error rate of 0.05. Likewise, the third step will be made only 
when the treatment effect tested in step1 and step 2 are statistically significant using a 2-sided 
type I error rate of 0.05. 
4.6 
Examination of subgroups 
To assess the consistency and robustness of the treatment effect on lumbar spine BMD, the 
primary analysis and selected secondary analyses will be performed for the following subgroups:  
• age group (< 75 years, ≥ 75 years)  
• region defined in section 3.7 (South, East, and North China) 
• Baseline lumbar spine BMD T-score (≤ -3, > -3 and ≤ -2.5, > -2.5; for lumbar spine BMD 
analysis only)  
• Baseline total hip BMD T-score (≤ -3, > -3 and ≤ -2.5, > -2.5; for total hip BMD analysis 
only)  
• Baseline femoral neck BMD T-score (≤ -3, > -3 and ≤ -2.5, > -2.5; for femoral neck 
BMD analysis only) 
• Baseline Vitamin D (≤ 40 ng/mL, > 40 ng/mL) and loading dose of vitamin D (Yes, No)   
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5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Subject disposition 
The numbers and percentages of subjects who were screened with screen failure reason for the 
ES. The number of subjects who did not meet study eligibility criteria will be listed for the ES. 
The numbers and percentages of subjects that were randomized, completed, prematurely 
discontinued from IMP, withdraw from study, reason for premature discontinuation from IMP 
and study, and successfully completing IMP and study will be summarized by the treatment 
groups and study periods (through Month 6, through OL period, Safety follow-up period, and 
through Month 15) for the RS. The number of subjects who completed each visit (as captured in 
the CRF) will also be listed. The number of subjects who withdrawal due to AE will be 
summarized and listed for the RS. In addition, the disposition of subjects into treatments groups 
and analysis sets (RS, FAS, SS, and PPS) will also be summarized on the RS.  
5.2 
Protocol deviations 
Important protocol deviations (IPD) will be identified at data cleaning meetings (DCMs) prior to 
taking a snapshot from the database for the analysis. The identified important protocol deviations 
will be classified by predefined items (eg., inclusion criteria, exclusion criteria, incorrect 
treatment, prohibited medication, treatment non-compliance and procedural non-compliance) and 
summarized by the treatment groups and study periods for the RS. In addition, the number of 
subjects with at least 1 IPD will be displayed by site.  
IPD related to COVID-19 protocol deviations will be summarized for treatment non-compliance 
and procedural non-compliance. 
5.3 
Impact of COVID-19  
A summary table of visits and reasons affected by COVID-19 will be presented based on the 
Randomized set. 
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
The demographics and other Baseline characteristics will be summarized descriptively based on 
FAS. In case FAS and SS are different, the demographics will also be summarized based on SS. 
6.1 
Demographics 
The continuous demographic variables:  
• Age at study entry (years) 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
BMI (kg/m2) will be calculated as: 
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BMI = Weight (kg)
(Height (m))2 
The categorical demographic variables: 
• Gender 
• Race  
• Ethnicity  
• Region 
• Country 
• EudraCT age categories (18-<65, 65 to <85, and ≥85)  
• Clinicaltrials.gov age categories (≤18, 19 to <65, and ≥65)  
• Age class (<65, ≥ 65 to <75, and ≥75)  
• Age class (<75, ≥75) 
• Age strata group from IVRS (<75, ≥75) 
• BMI (kg/m2) (<18.5, 18.5 to <23, 23 to <27.5, ≥27.5) 
6.2 
Other Baseline disease characteristics 
• BMD T-score at lumbar spine, total hip and femoral neck  
• BMD T-score categories at lumbar spine (≤ -3.0, > -3.0 to < -2.5, and ≥ -2.5), total hip (≤ 
-2.5 and > -2.5) and femoral neck (≤ -2.5 and > -2.5) 
• BMD (g/cm2) by machine type (Hologic vs. Lunar) at lumbar spine, total hip and femoral 
neck  
• bone turnover markers (sCTX [ng/L], P1NP [ug/L])  
• years since menopause (year) 
• laboratory parameters [calcium corrected by albumin, phosphorus, creatinine, serum 25 
hydroxy (OH) vitamin D level, thyroid-stimulating hormone (TSH), and intact 
parathyroid hormone (iPTH) Total cholesterol, low-density Lipoprotein (LDL), high-
density Lipoprotein (HDL), triglycerides]   
• prior osteoporosis medication use (Yes, No)  
• type of osteoporosis medication use (eg. oral bisphosphonate, IV bisphosphonate, 
denosumab, teriparatide (TPTD), parathyroid hormone (PTH), calcitonin, strontium, 
fluoride, hormone replacement therapy, traditional herbal medication, activated vitamin 
D, SERM, vitamin K, other)   
• Loading dose of vitamin D (Yes, No)  
• Baseline use of calcium (Yes, No)  
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• 10 year probability of major osteoporotic and hip fractures based on WHO risk factor 
criteria (FRAX, see in Appendix 13.3) calculated with femoral neck BMD T-score 
• 10 year probability of major osteoporotic and hip fractures based on WHO risk factor 
criteria (FRAX) calculated without femoral neck BMD T-score 
• parental hip fracture (Yes, No, Unknown)   
• glucocorticoid use (Yes, No) 
• secondary osteoporosis (Yes, No)  
• rheumatoid arthritis (Yes, No)  
• alcohol use (Yes, No, Unknown) 
• tobacco (Yes, No, Unknown) 
• caffeinated beverage use (Yes, No, Unknown) 
6.2.1 
Cardiovascular risk factors: 
• history of diabetes (type1, type2, No, Unknown) 
• history of hypertension (Yes, No, Unknown) 
• history of hyperlipidemia 
• history of hypercholesterolemia (Yes, No) 
• history of renal impairment (Yes, No, Unknown) 
• history of atherosclerosis (Yes, No, Unknown) 
• prior heart failure (Yes, No, Unknown) 
• prior transient ischaemic attack (Yes, No, Unknown) 
• prior angina pectoris (Yes, No, Unknown) 
• other prior cardiovascular ischaemic events (Yes, No, Unknown) 
6.3 
Medical history and concomitant diseases 
Previous and ongoing medical history will be summarized by MedDRA® SOC and PT. Medical 
procedures are not coded. The analysis will be performed based on FAS. 
Prior fracture profiles will be summarized: 
• fracture history (Yes, No, Unknown) 
• prevalent vertebral fracture as assessed by the central imaging vendor based on the lateral 
spine x-ray (Yes, No, Unknown) 
• number of prevalent vertebral fractures (0, 1, 2, ≥3, not readable/missing) and incidences 
of the grade of prevalent vertebral fracture (SQ0, SQ1, SQ2, SQ3) 
• historical fracture at or after age of 45 (Any historical fracture, historical osteoporotic 
fracture, historical nonvertebral fracture, historical major nonvertebral fracture) 
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• historical fracture at or after age of 55 (Any historical fracture, historical osteoporotic 
fracture, historical nonvertebral fracture, historical major nonvertebral fracture) 
• time since the most recent fracture (years) 
• time since the most recent fracture (< 12 months, ≥ 12 months) 
6.3.1 
Prevalent vertebral fracture 
A subject has a prevalent vertebral fracture if any vertebra from T4 to L4 has a grade of ≥ 1 at 
baseline assessed by the central imaging vendor based on the lateral spine x-ray. A subject does 
not have a prevalent vertebral fracture when all 13 grades from T4 to L4 are 0.  Otherwise, the 
subject will have an unknown status for prevalent vertebral fracture.   
6.3.2 
Any historical fracture  
Any Historical fracture is defined as any fracture recorded on the Subject Fracture History eCRF 
regardless of trauma severity or vertebral fracture based on baseline spinal radiograph.  
6.3.3 
Historical osteoporotic fracture  
Historical osteoporotic fracture is defined as any nonvertebral fracture recorded on the Subject 
Fracture History eCRF not including skull, facial bones, fingers, toes, spine and tailbone and not 
associated with known high trauma severity or pathologic fractures, or vertebral fracture based 
on baseline spinal radiograph  
6.3.4 
Historical nonvertebral fracture  
Historical nonvertebral fracture is defined as any fracture recorded on the Subject Fracture 
History eCRF not including skull, facial bones, fingers, toes, spine, and tailbone and not 
associated with known high trauma severity or pathologic fractures   
6.3.5 
Historical major nonvertebral fracture  
A subset of historical nonvertebral fractures including the following locations:  pelvis (not hip), 
hip, lower leg (not knee or ankle), ribs, shoulder, forearm, and wrist and not associated with 
known high trauma severity or pathologic fractures 
6.4 
Prior and concomitant medications 
Prior medications include any medications that started prior to the start date of IMP. Past 
medications are a subset of prior medications, and include prior medications with a stop date 
before the date of first dose of IMP. Any treatment other than IMP administered from the time of 
signing the ICF to the EOS Visit will be considered concomitant medication. This includes 
medications that were started before the study and are ongoing during the study. If study 
medications with missing start date and end date without ongoing status, the medications will 
regard as both prior and concomitant medication.  The analysis will be performed based on 
Randomized Set. 
Medications will be summarized by WHO Anatomical Therapeutic Chemical (ATC) 
Classification, presenting Anatomical Main Group (ATC Level 1), Pharmacological Subgroup 
(ATC level 3), and preferred term. 
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7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
The IMP will be administered at the study site by staff trained in the injection technique. Date 
and time of IMP administration during double-blind period and open-label period will be 
recorded in the subject’s eCRF.  
Drug accountability must be recorded on the Drug Accountability form. 
The expected day of administration will be based upon (1) the date of first IMP administration 
and (2) the previous injection date. The sum of the absolute difference in days between the actual 
and expected days will be summarized. In addition, a ratio of compliance will be computed 
based upon the actual and expected days for each of the 2 methods. The ratios of compliance will 
also be summarized as a continuous variable and categorically (<80% and ≥80%). The general 
formula for the compliance ratio is given as follows for double-blind period and overall period:   
Compliance Ratio (CR) during double-blind period= {[Study Duration (days) during double-
blind period] - [Cumulative Difference (days) during double-blind]} ÷ {Study Duration (days) 
during double-blind period}  
Compliance Ratio (CR) during overall period = {[Study Duration (days) during Romosozumab 
treatment period] - [Cumulative Difference (days) during  Romosozumab treatment period]} ÷ 
{Study Duration (days) during  Romosozumab treatment period}  
Compliance will be summarized as the number of doses received relative to the number of doses 
expected. Percent compliance will be calculated as:  
Percent compliance during double-blind period = 100 x number of doses received during double-
blind period ÷ number expected during double-blind period. 
Percent compliance during overall period = 100 x number of doses received during  
Romosozumab treatment period ÷ number expected during Romosozumab treatment period. 
Treatment compliance will be presented for SS. 
8 
EFFICACY ANALYSES 
The BMD efficacy analyses will be performed based on the FAS. The results from the central 
imaging vendor will be used in the FAS. PPS will also be utilized for sensitivity analyses. 
Statistical testing will be conducted as outlined in Section 4.5. For all confirmatory testing, both 
adjusted and unadjusted p-values will be provided. The derivation rules for the adjusted p-values 
are provided in Appendix 13.2. For each efficacy BMD endpoint, descriptive statistics will be 
provided for absolute values, change from baseline and percent change from baseline at post-
baseline visit by machine-type and visit. In addition, mean (±SE) plot by visit will be presented 
for primary endpoint and observed case. 
8.1 
Statistical analysis of the primary efficacy variable 
8.1.1 
Primary analysis of primary efficacy variable 
Primary analysis of Primary efficacy endpoint 
Estimands’s attributes to be considered for the evaluation of the primary endpoint 
(1) Target Population: Postmenopausal Chinese women with osteoporosis meet the inclusion and 
exclusion criteria 
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(2) Treatment: Romosozumab or PBO for 6 months 
(3) Endpoint: percentage change from baseline in BMD at lumbar spine at end of DBPC period 
(month 6). 
(4) Intercurrent Events (ICEs) and strategies to handle ICEs: 
(a) ICE #1: treatment discontinuation not due to COVID-19 will be handled by treatment 
policy strategy 
(b) ICE #2: alternative osteoporosis therapy will be handled by treatment policy strategy. 
(c) ICE #3: treatment interruption and impacted BMD data (missing or out of visit window) 
due to COVID-19 will be handled by hypothetical strategy 
(5) Population level outcome: difference of least square (LS) means for Romosozumab and PBO 
ICE #1 Treatment discontinuation not due to COVID-19 and ICE#2 use of alternative 
osteoporosis therapy is rare (not expected to happen frequently). They will follow treatment 
policy strategy which align with ITT principle. The treatment policy strategy will include all 
available data observed at Month 6 regardless of the occurrence of intercurrent events. This 
means the analysis includes on- and off-treatment values collected after study participants 
prematurely discontinued study treatment but agreed to remain on the study and continued to 
attend visits and provide assessments at those visits or data after alternative/prohibited 
medication administrated. Those observed values will be analyzed according to the study 
participant’s randomized treatment. 
During COVID-19 pandemic, study procedures (i.e. IMP administration and BMD assessment) 
are heavily impacted by sites close, participants quarantined or partially lock down. Thus, 
treatment was interrupted, or BMD assessment could not be performed or performed out of 
window. Treatment interruption and impacted BMD data (missing or out of visit window) due to 
COVID-19 will be considered as ICE #3. Hypothetical strategy, in which the interest is in the 
treatment effect if the ICE did not occur, is a recommended option for most pandemic-related 
ICEs (R. Daniel Meyer, et al., 2020).   
The data after ICE#1 and ICE#2 will be handled by treatment policy strategy and will use the 
observed data to do analysis. COVID-19 impacted data after ICE#3, then it will be setting to 
missing and imputed by multiple imputation (MI) under missing at random (MAR) assumption 
(MI-MAR). Details of this multiple imputation analysis are outlined in Appendix 13.4. This 
COVID-19 impacted data includes any BMD data after treatment interrupted (exceed 70 days 
since previous IMP, based on PK modeling which demonstrated that BMD loss begins after 70 
days without dosing) and any missing data or out of window (exceed 70 days since previous 
IMP) data due to Covid-19 (other than actual COVID-19 infection). Missing data other than due 
to COVID-19 impacted will be imputed by LOCF. 
Missing baseline BMD by DXA at any anatomical site will not be imputed and evaluated for the 
BMD analysis. Missing postbaseline BMD will be imputed using the LOCF approach (by 
carrying forward the last non-missing postbaseline value prior to the missing value from the 
same anatomical site) in the 6-month analysis.  
In all visits and including the screening visit, if duplicated DXA assessment were performed on 
the same visit the mean of the duplicated BMD values will be used for analysis. The corresponding 
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T-score at baseline will be converted using the mean of the duplicated BMD (checking missing 
DXA assessment during DEMs in section 4.2). 
If a subject has BMD values from different DXA machine types (ie, Hologic and Lunar) only 
those BMD values that are collected from the same machine type as the Baseline BMD will be 
used for analyses and imputation. For anatomical sites that can be measured on different body 
sides (ie, left and right), only those BMD values that are collected from the same body side as the 
Baseline BMD will be used for analyses and imputation. 
The comparison of the percent change from Baseline in lumbar spine DXA BMD at Month 6 
between treatment groups will be evaluated using an analysis of covariance (ANCOVA) model. 
The ANCOVA model will include treatment group, age strata group (stratification factor), 
Baseline BMD value, machine type at baseline, region, and interaction of Baseline BMD value 
and machine type at baseline as independent variables. Summaries for the results will include 
least squares (LS) means point estimates of the percent change from Baseline for each treatment 
arm.. Summaries including the LS mean, standard error, 2-sided 95% CI and associated p-values 
(unadjusted p-value and adjusted p-value) will be provided for the difference between the LS 
means for romosozumab and placebo.  
8.1.2 
Sensitivity and Supplementary analyses of the primary efficacy 
variable(s) 
• 
Sensitivity and supplementary analyses of the primary efficacy endpoint will be conducted: 
Approach 
Analysis Set 
ICE/ICE Strategy 
Missing Data 
Strategy 
Sensitivity analysis 1 
PPS 
NA 
Same with primary 
analysis 
Sensitivity analysis 2 
MMRM 
FAS 
Same with primary 
analysis 
Data after ICE#3 
will be setting to 
missing and leave it 
missing before 
running MMRM.  
No other imputation 
before MMRM. 
Sensitivity 3 
FAS 
Same with primary 
analysis 
Observed 
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Supplementary analysis 1 FAS 
ICE#1, ICE#2, and ICE#3 
from the primary estimand 
will all be handled by 
treatment policy strategy in 
this supplemental analysis. 
LOCF 
Supplementary analysis 2 FAS 
ICE #1: treatment 
discontinuation (BMD data 
collected >70 days after 
last IMP) will be handled 
by hypothetical strategy.  
ICE #2: alternative 
osteoporosis therapy will 
be handled by hypothetical 
strategy. 
Data after ICEs will 
be setting to 
missing and 
replaced with 
LOCF 
Supplementary analysis 3 FAS 
Same with Supplementary 
analysis 2 
Data after ICEs will 
be setting to 
missing and 
replaced with MI-
MAR 
For sensitivity analysis 2, a mixed effects model with repeated measures model (MMRM) will be 
fit with the percent change from Baseline at Months 3 and 6 in BMD of the lumbar spine as the 
dependent variable, and Baseline BMD, machine type at baseline, interaction of Baseline BMD 
and machine type at baseline, visit (categorical), treatment (categorical), interaction of treatment 
and visit, region and interaction of treatment and region as the independent variables. The MMRM 
analysis will include subject as a random effect, treatment, age strata group (stratification factor), 
region, visit, and treatment-by-visit interaction as fixed effects, with adjustment for baseline BMD 
value. The variance structure will allow for heteroskedasticity of variance between treatment 
groups. The FAS will be used for the repeated measurement model. If model cannot be estimated, 
region will be excluded from MMRM model. 
A blinded data review process will be implemented in which the missingness of data, statistical 
assumptions, eligibility of definition of categorical variables/thresholds will be assessed. If it turns 
out that the number of randomized subjects without Baseline and/or without BMD measurement 
at an on-treatment visit is high, then a sensitivity analysis will be pre-specified under blinded 
conditions using multiple imputation strategies under the “missing at random” assumption.  
Depending on the amount of missingness, additional sensitivity analyses under “missing not at 
random” assumptions may be defined. If the need of such analysis is indicated during the blinded 
data review process, the method of these analyses will be prespecified in the final SAP before 
unblinding and database lock. 
Further sensitivity analyses will be investigated in DEM of certain critical events listed in 
Section 4.2 which will be monitored throughout the blinded data review process. 
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Due to the exploratory nature of these analyses, even though the p-values will be computed for 
each analysis in an exploratory manner, formal significance testing will not be conducted. 
8.2 
Statistical analysis of the secondary efficacy variables 
For the secondary efficacy BMD endpoints during the DBPC Period (at total hip and femoral 
neck at Month 6), will be performed following the same analyses that for the primary endpoints. 
The main analysis and sensitivity/supplementary analyses of key secondary endpoints will 
follow same estimands than the primary endpoint except attribute of "Endpoint". COVID-19 
related intercurrent event is also added to the estimand of key secondary endpoints and same 
strategy in each analysis. 
• Percent change from baseline in BMD at the total hip at the end of the DBPC (Month 6) as 
assessed by DXA 
• Percent change from baseline in BMD at the femoral neck at the end of the DBPC Period 
(Month 6) as assessed by DXA  
• Percent change from baseline in BMD at the lumbar spine at the end of OL Treatment Period 
(Month 12) as assessed by DXA in subjects who are continuing with 6 months of 
romosozumab treatment after initially being randomized to 6 months of romosozumab 
treatment in the Double-Blind, Placebo-Controlled Period (for a total of 12 months of 
romosozumab treatment)  
• Percent change from baseline in BMD at the total hip at the end of OL Treatment Period 
(Month 12) as assessed by DXA in subjects who are continuing with 6 months of 
romosozumab treatment after initially being randomized to 6 months of romosozumab 
treatment in the Double-Blind, Placebo-Controlled Period (for a total of 12 months of 
romosozumab treatment) 
• Percent change from baseline in BMD at the femoral neck at the end of OL Treatment Period 
(Month 12) as assessed by DXA in subjects who are continuing with 6 months of 
romosozumab treatment after initially being randomized to 6 months of romosozumab 
treatment in the Double-Blind, Placebo-Controlled Period (for a total of 12 months of 
romosozumab treatment) 
The derivation rules specified in Section 8.1.1 will be applied for the calculation of the 
secondary BMD endpoints as well. 
8.2.1 
Secondary efficacy variables - DBPC Period 
For the secondary efficacy BMD endpoints during the DBPC Period (at total hip and femoral 
neck at Month 6), a percent change from Baseline in DXA BMD will employ an ANCOVA 
model. The ANCOVA model will include the same independent variables and interactions as 
described in Section 8.1.1. The FAS will be used for this analysis. This analysis will be 
performed with adjustment for multiplicity as described in Section 4.5. Nominal (unadjusted) p-
values will be provided as well for exploratory purposes. 
A sensitivity analysis will be performed on the analysis of the secondary efficacy variable as 
described in the above paragraph based the PPS. In addition, a MMRM will be fit with the 
percent change from Baseline at Months 3 and 6 in BMD of the total hip and femoral neck with 
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the same independent variables and interactions as described in Section 8.1.1.The FAS will be 
used for these analyses. 
For the secondary efficacy BMD endpoints at total hip and femoral neck, the following 2 further 
sensitivity analyses will be conducted: 
Only those values are included in analysis, which were assessed during the period when subjects 
received IMP and does not apply to any alternative osteoporosis therapy (licensed drugs only). In 
particular, all values which were assessed more than 70 days after last dose of IMP or were 
assessed after the first intake of alternative osteoporosis therapy (licensed drugs only) will be 
considered as missing data and will not be imputed. For one analysis, missing data imputation 
via LOCF will be applied, and for the other analysis via multiple imputation according to 
missing at random assumption will be applied.  
8.2.2 
Secondary efficacy variables - OL Treatment Period 
For the OL Treatment Period, only the post Month 6 value will be used for imputation, the 
values in the DBPC Period will not be carried forward into the OL Treatment Period.  
For the OL Treatment Period analyses, the secondary efficacy variables are the percent change 
from Baseline in BMD at lumbar spine, total hip, and femoral neck at the end of OL Period (at 
12 months) as assessed by DXA in subjects initially randomized to romosozumab only. The 
descriptive statistics will be performed for 12 months analysis. 
8.3 
Statistical analysis of other efficacy variable 
The other efficacy variables are defined as: 
• Percent change from baseline in BMD at the lumbar spine, total hip, and femoral neck at 
Month 3 as assessed by DXA – DBPC Period 
• Percent change from baseline in BMD at the lumbar spine, total hip, and femoral neck at the 
end of OL Treatment Period (Month 12) as assessed by DXA in subjects who are initially 
randomized to placebo in the DBPC Period and transition to romosozumab treatment for 
6 months – OL Treatment Period 
The derivation rules specified in Section 8.1.1 and Section 8.2.2 will be applied for the 
calculation of the other efficacy variables as well. 
The ANCOVA method described in Section Error! Reference source not found. for the 
primary efficacy variable will be performed. For Month 12 analysis, Only descriptive statistics 
will be summarized. 
 
9 
PHARMACOKINETICS AND PHARMACODYNAMICS  
Missing PK or PD values (either Baseline or postbaseline values) will not be imputed. 
Measurement values that are below the lower limit of quantification (BLQ) will be considered 
equal to the LLOQ/2 for all analyses. If more than 1/3 of the samples are BLQ at a particular 
visit no summary statistics will be calculated and only minimum and maximum values will be 
reported. 
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9.1 
Pharmacokinetics 
Pharmacokinetic variables will be analyzed for all subjects in the PK-PPS at both Month 6 and 
final analysis. The serum trough concentrations of romosozumab will be summarized based on 
the PK-PPS using descriptive statistics (n, geometric mean, 95% confidence interval for 
geometric mean, geometric CV%, mean, standard deviation, median, minimum value, maximum 
value) for the below analyses: 
• Month 1-6 of romosozumab/romosozumab treatment group at 6-month analysis 
• Month 1-12 of romosozumab/romosozumab treatment group at final analysis 
• Month 1-6 of romosozumab/romosozumab group pooled with month 6-12 of placebo/ 
romosozumab treatment group at final analysis 
Geometric mean (geometric coefficient of variation) and GeoMean (±95% CI) romosozumab 
serum concentration time profiles will be displayed graphically on a linear scale and semi-
logarithmic scale. 
Spaghetti plots of concentration-time profiles will be displayed graphically on a linear scale and 
semi-logarithmic scale. 
A population PK analyses will be conducted. Details of the analysis will be described in a 
separated data analysis plan and results will be reported separately. 
 
9.2 
Pharmacodynamics 
Pharmacodynamic variables will be analyzed for all subjects in the PD-PPS at both Month 6 and 
final analysis. 
For the BTMs (P1NP and sCTX), descriptive statistics (n, geometric mean, 95% confidence 
intervals, geometric CV%, mean, standard deviation, median, interquartile range, minimum 
value, maximum value) will be presented by treatment group. The following list of endpoints 
will be analysed: 
• observed values, change from Baseline and percent change from Baseline at all planned 
visits 
• maximum on-treatment  observed values, change from Baseline and percent change from 
Baseline (P1NP only) 
• minimum on-treatment  observed values, change from Baseline and percent change from 
Baseline (sCTX only) 
Pharmacodynamic-time plots in P1NP and sCTX with median+/-interquartile range will be 
generated for the actual value and percent change from Baseline for each PD parameter at each 
visit for both the romosozumab and placebo group and these plots will be displayed on a linear 
scale.  
For all PD endpoints, the following analyses are performed at: 
• romosozumab treatment group vs. placebo group for month 1-6 at Month 6 analysis 
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• romosozumab/romosozumab treatment group vs. placebo/romosozumab treatment group 
for month 1-12 at final analysis 
• romosozumab/romosozumab treatment group for month 1-6 vs. placebo/romosozumab 
treatment group for month 6-12 at final analysis 
10 
SAFETY ANALYSES 
Safety will be presented by treatment groups for the SS.  
10.1 
Extent of exposure 
The number of doses received will be summarized categorically (eg., 1, 2, 3, …) and with 
descriptive statistics. In addition, the cumulative duration of exposure will be summarized for 
subjects exposed for different duration categories (eg., at least one day, ≥ 1 months, ≥ 2 months, 
…, ≥12 months). 
Duration of exposure to IMP will be calculated as:  
Date of last administration of IMP – date of first IMP administration + 30 days 
Additionally, adjusted duration of exposure is calculated as: 
Date of last administration of IMP – date of first IMP administration + 30 days - cumulative 
gaps in exposure 
Calculate cumulative gaps are the number of days from date of previous dose + 30 days to next 
dose date summed up over the entire period. If subjects had gap of <=30 days between 
successive doses then gap in exposure will be 0 days for this period. 
 
10.2 
Adverse events 
Treatment emergent AEs (TEAE) are defined as all AEs started or worsened in severity on or 
after the date of receiving first dose of IMP and before EOS date except lipid-type AEs starting 
on the date of first dose of IMP and not worsening (and not deemed IMP related by the 
investigator). Lipid-type AEs will be defined by the Dyslipidaemia SMQ (see Appendix 13.7). 
The different handling of lipid-type AEs starting on the date of first dose of IMP is to ensure that 
pre-existing lipid abnormalities are not reported as TEAEs (lipids are only measured at Day 1 
before first IMP and not at Screening). 
All subsequently described displays in Section 10.2 will be compiled for the DBPC Period and 
for the overall study period (treatment start through Month 15). For the displays on the DBPC 
Period, TEAEs with a start date before or on the End of DBPC period date will be included. For 
the overall period, TEAEs with a start date before or on the EOS date will be included. 
Duration of AEs will not be calculated if there is missing stop date information.  If the intensity 
of an AE is unknown, it is considered as severe. If the relationship to study drug is missing, it is 
considered as related. Note that if the seriousness of an adverse event is unknown, every attempt 
should be made to resolve this prior to a snapshot for an interim analysis or database lock; in the 
exceptional case that the seriousness of an adverse event is still missing then no imputation 
should be applied for this characteristic. 
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If a TEAE occurs on the date of switch from the DBPC period to the OL period, the event is 
attributed to the DBPC treatment. The only exception that TEAEs of injection site reactions (see 
Appendix 13.5), potentially related to hypersensitivity (Standardized MedDRA® Query [SMQ], 
narrow scope) will be in OL period. 
The number and incidence of TEAEs will be summarized by treatment group, the MedDRA® 
SOC and PT with the SOC sorted alphabetically and within SOC the PT sorted by descending 
order of frequencies. The incidence of TEAEs will also be summarized by treatment group 
(including romosozumab total), intensity and relationship to IMP.  
Adverse events will be presented as “number of participants (percentage of participants) [number 
of events]”. In this style of output, “[number of events]” will include all cases of an AE including 
repeat occurrences in individual participants, while “number of participants” will count each 
participant only once. 
10.2.1 
Time at risk of exposure 
Time at risk for each subject represents the time a study participant is at risk for having an AE 
with romosozumab exposure period. 
In this study, time at risk (years) during the overall study period is defined as: 
 
(End of last romosozumab – Date of the first dose of romosozumab +1) / 365.25Study 
participant time at risk represents the time a participant is at risk for having an AE. The 
definitions for time at risk (in days) are outlined in Section Error! Reference source not 
found.. These definitions will be used for exposure-adjusted AE summaries. 
10.2.2 
Exposure adjusted incidence rate (EAIR) and exposure adjusted 
event rate (EAER)  
Selected AE summaries will include the EAIR with associated 95% confidence interval and 
EAER where the EAIR and EAER are expressed per 100 study participant-years of exposure. 
The EAIR is defined as the number of participants (n) with a specific AE adjusted for the 
exposure and will be scaled to 100 study participant-years:𝐸𝐴𝐼𝑅= 100 × 
𝑛
∑
(𝑇𝐸𝑋𝑃(𝑖))
𝑁
𝑖=1
 
where n is the total number of participants with AE of interest, N= number of participants at risk 
of an AE, and TExp(i) is the total exposure time for each participant: 
• For participantss with the specific AE of interest:time at risk in years to the first occurrence 
for the AE of interest at the level of coding evaluated 
• For participantss without the AE: the total time at risk in years.  
Exact Poisson 95% confidence intervals for incidence rates are calculated using the relationship 
between the Poisson and the Chi-square distribution (Ulm, 1990; Fay and Feuer, 1997): 
𝐿𝐶𝐿= 
𝑥2𝑛,𝛼/2
2
2
 
𝑈𝐶𝐿= 
𝑥2(𝑛+1),1−𝛼/2
2
2
 
 
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where n is the number of participants with a specific AE for the incidence rate of interest and is 
the basis for the number of the degrees of freedom for the chi-square quantile for the upper tail 
probability χ2. 
The EAER will be the number of AEs including repeat occurrences in individual participants 
divided by the total time at risk scaled to 100 study participant-years and calculated using: 
𝐸𝐴𝐸𝑅= 100 × 
𝑁𝐴𝐸
∑
(𝑇𝑅𝑖𝑠𝑘(𝑖))
𝑁
𝑖=1
 
where        is the total number of AEs, n is the total number of participants and TRisk(i) is the time at 
risk in years for each participant for each exposure period. 
No confidence interval will be computed for EAER. 
The following summaries will be provided by actual treatment group for the DBPC and the 
Overall Periods based on the SS. In addition, all summaries of TEAEs based on “100 participant- 
years” will include EAIR (with 95% confidence interval) and EAER. 
10.2.3 
Standard AE summaries 
• TEAEs overview during DBPC period 
• TEAEs overview per 100 patient-years during overall period 
• TEAEs by SOC and PT during DBPC period 
• TEAEs per 100 patient-years by SOC and PT during overall period 
• TEAEs by maximum intensity by SOC and PT during DBPC period 
• TEAEs by maximum intensity by SOC and PT during overall period 
• TEAEs by maximum relationship to IMP per the Investigator by SOC and PT during DBPC 
period 
• TEAEs by maximum relationship to romosozumab per the Investigator by SOC and PT 
during overall period 
• TEAEs leading to IMP discontinuation by SOC and PT during DBPC period 
• TEAEs leading to romosozumab discontinuation by SOC and PT during overall period 
• TEAEs leading to study discontinuation by SOC and PT during DBPC period 
• TEAEs leading to study discontinuation by SOC and PT during overall period 
• TEAEs leading to death by SOC and PT during DBPC period 
• TEAEs leading to death by SOC and PT during overall period 
• Serious TEAEs by SOC and PT during DBPC period 
• Serious TEAEs per 100 patient-years by SOC and PT during overall period 
• Serious TEAEs by maximum relationship to study medication per the Investigator by SOC 
and PT during DBPC period 
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• Serious TEAEs by maximum relationship to study medication per the Investigator by SOC 
and PT during overall period 
• Fatal TEAEs by maximum relationship to study medication per the Investigator by SOC and 
PT during DBPC period 
• Fatal TEAEs by maximum relationship to study medication per the Investigator by SOC and 
PT during overall period 
• Non-serious TEAEs above reporting frequency threshold of 5% by SOC and PT during 
DBPC period 
• Non-serious TEAEs above reporting frequency threshold of 5% by SOC and PT during 
overall period 
• TEAEs of interest by SOC and PT during DBPC period 
• TEAEs of interest by SOC and PT during overall period 
• TEAE of special interest (PDILI) by SOC and PT during DBPC period 
• TEAEs of special interest (PDILI) by SOC and PT during overall period 
• TEAEs of COVID-19 vaccine by SOC and PT during DBPC period  
TEAEs of COVID-19 vaccine by SOC and PT during overall period There is no planned 
statistical testing in the safety analyses. 
10.2.4 
Adverse events of interest 
Subject incidence of adverse events of interest of hypocalcemia, injection site reactions, 
potentially related to hypersensitivity (Standardized MedDRA® Query [SMQ], narrow scope), 
malignant or unspecified tumor (SMQ, narrow scope), hyperostosis, osteoarthritis, positively 
adjudicated adverse events of ONJ, AFF, and positively adjudicated serious CV events will be 
tabulated by PT and treatment group (see Appendix 13.5). Subcategories are added as 
appropriate (EG, MI, stroke and other CV events).     
10.2.4.1 
Osteonecrosis of the jaw adjudication 
The events of ONJ which occurred in the study will be adjudicated and the positively adjudicated 
ONJ will be summarized. All potential events of ONJ identified through a pre-defined search of 
the MedDRA® terms in the adjudication manual for ONJ will be submitted to the ONJ 
Adjudication Committee for blinded review and adjudication. The committee will determine 
whether the event meets the case definition criteria for ONJ.   
10.2.4.2 
Atypical femoral fracture adjudication   
The events of AFF which occurred in the study will be adjudicated and the positive adjudicated 
AFF will be summarized. All potential events of AFF identified through a pre-defined search of 
the MedDRA® terms in the adjudication manual for AFF will be submitted to the AFF 
Adjudication Committee for blinded review and adjudication. The committee will determine 
whether the event meets the case definition criteria for AFF.  
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10.2.4.3 
Adjudicated positive cardiovascular events 
All deaths and potential cardiovascular-related serious adverse events (SAEs) as predefined 
search of the MedDRA® terms according to the adjudication manual for cardiovascular event 
will be submitted to an external independent committee comprised of experienced cardiologists 
for blinded adjudication.  The committee will adjudicate the events and determine whether the 
event is cardiovascular in nature.   
Baseline cardiovascular risk factors will be summarized descriptively as listed in Section 6.2.1.  
Only events positively adjudicated by the adjudication committee to meet cardiovascular event 
definition criteria will be included for analyses. Positively adjudicated cardiovascular events of 
death, cardiac ischemic event, cerebrovascular event, non-coronary revascularization, heart 
failure and peripheral vascular events not requiring revascularization will be summarized using 
subject incidence rates, odds ratios and 95% confidence intervals.  No statistical tests will be 
performed. 
10.2.5 
Adverse events of special interest 
An AE of special interest is defined by potential drug-induced liver injury (PDILI) SMQ (see 
Appendix 13.6). 
10.3 
Clinical laboratory evaluations 
Actual values and changes from baseline of laboratory parameters (hematology and serum 
chemistry including iPTH and lipids) will be descriptively summarized at each available time 
point. In addition, last value, minimum value during treatment, and maximum value during 
treatment will be presented. End of treatment will be defined as last visit of Month 6 during 
DBPC period or Month 12 during OL period (defined in Section 3.2.4.2 and Section 3.2.4.3) not 
including the FU visit and during treatment for the minimum and maximum calculation will also 
exclude the FU visit. 
Shift tables from Baseline to each post-Baseline time point will be presented. In addition, shift 
tables regarding the normal range at end of treatment, minimum and maximum shift at any time 
will also be produced for each hematology and biochemistry laboratory parameter. The shifts 
will be categorized using L (low), N (normal), H (high), missing, and total. 
Graphs showing central tendency (median) and dispersion (interquartile range) of the absolute 
values and percent changes from baseline by visit will also be provided for the following 
laboratory parameters:  
• calcium corrected by albumin  
• phosphorus 
• alkaline phosphatase. 
10.3.1 
Potential drug-induced liver injury and potential Hy’s Law evaluation 
The count and percentage of subjects with potential drug-induced liver injury (PDILI) will be 
tabulated at baseline and on study. For the primary analysis, all on-study visits up to Month 6 
will be used, for final analysis all on-study visits with available values will be used. The 
following endpoints will be applied. 
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A table will be produced to summarize potential Hy’s Law cases. The following two endpoints 
will be calculated: 
Incidence of subjects with 
• [AST ≥3xULN or ALT ≥3xULN] and Total Bilirubin ≥2xULN 
• [AST ≥3xULN or ALT ≥3xULN] and Total Bilirubin ≥2xULN in the absence of ALP 
≥2xULN  
In order to meet either of the above criteria, a subject must experience the elevation in bilirubin 
and ALT or AST (and the absence of ALP elevation, if applicable) at the same visit. For 
example, a subject who experiences a ≥2 x ULN elevation of bilirubin at one visit and a ≥3xULN 
elevation in ALT (or AST) at a subsequent visit has not fulfilled the Hy’s law criteria.   
10.4 
Vital signs, physical findings, and other observations related to 
safety 
10.4.1 
Vital signs 
The following vital signs variables should be summarized: systolic blood pressure (mmHg), 
diastolic blood pressure (mmHg), body temperature (°C) and pulse rate (beats/min). The 
observed value and change from Baseline value for each vital sign variable by treatment group 
and visit will be summarized. A by-subject listing of all vital signs data will be provided. This 
listing should be presented by treatment group and will include: center, subject identifier, age, 
sex, race, weight, visit, vital sign variable and result. 
10.4.2 
Physical examinations 
Abnormal results of the physical examination together with details of abnormalities: abnormality 
clinically significant or not, will be listed by subject and visit. 
10.4.3 
Height and Weight 
Descriptive statistics of actual values and changes from Baseline in body weight, and BMI will 
be presented by scheduled visit will be summarized using the SS. 
10.4.4 
Electrocardiograms 
ECG data will be analyzed by treatment group and visit for SS.  
A summary of the number and percentage of subjects with normal, abnormal not clinically 
significant and abnormal clinically significant ECG results at all applicable visits will be 
provided.  
The following ECG variables will be summarized descriptively (absolute values and change 
from Baseline) by visit: QTcF, RR, PR, QRS and QT. 
A by-subject listing of all 12-lead ECG data will be provided. 
10.4.5 
Immunogenicity Analysis 
The incidence and percentage of subjects who develop anti-romosozumab antibodies up to 
Month 6 (for romosozumab group only) for the DBPC period and up to Month 12 (for both 
group) for the overall study period will be tabulated. This analysis will be repeated to further 
include all testing results from samples collected during the 3-month FU period.  For subjects 
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who develop anti-romosozumab antibodies, romosozumab serum concentrations may also be 
analyzed.  Additionally, exploratory analyses may be performed to assess any impact on safety 
or efficacy. 
 
Further antibody analyses will be provided and details in Appendix 13.8. 
 
11 
OTHER ANALYSES  
Not applicable. 
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12 
REFERENCES 
International Conference on Harmonization. Statistical Principles for Clinical Trials – ICH 
Harmonised Tripartite Guideline. Guidance for Industry, E9, FDA federal register, 63, 1998 
Osteonecrosis of the Jaw Adjudication Manual of Operations for OP0002 
Atypical Femoral Fracture Adjudication Manual of Operations for OP0002 
Cardiovascular Events Adjudication Manual of Operations for OP0002 
Fay MP, Feuer EJ. Confidence intervals for directly standardized rates: a method based on the 
gamma distribution. Stat Med. 1997; 16:791–801. 
Kanis JA, Johnell O, Oden A, Johansson H, McCloskey E. (2008) FRAXTM and the assessment 
of fracture probability in men and women from the UK. Osteoporosis International 19: 385-397. 
Kanis JA, McCloskey EV, Johansson H, Strom O, Borgstrom F, Oden A and the National 
Osteoporosis Guideline Group (2008) Case finding for the management of osteoporosis with 
FRAX® - Assessment and intervention thresholds for the UK. Osteoporos Int 19; 1395-1408. 
Ulm K. A simple method to calculate the confidence interval of a standardized mortality ratio. 
American Journal of Epidemiology 1990;131(2):373-375. 
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13 
APPENDICES 
13.1 
Alternative osteoporosis therapy (licensed drugs only) 
Potential alternative osteoporosis therapies (licensed drugs only) are including but not limited to: 
• Strontium (including strontium ranelate and over-the-counter strontium preparations) 
• Vitamin K and vitamin K analogs  
• iv bisphosphonates 
• Oral bisphosphonates  
• Denosumab 
• TPTD or any PTH analogs 
• Systemic oral or transdermal estrogen  
• SERMs  
• Calcitonin  
• Tibolone 
• Hormonal ablation therapy 
• Active vit D and analogs 
• Chinese herbal medicine for treating osteoporosis (including but not limited to TFRD, ICA) 
Patients who take any alternative osteoporosis therapy that listed above, will be reviewed and 
confirmed by UCB medical team within each DEMs. A finalized list will be provided prior to 
unblinding the study.  
  
 
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13.2 
Definitions of adjusted p-values for BMD endpoints 
Test ID 
Endpoint 
Endpoint 
Raw p-
value 
Adjusted p-
value 
1 
Lumbar spine BMD percent change from Baseline 
at 6 months 
p1 
p1 
2 
Total hip BMD percent change from Baseline at 6 
months 
p2 
Max (p1, p2) 
3 
Femoral neck BMD percent change from Baseline 
at 6 months 
p3 
Max (p1, p2, p3) 
 
 
 
 
 
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13.3 
Fracture Risk Assessment Tool: 10-year Probability of Major 
Osteoporotic Fracture (FRAX) 
 
FRAX is a computer-based algorithm (http://www.shef.ac.uk/FRAX) that provides 
country/ethnicity-specific models for the assessment of fracture probability in men and women 
[Kanis et al, 2008a, b].  The approach uses clinical risk factors to estimate 10-year probability of 
a major osteoporotic fracture (hip, clinical spine, forearm or humerus) or of a hip fracture alone.  
The estimate of probability can be calculated with clinical risk factors alone, or additionally with 
baseline femoral neck BMD.  The clinical risk factors used for the calculation include sex, age, 
BMI, a historical fragility fracture, parental history of hip fracture, current tobacco smoking, ever 
long-term use of oral glucocorticoids, rheumatoid arthritis, other causes of secondary 
osteoporosis, and daily alcohol consumption of 3 or more units daily. 
 
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13.4 
Multiple Imputations for BMD endpoints 
First, a repeated measures Gaussian model will be fitted to the data using a Bayesian approach, 
with non-informative priors for the mean and variance-covariance matrix to provide a joint 
posterior for the parameters in this model.  The repeated measures Gaussian model will include 
separate mean profiles for each treatment group and the same covariates as those in the primary 
ANCOVA analysis.  
Independent samples will then be drawn from the posterior distributions for the mean and variance-
covariance matrix to provide inputs into an imputation model.  For each subject with missing data, 
these sampled values of the parameters for mean vectors and the variance-covariance matrices 
specify a joint distribution for their observed and unobserved outcome data. 
Missing post-baseline BMD will be modelled under missing at random assumption. The 
ANCOVA model as in primary analysis will include fixed effects for treatment (two levels), 
Baseline BMD value, machine type at baseline, region, age strata group (stratification factor), and 
interaction of Baseline BMD value and machine type at baseline as independent variables. 
The MI-MAR method will be applied as follows based on raw values: 
• 
Step 1: Any observation after date of ICEs will be set to missing. 
• Step 2: Create a dataset, one for each treatment group, of study participants with observed 
values and those needing estimation by multiple imputation. For the imputation step, missing 
values will include non-monotone missing values (ie, intermittent missing values between 
completed assessments) and monotone missing values (ie, where all study participant data is 
missing after a given time point).  
− Step 2a: First, the intermittent missing values in each dataset will be imputed using the 
MCMC method with multiple chains, monotone missing data imputing pattern, and non-
informative priors for all parameters. Unless specified differently, the first 200 iterations 
will not be used (the ‘burn-in’ option). A total of 100 sets of imputations will be 
performed. The seed used for these imputations will be 2022 and all other multiple 
imputation procedures described in this SAP will use this same seed as well.  
The resulting 100 imputed data sets will have a monotone missing data pattern and will be 
imputed using a method for monotone missingness: 
− Step 2b: For monotone missing data, monotone regression will be used to impute missing 
data. A separate regression model is estimated for each variable with missing values (ie, 
measurement at each time point). Based on the resulting model, a new regression model 
is then drawn and is used to impute the missing values for the variable. Since the data set 
has a monotone missing data pattern, the process is repeated sequentially for variables 
with missing values. The procedure will be based on the 100 imputed datasets generated 
from the MCMC procedure and will be performed by Imputation.  
− Step 2c: If an imputed value falls outside of the pre-defined range of values for the given 
variable, the value will be truncated to be within the predefined range of values for the 
endpoint of interest. 
The SAS® PROC MI procedure will be used for the imputation. 
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The visits to include in the MCMC and monotone regression steps will be the same, and will 
correspond to all data available at the time of the analysis, as specified below: 
- 
For dry-runs conducted prior to the Month 6 analysis, all weeks up to Month 6 will be 
included, 
- 
For the Month 6 analysis, all weeks up to Month 6 will be included, 
- 
For the final analysis, all weeks up to Month 12 will be included. 
The stratification factors (age strata group) may be dropped from the imputation model to 
facilitate model convergence if required (and this holds true for all imputation models). The post-
Baseline values will need to be specified in chronological order in the imputation model so that 
the SAS® PROC MI imputes variables from left to right (ie, the Month 6 value will be first 
imputed using regression based on Month 3, and then the Month 12 value will be imputed using 
regression based on Month 3 and Month 6 values, etc.).  
The resulting datasets for each treatment arm will be combined into one complete dataset based 
on each of the 100 imputations (containing 100 times the number of study participants analyzed).  
The imputation model based on the MCMC method for intermittent missing values will only 
allow multivariate normal variables. Therefore, region which has 3 levels will be re-coded as 
indicator variable: 
One indicator variable (region1) will be defined as 0 for regions other than North and 1 for 
North. Two more indicator variables (region2 and region3) will be defined similarly replacing 
North with Eastern and South respectively. In the VAR statement of the imputation model, the 
indicator variables will be ordered as follows: region1 region2 and region3. In the eventuality 
that two regions required to be pooled due to a low percentage of study participants randomized 
in one region, the indicator variables defined above will be revised accordingly. 
− One indicator variable will be defined for the age stratification variable: will be coded as 
1 for <75 years and 0 for ≥75 years.  
− One indicator variable will be defined for the machine type at baseline variable: will be 
coded as 1 for Hologic and 0 for Lunar. 
To maintain consistency with the MCMC method for intermittent missing values, these indicator 
variables will also be used in the monotone regression step for monotone missing values and 
treated as continuous variables. 
• Step 3, the 100 imputed datasets from Step 2 will be combined, and simple means and 
standard errors will be calculated using Rubin’s rules (via SAS® PROC MIANALYZE). For 
calculation of other descriptive statistics (median, minimum and maximum), Rubin’s rules do 
not apply. Multiple imputation estimates will be computed by calculating arithmetic means 
of the estimates from the multiple repetitions of the imputation algorithm. Thus, for median, 
minimum and maximum the following approach will apply: 
− The data will be summarized by treatment, visit and imputation and the summary 
statistics will be computed.  
− Results will be summarized by taking the mean value of each summary statistic at each 
visit across all imputations.  
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− The number of decimal places will remain the same as the original for display purposes 
(ie, if the mean was presented to 1 decimal place, the mean of the means will also be 
presented to 1 decimal place). 
In Step 3, the analysis will be done on the percentage change from Baseline, and the model 
will be an ANCOVA model with treatment group and the same covariates as those in the 
primary ANCOVA analysis.  
In Step 5, the results obtained from the 100 ANCOVA analyses in Step 4 (ie, the Least Square 
Means for the treatment difference and the 95% CI for the contrasts) will be combined with 
Rubin’s rules. Pseudo SAS codes for the sensitivity ANCOVA model of the endpoint as follows: 
/******** for intermittent missing values *********/ 
PROC MI data=xxx NIMPUTE = 100 seed=xxx NOPRINT OUT=xxxx min=0 max=1; 
 BY trtp; 
 VAR type agegp region1 region2 base aval_m3 aval_m6 ;  
 MCMC CHAIN=multiple IMPUTE = monotone; 
run; 
/******** for monotone missing values **********/ 
proc mi data=xxx seed=xxx nimpute=1 NOPRINT out=xxxx; 
var agegp trtp region machinetype base aval_m3 aval_m6; 
class agegp trtp region machinetype; 
MONOTONE REGRESSION; 
BY _imputation_; 
run; 
 
PROC MIXED DATA=xxx; 
            BY _imputation_; 
            CLASS trtp type region agegp; 
            MODEL pchg=base trtp type agegp region base*type; 
            LSMEANS trtp / om cl stderr pdiff ; 
 
   ods output LSMeans=LMS Diffs=DIFF;  
RUN; 
 
*** MIANALYZE; 
proc sort data=DIFF; by _imputation_ ; run; 
 
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proc mianalyze data= DIFF; 
modeleffects estimate; 
stderr stderr; 
ods output ParameterEstimates=MIAN_lsdiffs; 
run; 
 
proc sort data=lsm; by trtp _imputation_ ; run; 
 
proc mianalyze data=lsm; 
by trtp; 
modeleffects estimate; 
stderr stderr; 
ods output ParameterEstimates=MIAN_lsm; 
run; 
 
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13.5 
Adverse Event of Interest 
 
MedDRA Version 24.1 
 
• Hypocalcemia (PTs) – Based on agreed Risk Management Plan search strategy 
 
Adjusted calcium decreased 
Blood calcium decreased 
Calcium deficiency 
Calcium ionised decreased 
Chvostek's sign 
Hypocalcaemia 
Hypocalcaemic seizure 
Trousseau's sign 
 
 
• Injection Site reaction (PTs) 
 
Administration site abscess 
Administration site pallor 
Injection site injury 
Administration site abscess 
sterile 
Administration site papule 
Injection site irritation 
Administration site anaesthesia 
Administration site 
paraesthesia 
Injection site ischaemia 
Administration site atrophy 
Administration site phlebitis 
Injection site joint discomfort 
Administration site bruise 
Administration site 
photosensitivity reaction 
Injection site joint effusion 
Administration site 
calcification 
Administration site plaque 
Injection site joint erythema 
Administration site cellulitis 
Administration site pruritus 
Injection site joint infection 
Administration site coldness 
Administration site pustule 
Injection site joint inflammation 
Administration site cyst 
Administration site rash 
Injection site joint movement 
impairment 
Administration site dermatitis 
Administration site reaction 
Injection site joint pain 
Administration site discharge 
Administration site reaction 
neonatal 
Injection site joint swelling 
Administration site 
discolouration 
Administration site recall 
reaction 
Injection site joint warmth 
Administration site discomfort 
Administration site scab 
Injection site laceration 
Administration site dryness 
Administration site scar 
Injection site lymphadenopathy 
Administration site 
dysaesthesia 
Administration site streaking 
Injection site macule 
Administration site eczema 
Administration site swelling 
Injection site mass 
Administration site erosion 
Administration site thrombosis 
Injection site movement 
impairment 
Administration site erythema 
Administration site ulcer 
Injection site necrosis 
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Administration site exfoliation 
Administration site urticaria 
Injection site nerve damage 
Administration site 
extravasation 
Administration site vasculitis 
Injection site nodule 
Administration site fibrosis 
Administration site vesicles 
Injection site oedema 
Administration site granuloma 
Embolia cutis medicamentosa 
Injection site pain 
Administration site haematoma Injected limb mobility 
decreased 
Injection site abscess 
Injection site pallor 
Administration site 
haemorrhage 
Injection site abscess sterile 
Injection site papule 
Administration site 
hyperaesthesia 
Injection site anaesthesia 
Injection site paraesthesia 
Administration site 
hypersensitivity 
Injection site atrophy 
Injection site phlebitis 
Administration site 
hypertrichosis 
Injection site bruising 
Injection site photosensitivity 
reaction 
Administration site 
hypertrophy 
Injection site calcification 
Injection site plaque 
Administration site 
hypoaesthesia 
Injection site cellulitis 
Injection site pruritus 
Administration site indentation 
Injection site coldness 
Injection site pustule 
Administration site induration 
Injection site cyst 
Injection site rash 
Administration site infection 
Injection site deformation 
Injection site reaction 
Administration site 
inflammation 
Injection site dermatitis 
Injection site recall reaction 
Administration site injury 
Injection site discharge 
Injection site scab 
Administration site irritation 
Injection site discolouration 
Injection site scar 
Administration site ischaemia 
Injection site discomfort 
Injection site streaking 
Administration site joint 
discomfort 
Injection site dryness 
Injection site swelling 
Administration site joint 
effusion 
Injection site dysaesthesia 
Injection site telangiectasia 
Administration site joint 
erythema 
Injection site eczema 
Injection site thrombosis 
Administration site joint 
infection 
Injection site erosion 
Injection site ulcer 
Administration site joint 
inflammation 
Injection site erythema 
Injection site urticaria 
Administration site joint 
movement impairment 
Injection site exfoliation 
Injection site vasculitis 
Administration site joint pain 
Injection site extravasation 
Injection site vesicles 
Administration site joint 
warmth 
Injection site fibrosis 
Injection site warmth 
Administration site laceration 
Injection site haematoma 
Malabsorption from injection 
site 
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Administration site 
lymphadenopathy 
Injection site haemorrhage 
 
Administration site macule 
Injection site hyperaesthesia 
 
Administration site mass 
Injection site hypersensitivity 
 
Administration site movement 
impairment 
Injection site hypertrichosis 
 
Administration site necrosis 
Injection site hypertrophy 
 
Administration site nerve 
damage 
Injection site hypoaesthesia 
 
Administration site nodule 
Injection site indentation 
 
Administration site odour 
Injection site induration 
 
Administration site oedema 
Injection site infection 
 
Administration site pain 
Injection site inflammation 
 
 
 
• Hyperostosis (PTs) -  
 
Acquired foramen magnum stenosis 
Foramen magnum stenosis 
Acral overgrowth 
High turnover osteopathy  
Bone formation increased 
Intracranial pressure increased 
Cervical spinal stenosis 
Lumbar spinal stenosis 
Diffuse idiopathic skeletal hyperostosis 
Macrogenia 
Enostosis 
Melorheostosis 
Exostosis 
Periostosis 
Exostosis of external ear canal 
Vertebral foraminal stenosis 
Exostosis of jaw 
Vertebral lateral recess stenosis 
Extraskeletal ossification 
 
 
 
• Osteoarthritis (PTs) -  
 
Ankle arthroplasty  
Nodal osteoarthritis 
Arthritis  
Osteoarthritis 
Arthropathy 
Osteoarthropathy 
Exostosis 
Polyarthritis 
Facet joint syndrome 
Rapidly progressive osteoarthritis 
Hip arthroplasty 
Shoulder arthroplasty  
Interspinous osteoarthritis 
Spinal osteoarthritis 
Joint arthroplasty 
Vertebral osteophyte 
Knee arthroplasty 
 
 
 
 
 
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13.6 
Adverse Event of Special Interest (PDILI) 
 
AESI are defined by the PTs for the PDILI SMQ. 
 
Acquired antithrombin III deficiency 
Acquired factor IX deficiency 
Acquired factor V deficiency 
Acquired factor VIII deficiency 
Acquired factor XI deficiency 
Acquired hepatocerebral degeneration 
Acquired protein S deficiency 
Acute graft versus host disease in liver 
Acute hepatic failure 
Acute on chronic liver failure 
Acute yellow liver atrophy 
Alanine aminotransferase abnormal 
Alanine aminotransferase increased 
Allergic hepatitis 
Alloimmune hepatitis 
Ammonia abnormal 
Ammonia increased 
Anti factor X activity abnormal 
Anti factor X activity decreased 
Anti factor X activity increased 
Antithrombin III decreased 
Ascites 
Aspartate aminotransferase abnormal 
Aspartate aminotransferase increased 
AST/ALT ratio abnormal 
Asterixis 
Autoimmune hepatitis 
Bacterascites 
Bile output abnormal 
Bile output decreased 
Biliary ascites 
Biliary cirrhosis 
Biliary fibrosis 
Bilirubin conjugated abnormal 
Bilirubin conjugated increased 
Bilirubin excretion disorder 
Bilirubin urine present 
Biopsy liver abnormal 
Blood bilirubin abnormal 
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Blood bilirubin increased 
Blood bilirubin unconjugated increased 
Blood fibrinogen abnormal 
Blood fibrinogen decreased 
Blood thrombin abnormal 
Blood thrombin decreased 
Blood thromboplastin abnormal 
Blood thromboplastin decreased 
Bromosulphthalein test abnormal 
Cardiohepatic syndrome 
Child-Pugh-Turcotte score abnormal 
Child-Pugh-Turcotte score increased 
Cholaemia 
Cholestasis 
Cholestatic liver injury 
Cholestatic pruritus 
Chronic graft versus host disease in liver 
Chronic hepatic failure 
Chronic hepatitis 
Coagulation factor decreased 
Coagulation factor IX level abnormal 
Coagulation factor IX level decreased 
Coagulation factor V level abnormal 
Coagulation factor V level decreased 
Coagulation factor VII level abnormal 
Coagulation factor VII level decreased 
Coagulation factor X level abnormal 
Coagulation factor X level decreased 
Coma hepatic 
Computerised tomogram liver abnormal 
Congestive hepatopathy 
Cryptogenic cirrhosis 
Diabetic hepatopathy 
Drug-induced liver injury 
Duodenal varices 
Flood syndrome 
Foetor hepaticus 
Galactose elimination capacity test abnormal 
Galactose elimination capacity test decreased 
Gallbladder varices 
Gamma-glutamyltransferase abnormal 
Gamma-glutamyltransferase increased 
Gastric variceal injection 
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Gastric variceal ligation 
Gastric varices 
Gastric varices haemorrhage 
Gastrooesophageal variceal haemorrhage prophylaxis 
Graft versus host disease in liver 
Guanase increased 
Hepaplastin abnormal 
Hepaplastin decreased 
Hepatectomy 
Hepatic artery flow decreased 
Hepatic atrophy 
Hepatic calcification 
Hepatic cirrhosis 
Hepatic cytolysis 
Hepatic encephalopathy 
Hepatic encephalopathy prophylaxis 
Hepatic enzyme abnormal 
Hepatic enzyme decreased 
Hepatic enzyme increased 
Hepatic failure 
Hepatic fibrosis 
Hepatic function abnormal 
Hepatic hydrothorax 
Hepatic hypertrophy 
Hepatic hypoperfusion 
Hepatic infiltration eosinophilic 
Hepatic lesion 
Hepatic mass 
Hepatic necrosis 
Hepatic pain 
Hepatic sequestration 
Hepatic steato-fibrosis 
Hepatic steatosis 
Hepatic vascular resistance increased 
Hepatic venous pressure gradient abnormal 
Hepatic venous pressure gradient increased 
Hepatitis 
Hepatitis acute 
Hepatitis cholestatic 
Hepatitis chronic active 
Hepatitis chronic persistent 
Hepatitis fulminant 
Hepatitis toxic 
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Hepatobiliary disease 
Hepatobiliary scan abnormal 
Hepatocellular foamy cell syndrome 
Hepatocellular injury 
Hepatomegaly 
Hepatopulmonary syndrome 
Hepatorenal failure 
Hepatorenal syndrome 
Hepatosplenomegaly 
Hepatotoxicity 
Hyperammonaemia 
Hyperbilirubinaemia 
Hypercholia 
Hyperfibrinolysis 
Hypertransaminasaemia 
Hypocoagulable state 
Hypofibrinogenaemia 
Hypoprothrombinaemia 
Hypothrombinaemia 
Hypothromboplastinaemia 
Icterus index increased 
Immune-mediated cholangitis 
Immune-mediated hepatic disorder 
Immune-mediated hepatitis 
International normalised ratio abnormal 
International normalised ratio increased 
Intestinal varices 
Intestinal varices haemorrhage 
Ischaemic hepatitis 
Jaundice 
Jaundice cholestatic 
Jaundice hepatocellular 
Kayser-Fleischer ring 
Liver dialysis 
Liver disorder 
Liver function test abnormal 
Liver function test decreased 
Liver function test increased 
Liver induration 
Liver injury 
Liver operation 
Liver palpable 
Liver scan abnormal 
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Liver tenderness 
Liver transplant 
Lupoid hepatic cirrhosis 
Lupus hepatitis 
Magnetic resonance imaging hepatobiliary abnormal 
Magnetic resonance proton density fat fraction measurement 
Mitochondrial aspartate aminotransferase increased 
Mixed liver injury 
Molar ratio of total branched-chain amino acid to tyrosine 
Nodular regenerative hyperplasia 
Nonalcoholic fatty liver disease 
Non-alcoholic steatohepatitis 
Non-cirrhotic portal hypertension 
Ocular icterus 
Oedema due to hepatic disease 
Oesophageal varices haemorrhage 
Parenteral nutrition associated liver disease 
Perihepatic discomfort 
Peripancreatic varices 
Portal fibrosis 
Portal hypertension 
Portal hypertensive colopathy 
Portal hypertensive enteropathy 
Portal hypertensive gastropathy 
Portal vein cavernous transformation 
Portal vein dilatation 
Portopulmonary hypertension 
Primary biliary cholangitis 
Protein C decreased 
Protein S abnormal 
Protein S decreased 
Prothrombin level abnormal 
Prothrombin level decreased 
Prothrombin time abnormal 
Prothrombin time prolonged 
Prothrombin time ratio abnormal 
Prothrombin time ratio increased 
Radiation hepatitis 
Regenerative siderotic hepatic nodule 
Renal and liver transplant 
Retrograde portal vein flow 
Reye's syndrome 
Reynold's syndrome 
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Splenic varices 
Splenic varices haemorrhage 
Spontaneous bacterial peritonitis 
Steatohepatitis 
Subacute hepatic failure 
Sugiura procedure 
Thrombin time abnormal 
Thrombin time prolonged 
Total bile acids increased 
Transaminases abnormal 
Transaminases increased 
Ultrasound liver abnormal 
Urine bilirubin increased 
Varices oesophageal 
Varicose veins of abdominal wall 
White nipple sign 
X-ray hepatobiliary abnormal 
 
13.7 
Lipid-Type of Adverse Event 
 
Lipid-type AEs are defined by the PTs for the dyslipidaemia SMQ. 
 
Acquired lipoatrophic diabetes 
Acquired mixed hyperlipidaemia 
Apolipoprotein B/Apolipoprotein A-1 ratio increased 
Autoimmune hyperlipidaemia 
Blood cholesterol abnormal 
Blood cholesterol decreased 
Blood cholesterol esterase increased 
Blood cholesterol increased 
Blood triglycerides abnormal 
Blood triglycerides decreased 
Blood triglycerides increased 
Diabetic dyslipidaemia 
Dyslipidaemia 
Familial high density lipoprotein deficiency 
Familial hypertriglyceridaemia 
Fat overload syndrome 
High density lipoprotein abnormal 
High density lipoprotein decreased 
High density lipoprotein increased 
Hypercholesterolaemia 
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Hyperlipidaemia 
Hypertriglyceridaemia 
Hypo HDL cholesterolaemia 
Hypotriglyceridaemia 
Intermediate density lipoprotein decreased 
Intermediate density lipoprotein increased 
LDL/HDL ratio decreased 
LDL/HDL ratio increased 
Lecithin-cholesterol acyltransferase deficiency 
Lipid metabolism disorder 
Lipids abnormal 
Lipids decreased 
Lipids increased 
Lipoprotein (a) abnormal 
Lipoprotein (a) decreased 
Lipoprotein (a) increased 
Lipoprotein abnormal 
Lipoprotein increased 
Lipoprotein metabolism disorder 
Low density lipoprotein abnormal 
Low density lipoprotein decreased 
Low density lipoprotein increased 
Metabolic syndrome 
Non-high-density lipoprotein cholesterol decreased 
Non-high-density lipoprotein cholesterol increased 
Primary hypercholesterolaemia 
Remnant hyperlipidaemia 
Remnant-like lipoprotein particles increased 
Total cholesterol/HDL ratio abnormal 
Total cholesterol/HDL ratio decreased 
Total cholesterol/HDL ratio increased 
Type I hyperlipidaemia 
Type II hyperlipidaemia 
Type IIa hyperlipidaemia 
Type IIb hyperlipidaemia 
Type III hyperlipidaemia 
Type IV hyperlipidaemia 
Type V hyperlipidaemia 
Very low density lipoprotein abnormal 
Very low density lipoprotein decreased 
Very low density lipoprotein increased 
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13.8 
Immunogenicity Analysis 
 
 ADA analysis: subject classification, incidence, time of onset and time profiles 
Anti-romosozumab antibodies (ADA) will be measured using a three-tiered assay approach: screening 
assay, confirmatory assay and titration assay.  
Samples will first be evaluated in the screening assay using a false positivity rate of 5% (reported as 
‘negative screen’ or ‘positive screen’), followed by analysis of screened positive samples in the 
confirmatory assay (which is a drug depletion assay) to confirm the true positivity of the samples (reported 
as ‘negative immunodepletion’ or ‘positive immunodepletion’). Samples that are confirmed as positive will 
be evaluated in a titration assay to quantify the ADA level and will be reported as titer (reciprocal dilution 
factor including minimum required dilution).  
 
Confirmed positive ADA samples will be subjected to an in vitro neutralizing antibody (NAb) assay. 
Placebo samples will not be analysed for ADA. The summaries and figures will be done for the 
following analyses: 
 
 
The ADA status should be determined for each visit where samples were taken for ADA 
analysis. 
• Sample values that are either ‘negative screen’ or ‘positive screen’ and ‘negative 
immunodepletion’ will be defined as ADA negative 
• Sample values that are ‘positive screen’ and ‘positive immunodepletion’ will be defined as 
ADA positive 
In addition, the anti-drug antibody status will be further classified based on subject levels as 
outlined below. This classification should be done for entire study duration (i.e. the treatment 
period including SFU sampling time point). 
1. Pre ADA negative – treatment induced ADA negative: Includes study participants who are 
negative at Baseline and antibody negative at all sampling points post treatment. This group 
also includes study participants who have a missing pre-treatment sample (either missing or 
insufficient volume) at Baseline with all ADA post-treatment samples negative. 
2. Pre ADA negative – treatment induced ADA positive: Includes study participants who are 
negative at Baseline and antibody positive at any sampling point post treatment. This group 
also includes study participants who have a missing pre-treatment sample (either missing or 
insufficient volume) at Baseline with one or more ADA positive post-treatment samples. 
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3. Pre ADA positive – treatment reduced ADA: Includes study participants who are positive 
at Baseline, and antibody negative at all sampling points post treatment  
4. Pre ADA positive – treatment unaffected ADA: Includes study participants who are 
positive at Baseline and are positive at any sampling point post treatment with titer values of 
the same magnitude as Baseline (ie, less than a predefined fold difference increase from the 
Baseline value, i.e. the minimum significant ratio (MSR) determined during assay 
validation). 
5. Pre ADA positive – treatment boosted ADA positive: Includes study participants who are 
positive at Baseline and are positive at any sampling point post treatment with increased titer 
values compared to Baseline (greater than a predefined fold difference increase from 
Baseline value , i.e. the minimum significant ratio (MSR) determined during assay 
validation). 
6. Inconclusive: Includes study participants who have a positive or negative pre-treatment 
sample and some post-treatment samples are missing, while other post-treatment samples are 
ADA negative. 
The fold difference increase (i.e. the minimum significant ratio (MSR) determined during assay 
validation) from baseline needed to consider a titer value reported post-treatment to be above the 
assay variation will be noted in the relevant tables, listings and figures. 
 
Based on the overall ADA subject classification above, the following will be determined and 
presented: 
o Total prevalence of pre-Ab : n/N % number of subjects that are preADA positive. 
o Total incidence of treatment-emergent ADA positive : n/N % number of subjects 
in category 2 and category 5 
In the case that a sample is collected one or more days following the scheduled visit date in 
which the drug was administered, the ADA results for that sample will be associated with the 
scheduled visit and summarized accordingly. Such samples will also be considered when ADA 
results are summarized over a given study period.  
The following summaries, figures and listings will be produced and will be presented using the 
SS.  
• 
Summary table displaying the number and percentage of study participants with a positive 
ADA status at the time of each visit by treatment group.  
• Summary tables displaying the number and percentage of study participant in each of the 
ADA subject categories as defined above by treatment group.  Total treatment emergent 
ADA positive and Pre ADA positive will be summarized with numbers and percentage 
• Summary tables (per treatment group) of the time point of the first occurrence of treatment 
emergent ADA positivity. This summary will include the following categories: 
− Category 2: Pre ADA negative – treatment induced ADA positive 
− Category 5: Pre ADA positive – treatment boosted ADA positive (ie. here the MSR need 
to be taken into account) 
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The table will summarize the number and percentage of subjects who are either treatment 
induced ADA positive or treatment boosted ADA positive for the first time at the specified 
time point and will include the cumulative number and percentage of subjects having an 
occurrence of treatment emergent ADA positive results at each time point. 
• The time to achieving treatment-emergent ADA positivity, separated by treatment group and 
ADA subject category as defined above, will be analyzed based on Kaplan-Meier methods. 
Subjects will be considered to have an event at the time point at which treatment-emergent 
ADA positivity is first achieved. This plot will include the following categories: 
− 4,5 2: Pre ADA negative – treatment induced ADA positive 
− Category 5: Pre ADA positive – treatment boosted ADA positive (this category will be 
included only in the event that >5% of subjects in either treatment group are classified as 
Category 5) 
• A box-plot of the ADA titer over time will be created per ADA subject category for:  
 Category 2: Pre ADA negative – treatment induced ADA positive 
 Category 4: pre ADA positive – treatment unaffected ADA positive 
 Category 5: pre ADA positive- treatment boosted ADA positive 
The ADA incidence will be indicated on the graph per time point with the numerator: number 
of ADA positive samples at that sampling time point and denominator: total subjects of SS. 
The ADA titer results will be presented on the log-scale.  
• Spaghetti plots of ADA titer (y-axis) by visit (x-axis),. This plot will include the following 
ADA subject categories: 
− Category 2: Pre ADA negative – treatment-induced ADA positive 
− Category 5: Pre ADA positive – treatment-boosted ADA positive 
− Category 4: Pre ADA positive – treatment unaffected ADA positive  
All categories will be presented on the same plot (visualized using different colors). Plots 
will be presented using a semi-logarithmic scale for the ADA titers (ADA negative samples 
will therefore be excluded from the plot). 
 
NAb analysis 
Positive ADA samples will be evaluated in a Nab assay and subjects will be classified as Nab 
positive or negative. 
• NAb negative: no NAb positive samples at baseline or post-baseline 
• NAb positive: one or more positive samples at baseline or post-baseline 
• Missing: relevant NAb samples are missing, e.g. if subject had samples selected for NAb 
testing based on their ADA levels, but there was insufficient sample left for NAb testing. 
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Summary table of the incidence of NAb, defined as (cumulative) proportion of subjects having 
NAb positive samples at any point up to and including that time point will be summarized 
Missing samples will not be included in the denominator.  
 
Correlation of ADA and/or NAb with changed PK, PD and/or efficacy 
• Individual plots of romosozumab plasma concentration ADA titer and the percent change from 
baseline in BMD of the lumbar spine. Each time, all three endpoints will be plotted on the Y-
axes by visit (x-axis) for the full treatment period with indication of dosing time points 
(indication if dosing was missed), including SFU. Plots should be labeled and grouped into the 
pre-defined ADA subject categories as defined above. The individual plots are to be done only 
for categories 2 and 5. 
• A summary of percent change from baseline in BMD of the lumbar spine versus time will be 
presented graphically including the following ADA categories (2 lines per plot). 
− Total treatment-emergent ADA positive (Category 2 and Category 5) 
− All other categories  
The figure will be repeated per treatment group including placebo.  
• Finally, all individual study participant-level ADA results will be listed including the results 
from the screening assay, confirmatory assay, and titers if applicable both  and the NAb 
results,  the ADA status, ADA subject classification and the NAb status. 
 
Evaluation relationship of ADA and NAb with immune related TEAE  
• A summary table of all immune related TEAEs by ADA Status. For this summary, 
subjects will be categorized by the overall ADA subject classification and will be 
presented for immune related TEAEs occurring prior to becoming treatment emergent 
ADA positive, TEAEs occurring after becoming TE ADA positive, and TEAEs for 
subjects who remained TE ADA negative.  
• Comparable summary table of all immune related TEAEs by NAb Status 
 
 
 
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13.9 
Region and Site Information 
 
Region 
Site Name 
Site Identifier 
East 
 
Shanghai Sixth People's Hospital 
 
Huadong Hospital Affiliated to 
Fudan University 
 
The Second Affiliated Hospital of 
Soochow University  
 
Shanghai First People's Hospital 
 
Shanghai Ninth People's Hospital 
 
Tongji University - Tongji Hospital 
 
Nanjing Drum Tower Hospital 
 
Zhejiang Rui'an People's Hospital - 
Gynecology 
 
Pingxiang People's Hospital 
 
The First Affiliated Hospital of 
Soochow University 
 
Jiangxi Provincial People's Hospital 
North 
 
Beijing Hospital 
Peking Union Medical College 
Hospital 
Tianjin Hospital 
Beijing Tsinghua Chang Gung 
Hospital - Endocrinology 
Beijing Luhe Hospital Capital 
Medical University 
Peking University First Hospital 
Beijing Pinggu District Hospital 
Beijing Jishuitan Hospital 
The First Affiliated of Zhengzhou 
University 
Tianjin Medical University General 
Hospital - Endocrinology 
 
Peking University Third Hospital 
South 
 
West China Hospital of Sichuan 
University 
Guangdong Provincial People's 
Hospital 
Union Hospital affiliated to Tongji 
Medical College of Huazhong 
University of Science and 
Technology  
The First Affiliated Hospital of Jinan 
University 
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Sichuan Provincial People’s 
Hospital - Endocrinology 
Yueyang Central Hospital 
West China Hospital of Sichuan 
University - Orthopedics 
Shunde Hospital of Southern 
Medical Univesity 
 
 
 
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13.10 
Statistical Analysis Plan Amendment 1 
Rationale for the amendment 
The major purpose of this amendment was to align with the protocol amendment 2 dated on Jan-
14-2020 to be sure the consistency between SAP and protocol. 
The following updates have been made in protocol which impact the SAP: 
• The serum trough concentrations normalized by body weight is unnecessary and removed 
from protocol 
• Stratification by prevalent vertebral fracture no longer necessary due to the new inclusion 
criterion #5. 
• Subjects has history of myocardial infarction or history of stroke were included as exclusion 
criteria (#4 and #5). 
Modifications and changes 
• The serum trough concentrations normalized by body weight was removed 
• Stratification by prevalent vertebral fracture was removed. 
• Center pooling strategy was added. 
• Rescue medication is replaced by prohibited and/or alternative osteoporosis therapy (licensed 
drugs only) 
• EudraCT age and Clinicaltrials.gov age categories were added.  
• 10 year probability of major osteoporotic and hip fractures based on WHO risk factor criteria 
calculated with femoral neck BMD T-score was added. 
• Treatment compliance was defined for double-blind and open-label period. 
• Classification of collection of cardiovascular risk factors. 
• Mixed effects model with repeated measures model (MMRM) was added. 
• Multiple imputation methods for BMD endpoints was added. 
Specific Changes 
SAP Section(s) 
impacted 
Previous SAP text 
Key components of revised SAP text 
2.3.2.1 
 
The other PK variables are serum 
trough concentrations of 
romosozumab and normalized 
serum trough concentrations by 
BW at Day 1 (baseline) and at 
Months 1, 3, and 6. 
The other PK variables are serum trough 
concentrations of romosozumab at Day 1 
(baseline) and at Months 1, 3, and 6. 
2.4.2.1 
 
• Serum trough concentrations of 
romosozumab and normalized 
serum trough concentrations by 
BW at Months 7, 9, and 12 in 
• Serum trough concentrations of 
romosozumab at Months 7, 9, and 12 in 
subjects who are continuing with 6 
months of romosozumab treatment 
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SAP Section(s) 
impacted 
Previous SAP text 
Key components of revised SAP text 
subjects who are continuing 
with 6 months of romosozumab 
treatment after initially being 
randomized to 6 months of 
romosozumab in the DBPC 
Period (a total of 12 months of 
romosozumab treatment). 
• Serum trough concentrations of 
romosozumab and normalized 
serum trough concentrations by 
BW at Months 7, 9, and 12 (1, 
3, and 6 months of 
romosozumab exposure, 
respectively) in subjects who 
are initially randomized to 
placebo in the DBPC Period and 
transition to romosozumab 
treatment for 6 months 
after initially being randomized to 6 
months of romosozumab in the DBPC 
Period (a total of 12 months of 
romosozumab treatment). 
• Serum trough concentrations of 
romosozumab at Months 7, 9, and 12 
(1, 3, and 6 months of romosozumab 
exposure, respectively) in subjects who 
are initially randomized to placebo in 
the DBPC Period and transition to 
romosozumab treatment for 6 months. 
 
2.5 
In the DBPC Period, after 
screening, approximately 300 
subjects will be randomized, 
stratified by age (<75 years, ≥75 
years) and prevalent vertebral 
fracture (yes, no), in a 2:1 ratio to 
receive either 210mg 
romosozumab subcutaneous (sc) 
treatment every month (QM) (200 
subjects) or matched placebo sc 
QM (100 subjects) in a blinded 
manner for 6 months to evaluate 
if romosozumab treatment for 6 
months, compared with placebo, 
is effective in increasing BMD, as 
assessed by DXA, at the lumbar 
spine, total hip, and femoral neck. 
In the DBPC Period, after screening, 
approximately 300 subjects will be 
randomized, stratified by age (<75 years, 
≥75 years), in a 2:1 ratio to receive either 
210mg romosozumab subcutaneous (sc) 
treatment every month (QM) (200 
subjects) or matched placebo sc QM 
(100 subjects) in a blinded manner for 6 
months to evaluate if romosozumab 
treatment for 6 months, compared with 
placebo, is effective in increasing BMD, 
as assessed by DXA, at the lumbar spine, 
total hip, and femoral neck. 
3.2.3 
For the Baseline assessment 
(excluding DXA), regardless of 
the width of the visit window, if 
there are multiple records within 
a Baseline window, the record 
that is the closest to and prior to 
date of first IMP administration 
will be considered as the Baseline 
value.  For the postbaseline 
assessment, if more than 1 visit 
falls within the defined window, 
the result from the visit closest to 
the target day will be used. If 2 
For the Baseline assessment and 
definition, please refer to section 3.3 for 
details. For the post-baseline assessment, 
if more than 1 visit measurement falls 
within the defined visit window, the 
result from the visit closest to the target 
day will be used for analysis and 
summarization. If 2 evaluations are of 
the same distance from the target day, 
the result from the later visit will be 
used.  Scheduled and unscheduled 
visits/measurements are considered for 
this purpose. 
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SAP Section(s) 
impacted 
Previous SAP text 
Key components of revised SAP text 
evaluations are of the same 
distance from the target day, the 
result from the later visit will be 
used 
3.2.3 
DXA Scans: 
Window definition (Study Day) 
for Baseline: Last evaluation 
prior to or on Study Day 1 
DXA Scans: 
Window definition (Study Day) for 
Baseline change to Last evaluation prior 
to first dose of IMP 
3.3 
For computation of change from 
Baseline BMD endpoints, 
Baseline will be identified as the 
average of all scans obtained on 
or prior to the first dose date. The 
randomization date will be used 
as reference for subjects who did 
not receive any dose of IMP but 
who had non-missing 
observations on study. For 
computation of other change from 
Baseline endpoints, Baseline will 
be identified as the last 
observation prior to the first dose 
of IMP (assuming that any 
observation on the same day as 
the first dose is prior to dosing). 
For computation of change from 
Baseline BMD of lumbar spine endpoint, 
Baseline will be identified as the average 
number of values (averaging is dedicated 
to the duplicate BMD values taken on 
the same day) obtained on or prior to the 
first dose of IMP (assuming that any 
observation on the same day as the first 
dose is prior to dosing, unless evidence 
stated). For computation of change from 
Baseline BMD of femoral neck and total 
hip, also other change from Baseline 
endpoints, the Baseline will be identified 
as the last observation prior to the first 
dose of IMP (assuming that any 
observation on the same day as the first 
dose is prior to dosing, unless evidence 
stated).The randomization date will be 
used as reference for subjects who did 
not receive any dose of IMP but who had 
non-missing observations on study.   
3.4 
 
Add: 
Since the PPS will be used for a 
supportive analysis of the primary 
endpoint which is assessed at Month 6, 
the exclusion from PPS is limited to the 
double-blind period, ie only study 
participants with IPD prior to Month 6 
can be excluded from the PPS. Study 
participants with IPD after Month 6 will 
not be excluded from the PPS, but might 
be excluded from PK-PPS and PD-PPS 
during OLE Period. 
3.7 
Center pooling strategy to define 
regions will be defined once the 
sites are selected. 
 
Center pooling strategy to define regions 
will be defined once the sites are 
selected. 
Based on the clusters of the sites with 
considerations of geographical and 
climate differences, the pooling strategy 
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SAP Section(s) 
impacted 
Previous SAP text 
Key components of revised SAP text 
is ended up with 3 regions: North, East 
and South. The majority of the sites are 
coming from the 3 biggest cities in 
China – Beijing, Shanghai and 
Guangzhou. 
Considering that due to Chinese 
Conference on Biometric Recognition’s 
(CCBR) involvement in Beijing (north 
China) and large number of sites in 
Yangtze Delta sites, these sites will have 
majority of the subjects. To 
counterbalance this dominance, the sites 
in Chengdu with Guangzhou and Hunan 
will be combined to form South China 
giving that Chengdu with Guangzhou 
have similar climate. 
4.2 
In the data evaluation meetings 
(DEM), the following blinded 
overall incidences will be 
monitored: 
• 
Incidence of subjects who 
discontinued IMP 
• 
Incidence of subjects who 
discontinued IMP due to lack of 
efficacy as per eCRF 
• 
Incidence of subjects who 
discontinued IMP due to a BMD 
reduction of 7% from Baseline at 
the total hip and/or lumbar spine 
• 
Incidence of subjects who 
discontinued IMP due to adverse 
events 
• 
Incidence of subjects who 
received prohibited medication 
during ongoing IMP treatment 
• 
Incidence of subjects who 
received prohibited medication 
after early termination of IMP 
• 
Incidence of subjects who 
died 
• 
Incidence of subjects having 
any of the events of the all above 
bullets  
For those sites which show 
abnormalities in comparison to 
the average and exceed 
prespecified margins for the 
In the data evaluation meetings (DEM), 
the following blinded overall incidences 
will be monitored for safety:  
• Incidence of subjects who discontinued 
IMP 
• Incidence of subjects who discontinued 
IMP by reasons   
• Incidence of subjects who discontinued 
IMP due to safety concern as per eCRF  
• Incidence of subjects who received 
prohibited medication during ongoing 
IMP treatment 
• Incidence of subjects who received 
alternative osteoporosis therapy during 
ongoing IMP treatment 
• Incidence of subjects who received 
alternative osteoporosis therapy after 
early termination of IMP 
•Incidence of subjects who died 
For those sites which show strong 
deviations from the average of all sites 
during the DEM, appropriate measures 
such as re-training, following-ups with 
corrective actions etc. would be 
considered. Further analyses including 
time to various discontinuation events 
(Kaplan-Meier plots), events by Baseline 
characteristics and events by efficacy 
endpoints may be conducted to explore 
the cause and impact of the 
discontinuations.   
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above assessments during the 
DEM, appropriate measures such 
as re-training, following-ups with 
corrective actions etc. would be 
considered. Further analyses 
including time to various 
discontinuation events (Kaplan-
Meier plots), events by Baseline 
characteristics and events by 
efficacy endpoints may be 
conducted to explore the cause 
and impact of the 
discontinuations.   
All the missing visit or missing data 
related to COVID-19 will be listed.  
Additional listings will be provided for 
the patients’ assessments with COVID-
19 impact.  Additional summary and 
sensitivity analyses will be provided if 
deems necessary.   
4.6 
 
Add:  
Baseline Vitamin D (< 20 ng/mL, ≥20 
ng/mL and ≤40 ng/mL, > 40 ng/mL) and 
Baseline use of loading dose of vitamin 
D (Yes, No)   
5.1 
The numbers and percentages of 
subjects that were screened, 
randomized, completed, 
prematurely discontinued from 
IMP and withdraw from study, 
reason for premature 
discontinuation from IMP and 
study, and successfully 
completing IMP and study will be 
summarized by the treatment 
groups and study periods 
(through Month 6, through Month 
12 and through Month 15) for the 
ES. The number of subjects who 
completed each visit (as captured 
in the CRF) will also be 
summarized. In addition, the 
number of subjects in each of the 
following analysis sets: RS, SS, 
FAS, PPS, PK-PPS, PD-PPS will 
be summarized as well. 
The numbers and percentages of subjects 
who were screened with screen failure 
reason for the ES. The number of 
subjects who did not meet study 
eligibility criteria will be listed for the 
ES. 
The numbers and percentages of subjects 
that were randomized, completed, 
prematurely discontinued from IMP, 
withdraw from study, reason for 
premature discontinuation from IMP and 
study, and successfully completing IMP 
and study will be summarized by the 
treatment groups and study periods 
(through Month 6, through Month 12 
and through Month 15) for the RS. The 
number of subjects who completed each 
visit (as captured in the CRF) will also 
be summarized. The number of subjects 
who withdrawal due to AE will be 
summarized and listed for the RS. In 
addition, the disposition of subjects into 
treatments groups and analysis sets (RS, 
FAS, SS, and PPS) will also be 
summarized on the RS. Total days on 
study medication is defined as date of 
dose received minus date of first dose 
received + 1. 
6.1 
The categorical demographic 
variables: 
The categorical demographic variables: 
• 
Gender 
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• 
Gender 
• 
Race  
• 
Ethnicity  
• 
Racial subgroup  
• 
Age class (<65, ≥ 65 to <75, 
and ≥75)  
• 
BMI class (<18.5, 18.5 to 
<23, 23 to <27.5, ≥27.5) 
• 
Race  
• 
Ethnicity  
• 
Country 
• 
EudraCT age categories (18-<65, 65 
to <85, and ≥85)  
• 
Clinicaltrials.gov age categories 
(≤18, 19 to <65, and ≥65)  
• 
Age class (<65, ≥ 65 to <75, and 
≥75)  
• 
Age class (<75, ≥75)  
• 
Age strata group from IVRS (<75, 
≥75) 
• 
BMI (kg/m2) (<18.5, 18.5 to <23, 23 
to <27.5, ≥27.5) 
6.2 
• 
BMD T-score at lumbar 
spine, total hip and femoral 
neck  
• 
BMD (g/cm2) by machine 
type (Hologic vs. Lunar) at 
lumbar spine, total hip and 
femoral neck  
• 
bone turnover markers (sCTX 
[ng/L], P1NP [ug/L])  
• 
years since menopause (year) 
• 
laboratory parameters 
[calcium corrected by 
albumin, phosphorus, 
creatinine, serum 25 hydroxy 
(OH) vitamin D level, 
thyroid-stimulating hormone 
(TSH), and intact parathyroid 
hormone (iPTH) Total 
cholesterol, low-density 
Lipoprotein (LDL), high-
density Lipoprotein (HDL), 
triglycerides]   
• 
osteoporosis medication use 
(Yes, No)  
• 
Duration of prior 
osteoporosis medication (<3 
months, 3-6 months, 6-12 
months, >12 months) 
• 
type of osteoporosis 
medication use (eg. Oral 
bisphosphonate, IV 
bisphosphonate, denosumab, 
teriparatide (TPTD), 
• 
BMD T-score at lumbar spine, total 
hip and femoral neck  
• 
BMD T-score categories at lumbar 
spine (≤-3.0, >-3.0 to <-2.5, and ≥ -
2.5), total hip (≤-2.5 and > -2.5) and 
femoral neck (≤-2.5 and > -2.5)    
• 
BMD (g/cm2) by machine type 
(Hologic vs. Lunar) at lumbar spine, 
total hip and femoral neck  
• 
bone turnover markers (sCTX 
[ng/L], P1NP [ug/L])  
• 
years since menopause (year) 
• 
laboratory parameters [calcium 
corrected by albumin, phosphorus, 
creatinine, serum 25 hydroxy (OH) 
vitamin D level, thyroid-stimulating 
hormone (TSH), and intact 
parathyroid hormone (iPTH) Total 
cholesterol, low-density Lipoprotein 
(LDL), high-density Lipoprotein 
(HDL), triglycerides]   
• 
prior osteoporosis medication use 
(Yes, No)  
• 
type of osteoporosis medication use 
(eg. Oral bisphosphonate, IV 
bisphosphonate, denosumab, 
teriparatide (TPTD), parathyroid 
hormone (PTH), calcitonin, 
strontium, fluoride, hormone 
replacement therapy, traditional 
herbal medication, activated vitamin 
D, SERM, vitamin K, other)   
• 
Baseline use of vitamin D (Yes, No)   
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parathyroid hormone (PTH), 
calcitonin, strontium, 
fluoride, hormone 
replacement therapy, 
traditional herbal medication, 
activated vitamin D, SERM, 
vitamin K, other)   
• 
glucocorticoid use (Yes, No)  
• 
Baseline use of vitamin D 
(Yes, No)  
• 
Baseline use of calcium (Yes, 
No)  
• 
parental hip fracture (Yes, 
No, Unknown)   
• 
secondary osteoporosis (Yes, 
No)  
• 
rheumatoid arthritis (Yes, 
No)  
• 
Baseline use of calcium (Yes, No)  
• 
10 year probability of major 
osteoporotic and hip fractures based 
on WHO risk factor criteria (FRAX, 
see in Appendix 13.3) calculated 
with femoral neck BMD T-score 
• 
10 year probability of major 
osteoporotic and hip fractures based 
on WHO risk factor criteria (FRAX) 
calculated without femoral neck 
BMD T-score 
• 
parental hip fracture (Yes, No, 
Unknown)   
• 
glucocorticoid use (Yes, No)  
• 
secondary osteoporosis (Yes, No)   
• 
rheumatoid arthritis (Yes, No)   
• 
smoking (Current, Former, Never) 
• 
alcohol (Current, Former, Never) 
• 
caffeinated beverage use (Current, 
Former, Never) 
6.2.1 
Cardiovascular risk factors 
• 
Age at study entry (years) 
• 
substance use in the past 5 
years including tobacco use 
(never, former, current); 
alcoholic beverages (none, ≤ 
2 per day, ≥ 3 per day); 
caffeinated beverage use 
(Yes, No) 
• 
history of diabetes (type1, 
type2, No) 
• 
history of hypertension (Yes, 
No) 
• 
history of 
hypercholesterolemia (Yes, 
No) 
• 
history of cardiovascular 
disease (Yes, No) 
• 
prior myocardial infarction 
(Yes, No) 
• 
prior Stroke (Yes, No) 
• 
prior MI or Stroke (Yes, No) 
Cardiovascular risk factors 
• 
history of diabetes (type1, type2, 
No) 
• 
history of hypertension (Yes, No) 
• 
history of 
hyperlipidemia/hypercholesterolemia 
(Yes, No) 
• 
history of renal impairment (Yes, 
No) 
• 
history of atherosclerosis (Yes, No) 
• 
prior heart failure (Yes, No) 
• 
prior transient ischaemic attack (Yes, 
No) 
• 
prior angina pectoris (Yes, No) 
• 
other prior cardiovascular ischaemic 
events (Yes, No) 
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6.3 
 
Add: 
• 
number of prevalent vertebral 
fractures (0, 1, 2, ≥3, not 
readable/missing) 
 
Changed incidences of the grade of 
prevalent vertebral fracture (0, 1, 2) to 
“incidences of the grade of prevalent 
vertebral fracture (SQ0, SQ1, SQ2, 
SQ3)”. 
7 
The IMP will be administered at 
the study site by staff trained in 
the injection technique. Date and 
time of IMP administration will 
be recorded in the subject’s 
eCRF.  
Drug accountability must be 
recorded on the Drug 
Accountability form. 
The expected day of 
administration will be based upon 
(1) the Baseline date and (2) the 
previous injection date. The sum 
of the absolute difference in days 
between the actual and expected 
days will be summarized. In 
addition, a ratio of compliance 
will be computed based upon the 
actual and expected days for each 
of the 2 methods. The ratios of 
compliance will also be 
summarized as a continuous 
variable and categorically (<0.80 
and ≥0.80). The general formula 
for the compliance ratio is given 
as follows:   
Compliance Ratio (CR) = 
{[Study Duration (days)] – 
[Cumulative Difference (days)]} 
÷ {Study Duration (days)}  
Compliance will be summarized 
as the number of injections 
received relative to the number of 
The IMP will be administered at the 
study site by staff trained in the injection 
technique. Date and time of IMP 
administration during double-blind 
period and open-label period will be 
recorded in the subject’s eCRF.   
Drug accountability must be recorded on 
the Drug Accountability form. 
The expected day of administration will 
be based upon (1) the  date of first IMP 
administration and (2) the previous 
injection date. The sum of the absolute 
difference in days between the actual and 
expected days will be summarized. In 
addition, a ratio of compliance will be 
computed based upon the actual and 
expected days for each of the 2 methods. 
The ratios of compliance will also be 
summarized as a continuous variable and 
categorically (<0.80 and ≥0.80). The 
general formula for the compliance ratio 
is given as follows for double-blind 
period and open-label period:   
Compliance Ratio (CR) during double-
blind period= {[Study Duration (days) 
during double-blind period] – 
[Cumulative Difference (days) during 
double-blind]} ÷ {Study Duration (days) 
during double-blind period}   
Compliance Ratio (CR) during open-
label period = {[Study Duration (days) 
during open-label period] – [Cumulative 
Difference (days) during open-label 
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injections expected. Percent 
compliance will be calculated as:  
Percent compliance = 100 x 
number of injections received ÷ 
number expected. 
Treatment compliance will be 
presented for SS. 
period]} ÷ {Study Duration (days) 
during open-label period}   
Compliance will be summarized as the 
number of injections received relative to 
the number of injections expected. 
Percent compliance will be calculated as:  
Percent compliance during double-blind 
period = 100 x number of injections 
received during double-blind period ÷ 
number expected during double-blind 
period. 
Percent compliance during open-label 
period = 100 x number of injections 
received during open-label period ÷ 
number expected during open-label 
period. 
8.1.3 
In addition, a repeated 
measurement model will be fit 
with the percent change from 
Baseline at Months 3 and 6 in 
BMD of the lumbar spine as the 
dependent variable, and Baseline 
BMD, machine type at baseline, 
interaction of Baseline BMD and 
machine type at baseline, visit 
(categorical), treatment 
(categorical), interaction of 
treatment and visit, region and 
interaction of treatment and 
region as the independent 
variables. 
In addition, a mixed effects model with 
repeated measures model (MMRM)will 
be fit with the percent change from 
Baseline at Months 3 and 6 in BMD of 
the lumbar spine as the dependent 
variable, and Baseline BMD, machine 
type at baseline, interaction of Baseline 
BMD and machine type at baseline, visit 
(categorical), treatment (categorical), 
interaction of treatment and visit, region 
and interaction of treatment and region 
as the independent variables. The 
MMRM analysis will include subject as 
a random effect, treatment, age strata 
group (stratification factor), region, visit, 
and treatment-by-visit interaction as 
fixed effects, with adjustment for 
baseline BMD value. The variance 
structure will allow for 
heteroskedasticity of variance. The FAS 
will be used for the repeated 
measurement model. 
9 
Missing PK or PD values (either 
Baseline or postbaseline values) 
will not be imputed. 
Measurement values that are 
below the lower limit of 
quantification (LLOQ) will be 
considered equal to the LLOQ/2 
for all analyses. 
Missing PK or PD values (either 
Baseline or postbaseline values) will not 
be imputed. Measurement values that are 
below the lower limit of quantification 
(LLOQ) (BLQ) will be considered equal 
to the LLOQ/2 for all analyses. If more 
than 1/3 of the samples are BLQ at a 
particular visit no summary statistics will 
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be calculated and only minimum and 
maximum values will be reported. 
9.1 
Pharmacokinetic variables will be 
analyzed for all subjects in the 
PK-PPS at both Month 6 and 
final analysis. The serum trough 
concentrations of romosozumab, 
actual values and normalized by 
body weight (BW) will be 
summarized based on the PK-PPS 
using descriptive statistics (n, 
geometric mean, 95% confidence 
intervals, geometric CV%, mean, 
standard deviation, median, 
minimum value, maximum value) 
for the below analyses: 
• Month 1-6 of 
romosozumab/romosozumab 
treatment group at 6-month 
analysis 
• Month 1-12 of 
romosozumab/romosozumab 
treatment group at final analysis 
• Month 1-6 of 
romosozumab/romosozumab 
group pooled with month 6-12 
of placebo/ romosozumab 
treatment group at final analysis 
The serum trough 
concentrations will be 
normalized by BW using below 
formula: 
BW normalized concentration = 
concentration x BW(kg) ÷ 70 
Pharmacokinetic variables will be 
analyzed for all subjects in the PK-PPS 
at both Month 6 and final analysis. The 
serum trough concentrations of 
romosozumab,  and actual values  will be 
summarized based on the PK-PPS using 
descriptive statistics (n, geometric mean, 
95% confidence intervals, geometric 
CV%, mean, standard deviation, median, 
minimum value, maximum value) for the 
below analyses: 
• Month 1-6 of 
romosozumab/romosozumab treatment 
group at 6-month analysis 
• Month 1-12 of 
romosozumab/romosozumab treatment 
group at final analysis 
Month 1-6 of 
romosozumab/romosozumab group 
pooled with month 6-12 of placebo/ 
romosozumab treatment group at final 
analysis 
9.1 
 
Added: 
A population PK analyses will be 
conducted. Details of the analysis will be 
described in a separated data analysis 
plan and results will be reported 
separately. 
10.2 
 
Add: 
The incidence of patient-year will be 
also summarized. 
 
Add the AE summary for 
romosozumab total exposure. 
10.2.1 
The adverse events of interest 
including injection site reactions, 
Subject incidence of adverse events of 
interest of hypocalcemia, injection site 
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Key components of revised SAP text 
events potentially related to 
hypersensitivity, hypocalcemia, 
hyperostosis, osteoarthritis, 
malignancy, and positively 
adjudicated osteonecrosis of the 
jaw (ONJ), atypical femoral 
fracture (AFF), and CV events 
will be tabulated by treatment 
group. 
Subject incidence of adverse 
events corresponding to preferred 
terms of events of interest of 
hypocalcemia, injection site 
reactions, potentially related to 
hypersensitivity (Standardized 
MedDRA® Query [SMQ], 
narrow scope), malignant or 
unspecified tumor (SMQ, narrow 
scope), hyperostosis, 
osteoarthritis, adjudicated adverse 
events of ONJ), and AFF will be 
provided. 
reactions, potentially related to 
hypersensitivity (Standardized 
MedDRA® Query [SMQ], narrow 
scope), malignant or unspecified tumor 
(SMQ, narrow scope), hyperostosis, 
osteoarthritis, positively adjudicated 
adverse events of ONJ, AFF, and 
positively adjudicated serios CV events 
will be tabulated by PT and treatment 
group ( see Appendix 13.5). 
Subcategories are added as appropriate 
(EG, MI, stroke and other CV events).       
10.3 
Laboratory parameters 
(hematology and serum chemistry 
including iPTH and lipids in 
changes from Baseline will be 
descriptively summarized at each 
available time point. 
Actual values and changes from baseline 
of laboratory parameters (hematology 
and serum chemistry including iPTH and 
lipids) will be descriptively summarized 
at each available time point. 
10.4.1 
 
Removed: 
(with abnormal values flagged as “L” or 
“H” accordingly) 
10.4.2 
Descriptive statistics of actual 
values and changes from Baseline 
in body weight, and BMI will be 
presented by scheduled visit will 
be summarized using the SS. 
Abnormal results of the physical 
examination together with details of 
abnormalities: abnormality clinically 
significant or not, will be listed by 
subject and visit. 
10.4.3 
Abnormal results of the physical 
examination together with details 
of abnormalities: abnormality 
clinically significant or not, will 
be listed by subject and visit for 
SS. 
Descriptive statistics of actual values and 
changes from Baseline in body weight, 
and BMI will be presented by scheduled 
visit will be summarized using the SS 
10.4.5 
The incidence and percentage of 
subjects who develop anti-
romosozumab antibodies 
(binding, and if positive, 
neutralizing) up to Month 6 (for 
The incidence and percentage of subjects 
who develop anti-romosozumab 
antibodies (binding, and if positive, 
neutralizing) up to Month 6 (for 
romosozumab group only) for the DBPC 
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Key components of revised SAP text 
romosozumab group only) for the 
DBPC period and up to Month 12 
(for both group) for the overall 
study period will be tabulated. 
This analysis will be repeated to 
further include all testing results 
from samples collected during the 
3-month FU period.  For subjects 
who develop anti-romosozumab 
antibodies, romosozumab serum 
concentrations may also be 
analyzed.  Additionally, 
exploratory analyses may be 
performed to assess any impact 
on safety or efficacy. 
 
Subjects who test positive for 
binding antibodies against 
romosozumab will be interpreted 
as transient positive if the binding 
antibody status was negative at 
the subject’s last time point tested 
within the study period. Subjects 
who test positive for neutralizing 
antibodies against romosozumab 
will be interpreted as transient 
positive if the neutralizing 
antibody status was negative at 
the subject’s last time point tested 
within study period.  
If a subject test positive for 
antibodies against romosozumab 
through Month 6 (for the 6-month 
analysis) and through Month 15 
(for the final analysis), the 
relationship between the presence 
of antibodies, adverse events, 
concomitant medications, and 
bone mineral density could be 
evaluated. 
period and up to Month 12 (for both 
group) for the overall study period will 
be tabulated. This analysis will be 
repeated to further include all testing 
results from samples collected during the 
3-month FU period.  For subjects who 
develop anti-romosozumab antibodies, 
romosozumab serum concentrations may 
also be analyzed.  Additionally, 
exploratory analyses may be performed 
to assess any impact on safety or 
efficacy. 
 
Further antibody analyses will be 
provided and details in Appendix 13.6. 
12 
 
Added reference: 
Kanis JA, Johnell O, Oden A, Johansson 
H, McCloskey E. (2008) FRAXTM and 
the assessment of fracture probability in 
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Key components of revised SAP text 
men and women from the UK. 
Osteoporosis International 19: 385-397. 
Appendix 13.1 
 
Added Appendix 13.1 Alternative 
osteoporosis therapy (licensed drugs 
only) 
Appendix 13.3 
 
Added Appendix 13.3 Fracture Risk 
Assessment Tool: 10-year Probability of 
Major Osteoporotic Fracture (FRAX) 
Appendix 13.4 
 
Added Appendix 13.4 Multiple 
Imputations for BMD endpoints 
Appendix 13.5 
 
Added Appendix 13.5 Adverse Event of 
Interest 
Appendix 13.6 
 
Added Appendix 13.6 Immunogenicity 
Analysis 
  
 
 
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13.11 
Statistical Analysis Plan Amendment 2 
Rationale for the amendment 
The major purpose of this amendment 2 was to align with the protocol amendment 3 dated on 
Mar-23-2022 to be sure the consistency between SAP and protocol. 
The following updates have been made in protocol which impact the SAP: 
• The safety analyses in the 6-month analysis will include all available data collected up to the 
time of 6-month data snapshot. 
Modifications and changes 
• The safety analyses in the 6-month analysis will include all available data collected up to the 
time of 6-month data snapshot. 
• Exposure adjusted AEs was added. 
• Estimands and sensitivity analyses for primary and key secondary endpoints were added 
based on ICH E9R1 addendum.  
• Visit window for Month 6 was modified. 
Specific Changes 
SAP Section(s) 
impacted 
Previous SAP text 
Key components of revised SAP text 
3.2.1.1 
The safety objective of the 6-month 
analysis will compare the safety of 
romosozumab treatment with 
placebo in postmenopausal Chinese 
women with osteoporosis. 
The safety analyses of the 6-month 
analysis will compare the safety of 
romosozumab treatment with placebo 
in postmenopausal Chinese women 
with osteoporosis. The safety 
analyses in the 6-month analysis will 
include all available data collected up 
to the time of 6-month data snapshot. 
3.2.3 
 
DXA Scans 
Window definition for Month 6: 
Day 136 – 270 
Window definition for Month 12: 
≥ Day 271 
 
 
BTMs 
Window definition for Month 6: 
Day 136 – 195 
Window definition for Month 2: 
≥ Day 316 
 
 
Vital signs 
Window definition for Month 6: 
Day 106 – 195 
DXA Scans 
Window definition for Month 6: 
Day 136 - End of DBPC period +14 
(note: M6 IMP will belong to OL) 
Window definition for Month 12: 
≥ Day End of DBPC period + 15 
 
BTMs 
Window definition for Month 6: 
Day 136 – End of DBPC period (note: 
M6 IMP will belong to OL) 
Window definition for Month 2: 
≥ Day End of DBPC period + 1 - 240 
 
 
Vital signs 
Window definition for Month 6: 
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Key components of revised SAP text 
Window definition for Month 7: 
≥ Day 286 
 
Day 106 – End of DBPC period (note: 
M6 IMP will belong to OL) 
Window definition for Month 7: 
≥ Day End of DBPC period + 1 - 285 
 
Added ECG analysis visit window 
3.2.4 
3.2.4.1 End of study date 
End of study (EOS) date is defined as 
the date of the last assessment for the 
Month 15 visit for subjects who 
completed the study; or the date of the 
last assessment for the early 
termination (ET) visit for subjects who 
discontinued the study. 
3.2.4.2 End of DBPC Period date 
End of DBPC Period date is defined as 
the last date of the assessments of the 
Month 6 visit. For subjects who 
discontinued from the study before 
completing Month 6, the EOS date is 
used for the end of DBPC period date 
if this date is before Day 180. For 
those subjects who remained on 
study but missed the Month 6 visit, the 
target date for the Month 6 visit (Day 
180) will be used as the end of DBPC 
period date. 
3.2.4.3 End of Open-Label 
Treatment Period date 
End of OL Treatment Period date is 
defined as the date of the last 
assessment of the Month 12 visit. For 
subjects who discontinued from the 
study before completing Month 12, the 
EOS date is used for the end of 12-
month OL Treatment Period date. For 
those subjects who remained on study 
but missed the month 12 visit, the 
target date for the month 12 visit (Day 
360) will be used as the end of 12-
month treatment period date. 
3.2.4.4 End of Follow-Up Period date 
End of FU Period date is defined as the 
date of the last assessment of the FU 
visit. For subjects who discontinued 
from the study before completing FU 
visit, the last contact date is used for 
the end of FU period date. For those 
Update the Timing of analysis cut-off: 
3.2.4.1 End of study date 
End of study (EOS) date is defined as the 
date of the last contact; or the date of the 
last assessment for the early termination 
(ET) visit for subjects who discontinued 
the study if no last contact date in EDC 
CRF form.  
3.2.4.2 End of DBPC Period date 
End of DBPC Period date is defined as 
the last date of the assessments of the 
Month 6 visit or start date of OL visits if 
Month 6 visit is missed. For subjects 
who discontinued from the study before 
completing Month 6, the ET date is used 
for the end of DBPC period date.  
3.2.4.3 Start of Open-Label Period 
For subjects entering in the open-label 
period, the end of double-blind period 
date is the beginning of the open-label 
period date.  All scheduled assessments 
occurring on this date are attributed to 
the double-blind period.  The month 6 
dose of ROMO is considered as 
occurring in the open-label period. 
3.2.4.4 End of Open-Label Treatment 
Period date 
End of OL Treatment Period date is 
defined as the date of the last assessment 
of the Month 12 visit. For subjects who 
discontinued from the study before 
completing Month 12, the ET date is 
used for the end of 12-month OL 
Treatment Period date. For those 
subjects who remained on study but 
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subjects who remained on study but 
missed the FU, the target 
date for the FU visit (Day 450) will be 
used as the end of FU period date. 
missed the month 12 visit, last OL 
Treatment + 30 days will be used as the 
end of 12-month treatment period date.  
3.2.4.5 End of Follow-Up Period date 
End of FU Period date is defined as the 
date of the last assessment of the FU 
visit. For subjects who discontinued 
from the study before completing FU 
visit, the last contact date is used for the 
end of FU period date. For those subjects 
who remained on study but missed the 
FU, the final visit + 3 month or final 
administration of IMP + 4 month will be 
used as the end of FU period date. 
3.7 
Center pooling strategy to define 
regions will be defined once the sites 
are selected. 
The appropriateness of including site 
as a factor in all analyses where 
specified will be assessed 
prior to unblinding the study. 
Based on the clusters of the sites with 
considerations of geographical and 
climate differences, the pooling 
strategy is ended up with 3 regions: 
North, East and South. The majority of 
the sites are coming from the 3 biggest 
cities in China – Beijing, Shanghai and 
Guangzhou. 
Considering that due to Chinese 
Conference on Biometric 
Recognition’s (CCBR) involvement in 
Beijing (North China) and large 
number of sites in Yangtze Delta sites 
(East China), these sites will have 
majority of the subjects. To 
counterbalance this dominance, the 
sites in Chengdu with 
Guangzhou and Hunan will be 
combined to form South China giving 
that Chengdu with Guangzhou have 
similar climate. 
Updated center pooling strategy: 
Based on the clusters of the sites with 
considerations of geographical and 
climate differences, the pooling 
strategy will consider the following 3 
regions: North, East and South. The 
detail of site and corresponding 
region is listed in Appendix 13.7. 
 
3.9 
 
Added: 
Section 13.6 of the protocol amendment 
3 describes the primary and secondary 
analysis to be used in this study. More 
specifically, the protocol describes 
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primary analysis using last observation 
carried forward (LOCF) as the method 
for handling missing data. This SAP has 
been modified such that the missing data 
due to COVID-19 impact will be 
imputed by multiple imputation. The 
LOCF method will be also applied in 
sensitivity analysis. The modification is 
provided in Section 8.1 in this SAP. 
4.6 
Subgroup for Baseline Vitamin D was 
defined as: 
Baseline Vitamin D (< 20 ng/mL, ≥ 20 
ng/mL and ≤ 40 ng/mL, > 40 ng/mL) 
and Baseline use of loading dose of 
vitamin D (Yes, No)   
Updated to: 
Baseline Vitamin D (≤ 40 ng/mL, > 40 
ng/mL) and loading dose of vitamin D 
(Yes, No). 
5.3 
 
Added Impact Covid-19 section 
6.2 
• 
Baseline use of loading dose of 
vitamin D (Yes, No)  
• 
alcohol use (Current, Former, 
Never) 
• 
tobacco (Current, Former, Never) 
• 
caffeinated beverage use (Current, 
Former, Never) 
 
Updated to: 
• 
Loading dose of vitamin D (Yes, 
No)  
• 
alcohol use (Yes, No, Unknown) 
• 
tobacco (Yes, No, Unknown) 
• 
caffeinated beverage use (Yes, No, 
Unknown) 
 
6.2.1 
 
Add “Unknown” category for risk 
factors. 
7 
 
Updated “exposure during open-lable 
period to “overall period”. 
8 
The primary efficacy variable is 
percent changes from Baseline in 
BMD at the lumbar spine at the end of 
the DBPC Period (Month 6) as 
assessed by DXA. 
Missing baseline BMD by DXA at any 
anatomical site will not be imputed and 
evaluated for the BMD analysis. 
Missing postbaseline BMD will be 
imputed using the LOCF approach (by 
carrying forward the last non-missing 
postbaseline value prior to the missing 
value from the same anatomical site) in 
the 6-month analysis. 
In all visits and including the screening 
visit, if duplicated DXA assessment 
were performed on the same visit the 
mean of the duplicated BMD values 
will be used for analysis. The 
corresponding T-score at baseline will 
Estimands and sensitivity analyses for 
primary and key secondary were added 
based on ICH E9R1 addendum to handle 
COVID-19 impacted missing 
data.Section 8.1.1 was update to: 
 
Primary analysis of Primary efficacy 
endpoint 
Estimands’s attributes to be considered 
for the evaluation of the primary 
endpoint 
(1) Target Population: Postmenopausal 
Chinese women with osteoporosis meet 
the inclusion and exclusion criteria 
(2) Treatment: Romosozumab or PBO 
for 6 months 
(3) Endpoint: percentage change from 
baseline in BMD at lumbar spine at end 
of DBPC period (month 6). 
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be converted using the mean of the 
duplicated BMD (checking missing 
DAX assessment during DEMs in 
section 4.2). 
If a subject has BMD values from 
different DXA machine types (ie, 
Hologic and Lunar) only those BMD 
values that are collected from the same 
machine type as the Baseline BMD 
will be used for analyses and 
imputation. For anatomical sites that 
can be measured on different body 
sides (ie, left and right), only those 
BMD values that are collected from 
the same body side as the Baseline 
BMD will be used for analyses and 
imputation. 
(4) Intercurrent Events (ICEs) and 
strategies to handle ICEs: 
(a) ICE #1: treatment 
discontinuation not due to COVID-19 
will be handled by treatment policy 
strategy 
(b) ICE #2: alternative osteoporosis 
therapy will be handled by treatment 
policy strategy. 
(c) ICE #3: treatment interruption 
and impacted BMD data (missing or 
out of visit window) due to COVID-
19 will be handled by hypothetical 
strategy 
(5) Population level outcome: difference 
of least square (LS) means for 
Romosozumab and PBO 
 
ICE #1 Treatment discontinuation not 
due to COVID-19 and ICE#2 use of 
alternative osteoporosis therapy is rare 
(not expected to happen frequently). 
They will follow treatment policy 
strategy which align with ITT principle. 
The treatment policy strategy will 
include all available data observed at 
Month 6 regardless of the occurrence of 
intercurrent events. This means the 
analysis includes on- and off-treatment 
values collected after study participants 
prematurely discontinued study 
treatment but agreed to remain on the 
study and continued to attend visits and 
provide assessments at those visits or 
data after alternative/prohibited 
medication administrated. Those 
observed values will be analyzed 
according to the study participant’s 
randomized treatment. 
During COVID-19 pandemic, study 
procedures (i.e. IMP administration and 
BMD assessment) are heavily impacted 
by sites close, participants quarantined or 
partially lock down. Thus, treatment was 
interrupted, or BMD assessment could 
not be performed or performed out of 
window. Treatment interruption and 
impacted BMD data (missing or out of 
visit window) due to COVID-19 will be 
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Key components of revised SAP text 
considered as ICE #3. Hypothetical 
strategy, in which the interest is in the 
treatment effect if the ICE did not occur, 
is a recommended option for most 
pandemic-related ICEs (R. Daniel 
Meyer, et al., 2020).   
The data after ICE#1 and ICE#2 will be 
handled by treatment policy strategy and 
will use the observed data to do analysis. 
COVID-19 impacted data after ICE#3, 
then it will be setting to missing and 
imputed by multiple imputation (MI) 
under missing at random (MAR) 
assumption (MI-MAR). Details of this 
multiple imputation analysis are outlined 
in Appendix 13.4. This COVID-19 
impacted data includes any BMD data 
after treatment interrupted (exceed 70 
days since previous IMP, based on PK 
modeling which demonstrated that BMD 
loss begins after 70 days without dosing) 
and any missing data or out of window 
(exceed 70 days since previous IMP) 
data due to Covid-19 (other than actual 
COVID-19 infection). Missing data 
other than due to COVID-19 impacted 
will be imputed by LOCF. 
10.1 
 
Added: 
Additionally, adjusted duration of 
exposure is defined as the duration of 
exposure: 
Date of last administration of IMP – 
date of first IMP administration + 30 
days - cumulative gaps in exposure 
Calculate cumulative gaps are the 
number of days from date of previous 
dose + 30 days to next dose date 
summed up over the entire period. If 
subjects had gap of <=30 days between 
successive doses then gap in exposure 
will be 0 days for this period. 
10.2 
 
Treatment emergent AEs (TEAE) are 
defined as all AEs started or worsened 
in severity on or after the date of 
receiving first dose of IMP and before 
Updated to: 
Treatment emergent AEs (TEAE) are 
defined as all AEs started or worsened in 
severity on or after the date of receiving 
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end-of-study. AEs reported during the 
OL Treatment Period with no IMP 
administered during the same period 
will not be considered treatment 
emergent. No summaries of these 
events will be produced although they 
will be included in listings. 
first dose of IMP and before EOS date 
except lipid-type AEs starting on the 
date of first dose of IMP and not 
worsening (and not deemed IMP related 
by the investigator). Lipid-type AEs will 
be defined by the Dyslipidaemia SMQ 
(see Appendix 13.7). The different 
handling of lipid-type AEs starting on 
the date of first dose of IMP is to ensure 
that pre-existing lipid abnormalities are 
not reported as TEAEs (lipids are only 
measured at Day 1 before first IMP and 
not at Screening). 
10.2 
 
Added: 
TEAEs of injection site reactions, 
potentially related to hypersensitivity 
(Standardized MedDRA® Query 
[SMQ], narrow scope) will be in OL and 
others in DB period. 
10.2.1 
 
Added section to define time at risk of 
exposure. 
10.2.2 
 
Added section to define for exposure 
adjusted incidence rate (EAIR) and 
exposure adjusted event rate (EAER) 
10.2.3 
 
Added TEAE for COVID-19 vaccine 
related TEAE. 
10.2.5 
 
Added the AE of special interest for 
PDILI. 
Appendix 13.4 
 
Updated multiple imputation for BMD 
endpoints. 
Appendix 13.6 
 
Added SMQ terms for PDILD. 
Appendix 13.7 
 
Added SMQ terms for dyslipidaemia. 
Appendix 13.9 
 
Added: 
Region and site information. 
 
 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the 
Statistical Analysis Plan (SAP) or amended SAP is released for execution. 
 
Lead Clinical Development Representative 
 
 
 
Date/Signature                                           
Clinical Trial Statistician 
 
 
 
Date/Signature                                           
 
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Approval Signatures
Name:
OP0002-sap-amend-2
Version:
1. 0
Document Number:
CLIN-000215227
Title:
OP0002 SAP Amendment 2
Approved Date:
07 Mar 2023
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 03-Mar-2023 12:44:37 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 07-Mar-2023 02:16:35 GMT+0000
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