Clinical trial NCT05338086
Conditions: Postmenopausal Women With Osteoporosis
Sponsor: mAbxience Research S.L.
Start date: 2022-03-16; Completion date: 2024-05-22
Enrollment: 558 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a randomized, double-blind, parallel, multicenter, multinational study to compare the efficacy, pharmacokinetics, pharmacodynamics, safety and immunogenicity of MB09 versus Prolia® in postmenopausal women with osteoporosis

Detailed description:
The study was planning to randomise approximately 528 postmenopausal women with osteoporosis aged ≥55 and ≤80 years old with a Bone Mineral Density (BMD) consistent with T-score of ≤ -2.5 and ≥ -4 at the lumbar spine or total hip as measured by DXA during the Screening Period. Screening evaluations were to be completed within 28 days prior to randomisation.

On Day 1, 528 eligible postmenopausal women with osteoporosis were to be randomised in a 2:1:1 ratio to receive MB09-MB09 (Arm 1), Prolia-MB09 (Arm 2), or Prolia-Prolia (Arm 3) using an Interactive Response Sys-tem (IRT).

During the Main Treatment Period, subjects received one subcutaneous injection (60 mg/mL) of study drug on Day 1 and at Month 6. At Month 12, after all efficacy and safety assessments have been performed, the subject were to be enter the Transition/Safety Follow Up Period and were to receive the third dose of study drug. Subjects assigned to the MB09 MB09 arm (Arm 1) received MB09 on Day 1, at Month 6 and at Month 12. Subjects assigned to the Prolia MB09 arm (Arm 2) received EU-Prolia on Day 1 and at Month 6, and MB09 at Month 12. Subjects assigned to the Prolia-Prolia arm (Arm 3) received EU-Prolia on Day 1, at Month 6, and at Month 12. All subjects were to be followed up to Transition Period Month 6.

All subjects received daily supplementation of calcium and vitamin D.

Arms: arm 1: Subjects randomised into MB09-MB09 group were administered MB09 (60 mg in 1 mL) SC injection every 6 months. arm 2: Subjects randomised into Prolia- MB09 group were administered Prolia® (60 mg in 1 mL) SC injection every 6 months. arm 3: Subjects randomised into Prolia-Prolia group were administered Prolia® (60 mg in 1 mL) SC injection every 6 months.
Interventions: intervention 1: MB09 (denosumab biosimilar) intervention 2: EU-Prolia intervention 3: Elemental Calcium intervention 4: Vitamin D
Intervention descriptions: intervention 1: Pre-filled syringe (PFS) 60 mg/mL solution, administered as subcutaneous injection intervention 2: PFS 60 mg/mL solution, administered as subcutaneous injection intervention 3: at least 1000 mg daily intervention 4: at least 400 IU daily

Protocol documents:
Prot_000.pdf: 
Protocol Title: 
A randomised, double-blind, parallel, 
multicentre, multinational study to compare 
the efficacy, pharmacokinetics, 
pharmacodynamics, safety and 
immunogenicity of MB09 (proposed 
denosumab biosimilar) versus Prolia® (EU-
sourced) in postmenopausal women with 
osteoporosis (SIMBA Study) 
NCT Number: 
NCT05338086 
Protocol version 
date: 
Version 2.0, 07 November 2022 















































































































































































































































































































SAP_001.pdf: 
Protocol Title: 
A randomised, double-blind, parallel, 
multicentre, multinational study to compare 
the efficacy, pharmacokinetics, 
pharmacodynamics, safety and 
immunogenicity of MB09 (proposed 
denosumab biosimilar) versus Prolia® (EU-
sourced) in postmenopausal women with 
osteoporosis (SIMBA Study) 
NCT Number: 
NCT05338086 
Statistical 
Analysis Plan 
version date: 
Version 2.0, 18 January 2024 
 




mAbxience Research S.L 
 
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Date Issued: 18JAN2024 
 
 
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Table of Contents 
 
TABLE OF CONTENTS ............................................................................................................ II 
LIST OF ABBREVIATIONS ...................................................................................................... V 
1. 
INTRODUCTION ............................................................................................................ 7 
2. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS ....................................................... 8 
3. 
INVESTIGATIONAL PLAN ........................................................................................ 12 
3.1. OVERALL STUDY DESIGN AND PLAN ................................................................................ 12 
4. 
GENERAL STATISTICAL CONSIDERATIONS ..................................................... 14 
Missing Start and Stop Dates ....................................................................................... 16 
4.1. SAMPLE SIZE .................................................................................................................... 17 
4.2. RANDOMISATION, STRATIFICATION, AND BLINDING ........................................................ 17 
Stratification ................................................................................................................. 17 
Blinding ........................................................................................................................ 17 
Breaking the Blind Methods for Unblinding a Subject ................................................ 18 
4.3. INTERCURRENT EVENTS AND ESTIMANDS ........................................................................ 19 
Intercurrent Events ....................................................................................................... 19 
Estimands ..................................................................................................................... 19 
4.4. ANALYSIS SETS ................................................................................................................ 20 
4.4.1. 
All Enrolled Analysis Set .......................................................................................... 20 
4.4.2. 
All Randomised Analysis Set ..................................................................................... 21 
4.4.3. 
Safety Analysis Set .................................................................................................... 21 
4.4.4. 
Safety Analysis Set for the Transition Period ........................................................... 21 
4.4.5. 
Full Analysis Set ....................................................................................................... 21 
4.4.6. 
Modified Full Analysis Set ........................................................................................ 21 
4.4.7. 
Full Analysis Set for the Transition Period .............................................................. 21 
4.4.8. 
Modified Full Analysis Set for the Transition Period ............................................... 21 
The term mFAS-TP will be used to define the analysis data set with a data record at each 
time for subjects in the FAS-TP but excludes subjects who failed eligibility criteria and data 
observed after the first occurrence of ICE. ............................................................................ 21 
4.4.9. 
Pharmacokinetic Analysis Sets ................................................................................. 21 
5. 
SUBJECT DISPOSITION ............................................................................................. 22 
5.1. DISPOSITION ..................................................................................................................... 22 
5.2. MAJOR PROTOCOL DEVIATIONS ....................................................................................... 22 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 23 
6.1. DEMOGRAPHICS ................................................................................................................ 23 
6.2. MEDICAL HISTORY ........................................................................................................... 24 
6.3. INCLUSION AND EXCLUSION CRITERIA ............................................................................. 24 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 24 
7.1. PRIOR AND CONCOMITANT MEDICATIONS ........................................................................ 24 
7.2. PROHIBITED CONCOMITANT MEDICATIONS ...................................................................... 25 


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7.3. VITAMIN D AND CALCIUM SUPPLEMENTATION ................................................................ 26 
7.4. STUDY TREATMENTS ........................................................................................................ 26 
8. 
EFFICACY ANALYSIS................................................................................................. 27 
8.1. OVERVIEW OF STATISTICAL METHODS: ESTIMATION OF ESTIMANDS AND SENSITIVITY 
ANALYSES .................................................................................................................................. 27 
8.2. PRIMARY EFFICACY ENDPOINT ......................................................................................... 32 
8.2.1. 
Main Estimation of Estimand 1a (Primary).............................................................. 32 
8.2.2. 
Sensitivity Analysis of Primary Efficacy Endpoint ................................................... 33 
8.2.2.1. Multiple Imputation Model Under Missing at Random ............................................ 33 
Data Pre-processing...................................................................................................... 33 
Imputation Model Step 1 .............................................................................................. 33 
Imputation Model Step 2 .............................................................................................. 34 
Data Post-Processing .................................................................................................... 34 
Multiple Imputation: Analysis Phase ........................................................................... 35 
Multiple Imputation: Combining Phase ....................................................................... 35 
8.2.2.2. Sensitivity Using Tipping Point ................................................................................ 35 
8.2.3. 
Main Estimation of Estimand 1b (Supportive).......................................................... 36 
8.2.3.1. Return to Baseline Multiple Imputation using Treatment-Failure Penalty .............. 36 
8.2.4. 
Tipping Point Sensitivity Analysis of Estimand 1b (Supportive) .............................. 37 
8.2.5. 
Supplementary Analysis of Primary Efficacy Endpoint ............................................ 37 
8.3. ANALYSIS OF KEY SECONDARY EFFICACY ENDPOINTS .................................................... 37 
8.3.1. 
Main Estimation of Hypothetical Estimand 2a-4a.................................................... 37 
8.3.2. 
Main Estimation of Treatment Policy Estimand 2b-4b............................................. 38 
8.4. SUBGROUP ANALYSES ...................................................................................................... 38 
9. 
SAFETY ANALYSIS ..................................................................................................... 38 
9.1. ADVERSE EVENTS ............................................................................................................. 39 
9.1.1. 
Treatment Emergent Adverse Events ........................................................................ 40 
9.1.2. 
Incidence of Adverse Events ..................................................................................... 40 
9.1.3. 
Relationship of Adverse Events to Study Drug ......................................................... 41 
9.1.4. 
Severity of Adverse Event.......................................................................................... 41 
9.1.5. 
Serious Adverse Events ............................................................................................. 42 
9.1.6. 
Serious Adverse Events, Related to Study Drug ....................................................... 42 
9.1.7. 
Adverse Events of Special Interest ............................................................................ 42 
9.1.8. 
Serious Adverse Events of Special Interest ............................................................... 43 
9.1.9. 
Adverse Events Leading to Treatment Discontinuation............................................ 43 
9.1.10. Adverse Events Leading to Death ............................................................................. 43 
9.1.11. Death ......................................................................................................................... 43 
9.1.12. Overview summary.................................................................................................... 43 
9.1.13. Summary of Non-Traumatic Fractures ..................................................................... 43 
9.2. CLINICAL LABORATORY EVALUATIONS ........................................................................... 43 
9.2.1. 
Haematology ............................................................................................................. 44 
9.2.2. 
Clinical Chemistry .................................................................................................... 44 
9.2.3. 
Coagulation............................................................................................................... 45 
9.2.4. 
Urinalysis .................................................................................................................. 45 
9.3. VITAL SIGN MEASUREMENTS ........................................................................................... 45 


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9.4. PHYSICAL EXAMINATION ................................................................................................. 45 
9.5. ELECTROCARDIOGRAM ..................................................................................................... 46 
9.6. OTHER SAFETY DATA ....................................................................................................... 46 
9.6.1. 
Injection Site Reaction .............................................................................................. 46 
9.6.2. 
Hypersensitivity/Allergic Reaction ........................................................................... 47 
10. 
PHARMACOKINETICS AND PHARMACODYNAMICS ...................................... 48 
10.1. PHARMACOKINETICS ........................................................................................................ 48 
10.2. PHARMACODYNAMICS ...................................................................................................... 49 
11. 
IMMUNOGENICITY ASSESSMENTS....................................................................... 51 
12. 
COVID-19 REMOTE VISITS ....................................................................................... 53 
13. 
INTERIM ANALYSIS ................................................................................................... 53 
14. 
CHANGES IN THE ANALYSIS................................................................................... 53 
14.1. CHANGES FROM THE PROTOCOL IN THE PLANNED ANALYSIS ........................................... 53 
14.2. CHANGES FROM THE PRIOR SAP VERSION ........................................................................ 55 
15. 
REFERENCES ................................................................................................................ 55 
16. 
APPENDICES ................................................................................................................. 57 
16.1. SCHEDULE OF EVENTS ...................................................................................................... 57 
16.2. SAMPLE SIZE ASSUMPTIONS AND CALCULATION MB09 .................................................... 62 
 
 
 


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List of Abbreviations 
%CfB 
percentage change from baseline 
25-OH vitamin D 
25-hydroxy vitamin D 
ADA 
anti drug antibody 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
aPTT 
activated partial thromboplastin time 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the concentration-time curve 
AUC0-6 months 
area under the concentration-time curve from zero to 6 months 
AUEC 
area under the effect-time curve 
AUEC0-6 months 
area under the effect-time curve from zero to 6 months 
BMD 
bone mineral density 
BMI 
body mass index 
CI 
confidence interval 
Cmax 
observed maximum serum concentration  
COVID-19 
Coronavirus disease 19 
CRF 
case report form 
Ctrough 
trough (predose) serum concentration 
CTCAE 
Common Terminology Criteria for Adverse Events  
DSMB 
Data and Safety Monitoring Board 
DXA 
dual-energy X-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
EOS 
End of Study 
EOT 
End of Treatment 
EU 
European Union 
EU-Prolia 
EU-Sourced Prolia 
FAS 
full analysis set 
FAS-TP 
full analysis set for the transition period 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV-1/HIV-2 
human immunodeficiency virus subtype-1 and subtype-2 
ICE 
intercurrent event 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IgG 
immunoglobulin G 
INR 
International Normalised Ratio 
IRT 
interactive response technology 
L1 
first lumbar vertebra 
L4 
lumbar vertebra 4 
MAR 
missing at random 


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MedDRA 
Medical Dictionary for Regulatory Activities 
mFAS 
modified full analysis set 
mFAS-TP 
modified full analysis set for the transition period 
MI 
multiple imputation 
MMRM 
mixed model for repeated measures 
NAb 
neutralizing antibody 
NYHA 
New York Heart Association 
PD 
pharmacodynamic(s) 
PFS 
pre-filled syringe 
PK 
pharmacokinetic(s) 
PKCS 
PK concentration set for the main treatment period 
PKCS-TP 
PK concentration set for the transition period 
PKPS 
PK parameter set for the main treatment period 
PKPS-TP 
PK parameter set for the transition period 
PT 
prothrombin time 
RANK 
receptor activator of nuclear factor-ƘB 
RANKL 
receptor activator of nuclear factor-ƘB ligand 
REC 
Research Ethics Committee 
RMP 
reference medicinal product 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SAF 
safety analysis set 
SAF-TP 
safety analysis set for the transition period 
sCTX 
serum carboxy-terminal cross-linking telopeptide of type I collagen 
SD 
standard deviation 
SI 
International System of Units 
SUSAR 
suspected unexpected serious adverse reaction 
TB-ADA 
treatment-boosted anti drug antibody 
TI-ADA 
treatment-induced anti drug antibody 
TP 
transition period 
ULN 
upper limit of normal 
US/USA 
United States/United States of America 
WHODRUG 
World Health Organization Drug Dictionary 
 


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1. Introduction 
MB09 is a medicinal product containing the mAb denosumab as the active substance and 
being developed by mAbxience as a biosimilar product to Prolia® (Prolia USPI 2020, Prolia 
SmPC 2020) which is used for the treatment of osteoporosis in postmenopausal women at 
increased risk of fractures and for the treatment of bone loss associated with hormone 
ablation in men with prostate cancer and in women with breast cancer at increased risk of 
fractures. 
The purpose of MB09-C-01-19 study (SIMBA Study) is to compare the efficacy, 
pharmacokinetics (PK), pharmacodynamics (PD), safety and immunogenicity of MB09 
(proposed denosumab biosimilar) versus Prolia® (EU-sourced) in postmenopausal women 
with osteoporosis. After collecting the totality of evidence proving its biosimilarity to 
Prolia®, MB09 may provide an opportunity to improve access to treatment while delivering 
substantial cost savings. 
The purpose of this statistical analysis plan (SAP) is to define the planned statistical analysis 
of the study data consistent with the study objectives and at the same time to ensure that the 
data listing, summary tables, and figures which will be produced are complete and 
appropriate to allow valid conclusions regarding the study objectives. This document does 
not fully cover the details of the planned analyses for the Data and Safety Monitoring Board 
(DSMB). The DSMB charter and a DSMB Table, Listing, and Figure Shells document will 
outline the sequential nature of these reviews. 
This SAP is based on International Council for Harmonization (ICH) of Technical 
Requirements for Pharmaceuticals for Human Use - E3 and E9 Guidelines.  
 
 


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2. Objectives, Endpoints and Estimands 
Study objectives with estimands and endpoints that will be studied in the Main Treatment 
Period are presented in Tables 2-1, 2-2, and 2-3. The key secondary objectives and endpoints 
that will be studied in the Transition/Safety Follow-Up Period are presented in Table 2-4. 
Table 2-1 
Primary Objective, Estimands and Endpoints for the Main 
Treatment Period 
Primary Objective 
Endpoint and Estimand Descriptions 
To demonstrate equivalent efficacy of MB09 to 
EU-Prolia in postmenopausal women with 
osteoporosis in terms of lumbar spine BMD at 
Month 12. 
Endpoint: Percentage change from baseline (%CfB) 
in lumbar spine BMD after 52 weeks (12 months). 
Estimand 1a (Primary): Difference in means 
(MB09 minus EU-Prolia) in  
x 
composite endpoint of %CfB in lumbar spine 
BMD after 52 weeks/12 months 
(where %CfB of zero is taken for anyone who 
dies)  
in postmenopausal women[1] with osteoporosis treated 
with subcutaneous denosumab injections every 
6 months assuming that all women receive two 
denosumab doses without any errors or deviation in 
dosing and without receipt of any prohibited therapies 
or other osteoporosis medications. 
 
Estimand 1b (Supportive): Difference in means 
(MB09 minus EU-Prolia) in 
composite endpoint of %CfB in lumbar spine BMD 
after 52 weeks/12 months (where %CfB of zero is 
taken for anyone who dies) 
in postmenopausal women[1] with osteoporosis treated 
with subcutaneous denosumab injections every 
6 months irrespective of discontinuation of treatment 
for any reason, errors or deviations in dosing and 
whether any prohibited therapies or other osteoporosis 
medications are taken. 
[1] Women will not have been previously treated with denosumab but may have had prior treatment with 
bisphosphonates and will be co-administered calcium and vitamin D supplements. 
Abbreviations: %CfB, percentage change from baseline; BMD, bone mineral density; EU-Prolia, EU-sourced 
Prolia; ICEs, intercurrent events. 
Note that Estimands 1a and 1b take primarily hypothetical and treatment policy approaches, respectively, to 
handle ICEs and a composite strategy for death. The formation of antidrug antibodies and potential 
adjustments to calcium and vitamin D supplements are not explicitly mentioned in the estimand description 
summaries above but will be handled by a treatment policy approach in both estimands. Further details of 
ICEs and more detailed breakdown of the estimand attributes can be found in Section 4.3. 
Note: The screening BMD assessment will be taken as the baseline BMD assessment. 
 


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Table 2-2 
Secondary Objectives, Estimands and Endpoints for the Main 
Treatment Period 
Secondary Objectives 
Estimand Description (Including Endpoint) 
To assess the efficacy of 
MB09 to EU-Prolia in 
postmenopausal women with 
osteoporosis in terms of 
lumbar spine BMD at 
Month 6, and hip and femur 
neck BMD at Month 6 and 
Month 12. 
Estimand 2a\3a\4a: Difference in means (MB09 minus EU-Prolia) in  
composite endpoint of %CfB (zero is taken for anyone who dies) in  
x 
(2a) lumbar spine BMD after 6 months.  
x 
(3a) hip BMD after 6 and 12 months. 
x 
(4a) femur neck BMD after 6 and 12 months. 
in postmenopausal women[1] with osteoporosis treated with subcutaneous 
denosumab injections every 6 months assuming that all women receive 
scheduled denosumab dose(s) without any errors or deviation in dosing and 
without receipt of any prohibited therapies or other osteoporosis medications. 
Estimand 2b\3b\4b: Same as Estimand 1b for each endpoint above 
irrespective of discontinuation of treatment for any reason, errors or 
deviations in dosing and whether any prohibited therapies or other 
osteoporosis medications are taken.  
To assess the PD profile of 
MB09 to EU-Prolia in 
postmenopausal women with 
osteoporosis in terms of sCTX 
AUEC up to Month 6 and 
sCTX at Month 12. 
Estimand 5: Ratio of geometric means (MB09/EU-Prolia) in  
sCTX AUEC0-6 months  
in postmenopausal women[1] with osteoporosis treated with subcutaneous 
denosumab injections every 6 months assuming all women receive their first 
denosumab dose without any errors in dosing and without receipt of any 
prohibited therapies or other osteoporosis medications up to 6 months after 
first dose. 
Additional summary: Mean difference in sCTX at 11 days; 1, 3 and 
6 months after the first dose; and 6 months after the second dose of study 
drug.  
[1] Women will not have been previously treated with denosumab but may have had prior treatment with 
bisphosphonates and will be co-administered calcium and vitamin D supplements. 
Abbreviations: %CfB, percentage change from baseline; AUEC, area under the effect curve; 
AUEC0-6 months, area under the effect curve from zero to 6 months; BMD, bone mineral density; 
EU-Prolia, EU-sourced Prolia; PD, pharmacodynamic; sCTX, serum carboxy-terminal cross-linking 
telopeptide of type I collagen.  
Note: The screening BMD assessment will be taken as the baseline BMD assessment. 
 


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Table 2-3 
Secondary Objectives and Endpoints for the Main Treatment 
Period 
Secondary Objectives 
Endpoints 
To assess the PK profile of 
MB09 compared with 
EU-Prolia. 
x 
AUC0-6 months and Cmax following the first dose. 
x 
Ctrough of serum denosumab at Month 6 and Month 12. 
To evaluate the safety profile 
of MB09 compared with 
EU-Prolia. 
x 
Subject incidence of treatment-emergent adverse events up to and 
including Month 12. 
x 
Subject incidence of adverse events of special interest (injection site 
reaction, drug-related hypersensitivity/allergic reaction, infection, 
hypocalcaemia, osteonecrosis of the jaw, dermatologic reaction and 
atypical femoral fracture) up to and including Month 12. 
x 
Subject incidence of clinically significant changes in physical 
examinations, laboratory safety tests, ECG and vital signs from baseline 
and up to and including Month 12. 
x 
Subject incidence of deaths and serious adverse events up to Month 12. 
To assess the immunogenicity 
of MB09 compared with 
EU-Prolia assessed through 
antidrug antibodies. 
x 
Binding and neutralising serum denosumab antibodies from baseline and 
up to and including Month 12. 
Abbreviations: AUC0-6 months, area under the concentration-time curve from zero to 6 months; Cmax, 
observed maximum serum concentration after administration; Ctrough, trough (predose) serum concentration; 
ECG, electrocardiogram; EU-Prolia, EU-sourced Prolia; PK, pharmacokinetic.  


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Table 2-4 
Secondary Objectives and Endpoints for the 
Transition/Follow-Up Period 
Secondary Objectives 
Endpoints 
To assess the PK profile: 
i. 
after the single transition 
from EU-Prolia to MB09 
ii. 
on MB09 throughout each 
compared with those on 
EU-Prolia throughout. 
x 
Transition Period AUC0-6 months and Cmax following the third dose at 
Month 12. 
x 
Ctrough of serum denosumab at Transition Period Month 6. 
 
To assess the PD profile: 
i. 
after the single transition 
from EU-Prolia to MB09 
ii. 
on MB09 throughout each 
compared with those on 
EU-Prolia throughout. 
x 
Transition Period sCTX AUEC up to Transition Period Month 6.  
x 
Ctrough of sCTX at Month 12 and Transition Period Month 6. 
 
To assess the risk of 
hypersensitivity and adverse events:  
i. 
after the single transition 
from EU-Prolia to MB09 
ii. 
on MB09 throughout each 
compared with those on 
EU-Prolia throughout. 
x 
Subject incidence of treatment-emergent adverse events from third 
dose at Month 12 and up to and including Transition Period 
Month 6. 
x 
Subject incidence of adverse events of special interest (injection site 
reaction, drug-related hypersensitivity/allergic reaction, infection, 
hypocalcaemia, osteonecrosis of the jaw, dermatologic reaction, and 
atypical femoral fracture) from third dose at Month 12 and up to 
and including Transition Period Month 6. 
x 
Subject incidence of clinically significant changes in physical 
examinations, laboratory safety tests, ECG and vital signs from 
third dose at Month 12 and up to and including Transition Period 
Month 6. 
x 
Subject incidence of deaths and serious adverse events from third 
dose at Month 12 and up to and including Transition Period 
Month 6. 
To assess the risk of 
immunogenicity through formation 
of antidrug antibodies: 
i. 
after the single transition 
from EU-Prolia to MB09 
ii. 
on MB09 throughout each 
compared with those on 
EU-Prolia throughout. 
x Binding and neutralising serum denosumab antibodies from 
Month 12 and up to and including Transition Period Month 6. 
Abbreviations: AUC0-6 months, area under the concentration-time curve from zero to 6 months; AUEC, area 
under the effect curve; Cmax, observed maximum serum concentration after administration; Ctrough, trough 
(predose) serum concentration; ECG, electrocardiogram; EU-Prolia, EU-sourced Prolia; PD, 
pharmacodynamic; PK, pharmacokinetic; sCTX, serum carboxy-terminal cross-linking telopeptide of type I 
collagen.  
 
 


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3. Investigational Plan 
3.1. 
Overall Study Design and Plan 
This is a randomised, double-blind, parallel, multicentre, multinational study to compare the 
efficacy, PK, PD, safety, and immunogenicity of MB09 (proposed denosumab biosimilar) 
and EU-Prolia in postmenopausal women with osteoporosis.  
The study will randomise approximately 528 postmenopausal women with osteoporosis 
aged ≥ 55 and ≤ 80 years old with a bone mineral density (BMD) consistent with T-score of 
≤ -2.5 and ≥ -4 at the lumbar spine or hip as measured by dual-energy X-ray absorptiometry 
(DXA) during the Screening Period. Screening evaluations will be completed within 28 days 
prior to randomisation. 
On Day 1, 528 eligible postmenopausal women with osteoporosis will be randomised in a 
2:1:1 ratio to receive MB09-MB09 (Arm 1), Prolia-MB09 (Arm 2), or Prolia-Prolia (Arm 3) 
using an interactive response technology (IRT) system. 
The randomisation will be stratified by baseline BMD T-score at the lumbar spine (≤ -3.0 
and > -3.0 standard deviation [SD]), body mass index (< 25 and ≥ 25 kg/m2), age at study 
entry (≥ 55 to < 68 years versus ≥ 68 to ≤ 80 years) and prior bisphosphonate medication use 
at study entry (prior use of bisphosphonates versus no prior bisphosphonate use). 
This study will involve a screening period, a Main Treatment Period, and a Transition/Safety 
Follow-Up Period. During the Main Treatment Period, subjects will receive one 
subcutaneous injection (60 mg/mL) of study drug on Day 1 and at Month 6. At Month 12, 
after all efficacy and safety assessments have been performed, the subject will enter the 
Transition/Safety Follow-Up Period and will receive the third dose of study drug. Subjects 
assigned to the MB09-MB09 arm (Arm 1) will receive MB09 on Day 1, at Month 6, and at 
Month 12. Subjects assigned to the Prolia-MB09 arm (Arm 2) will receive EU-Prolia on 
Day 1 and at Month 6, and MB09 at Month 12. Subjects assigned to the Prolia-Prolia arm 
(Arm 3) will receive EU-Prolia on Day 1, at Month 6, and at Month 12. All subjects will be 
followed up to Transition Period Month 6. Of note, only subjects who tolerated the initial 
two doses and are willing to take the third dose will proceed to the Transition/Safety 
Follow-up Period. 
A schematic diagram of the overall study design is presented in Figure 1. 


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Figure 1 
Study Scheme 
 
The maximum study duration for a subject will be approximately 19 months: 28 days for 
screening, a Main Treatment Period of 12 months, and a Transition/Safety Follow-Up Period 
of 6 months. There will be two analyses after each study period is complete: primary efficacy 
analysis after all subjects have received the Month 12 assessments (prior to the third 
administration of study drug) or have terminated the study before Month 12 and a safety 
addendum at month 18 when the last subject completes the End of Study (EOS) visit or 
withdraws early from the study. 
If the subject has known SARS-CoV-2 exposure (even without symptoms related to 
COVID-19), the study visit for the administration of study drug will be rescheduled at the 
discretion of the investigator according to local regulations. Treatment with study drug can 
be re-introduced if the subject has tested negative for COVID-19 or after two weeks of 
symptom-free observation. 
Administration of study drug should be interrupted if the subject has documented a 
presumptive COVID-19 infection and until the subject is recovered. Treatment with study 
drug can be re-introduced in line with local practice following the recovery of the subject 
and following discussion with the medical monitor and with his/her agreement. 


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An independent radiology review committee will assess the BMD using DXA at Month 6 
and Month 12. The central reading and analysis of imaging data will be used to evaluate 
drug efficacy, including estimation of the primary Estimand 1a, i.e. difference in means 
(MB09 minus EU-Prolia) in composite endpoint of %CfB in lumbar spine BMD after 
52 weeks/12 months (where %CfB of zero is taken for anyone who dies) in postmenopausal 
women with osteoporosis treated with subcutaneous denosumab injections every 6 months 
assuming that all women receive two denosumab doses without any errors or deviation in 
dosing and without receipt of any prohibited therapies or other osteoporosis medications of 
the trial. 
A DSMB will assess the safety data periodically and will recommend to mAbxience whether 
to continue, modify, or stop the study. This decision will be based on reviewed data (see 
protocol Section 7.9 for further details). 
All assessments performed in the study are summarised in the schedule of events provided 
in the Appendix 16.1. 
4. General Statistical Considerations 
Specific statistical methods will be described in the Efficacy Analysis Section 8 below. 
As stratification factors are known to be incorrect for some subjects (due to errors in 
stratification) the actual/corrected stratification covariates will be used whenever a stratified 
analysis is specified. This is to reduce variability and increase precision of analysis as well 
as to attain a power at a level similar to the case where there are no errors. The source data 
for the corrected stratification covariates is presented in Table 4-1. 
Table 4-1 
Source Data for the Corrected Stratification Covariates  
Stratification Covariate 
Source Data 
Baseline BMD T-score at the lumbar spine (≤ -3.0 
and > -3.0 SD) 
Clario  
Baseline BMI (< 25 and ≥ 25 kg/m2) 
 CRF 
Age at randomisation date (≥ 55 to < 68 years versus 
≥ 68 to ≤ 80 years) 
CRF 
Prior bisphosphonate medication use at study entry 
(prior use of bisphosphonates versus no prior 
bisphosphonate use) 
CRF 
Abbreviations: BMD, bone mineral density; BMI, body mass index; CRF, case report form; IRT, interactive 
response technology; SD, standard deviation.  
Data collected in this study will be presented using summary tables, subject data listings and 
figures. Continuous variables will be summarised using the mean, SD, median, minimum 
value, and maximum value. Categorical variables will be summarised using frequency 
counts and percentages. Data will be listed in data listings. For ordinal-scaled variables, a 
combination of presentations may be employed as appropriate: frequency and percentage of 


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observations within a category and means and SDs of the scores of the categories. For 
categorical and ordinal variables unless otherwise specified, percentages will be calculated 
based on the N of the analysis set and number of subjects with missing data will also be 
included.  
For the summary statistics of all numerical variables unless otherwise specified, minimum 
and maximum will be displayed to the same level of precision as reported. Mean and median 
will be displayed to one level of precision greater than the data collected. Standard deviation 
will be displayed to two levels of precision greater than the data collected. 
All confidence intervals (CIs) presented will be 95% (two-sided) CIs. For primary efficacy, 
therapeutic equivalence is demonstrated if the 95% CI falls entirely within predefined 
margins; this approach is equivalent to two one-sided tests at the 2.5% significance level.  
Unless otherwise specified, baseline will be defined as the last non-missing assessment prior 
to the study drug administration including both scheduled and unscheduled visits and 
assessments. 
The periods of the study will be summarised separately so that: 
x In the Main Treatment Period, subjects will be summarised by treatment 
(MB09 versus Prolia) up to Month 12 (predose). The Prolia group will pool subjects 
from Arm 2 Prolia-MB09 and Arm 3 Prolia-Prolia. 
x In the Transition /Safety Follow-Up Period, subjects will be summarised by treatment 
arm (Prolia-MB09, Prolia-Prolia) up to Transition Period Month 6. 
x In the whole study period (cumulative safety data analysis), subjects that started 
MB09 at randomisation will be compared to subjects that started Prolia at 
randomisation and did not switch to MB09 in the transition period.   
Study day will be calculated relative to the first dosing date as: 
x If assessment date is on or after the first dosing date, then Study Day = Assessment 
Date – First Dosing Date + 1 
x Otherwise, Study Day = Assessment Date – First Dosing Date 
All analyses will be conducted using SAS Version 9.4 or higher. 
All data are summarised based on the visit name collected on the CRF page.  


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Missing Start and Stop Dates 
For the purpose of inclusion in prior and/or concomitant medication and AE tables, 
incomplete medication start and stop dates will be imputed as follows: 
Missing start dates (where UK and UKN indicate unknown or missing day and month 
respectively):  
x UK-UKN-YYYY:  
o If the year of the start date is the same as the first dose of study drug year, and the 
end date (after any imputation) is on or after the first dose of study drug or the end 
date is missing, then the start date is imputed as the date of first dose of study 
drug. 
o If the year of the start date is the same as the first dose of study drug and the end 
date (after any imputation) is prior to the first dose of study drug, then assume the 
end date for the onset date. 
o If the year of the start date is different from the year of the date of first dose of 
study drug, then 01 January will be assigned to the missing fields. 
o If missing only the month of the start date, then the day will be treated as missing 
and both month and day will be replaced according to the missing day and month 
logic above. 
x UK-MMM-YYYY: 
o If the month and year of the start date are different from the month and year of the 
date of first dose of study drug, then the first day of the month will be assigned to 
the missing day. 
o If month and year of the start date are the same as the month and year of the first 
dose of study drug, and the end date (after any imputation) is on or after the date 
of first dose of study drug or the end date is missing, then assume the date of the 
first dose of study drug. 
o If the month and year of the start date are the same as the date first dose of study 
drug month and year, and the end date (after any imputation) is prior to the date 
of first dose of study drug, then assume the end date for the start date. 
If the start date is not recorded on CRF then no date imputation will be performed. 
Missing end dates (where UK and UKN indicate unknown or missing day and month 
respectively):  
x UK-MMM-YYYY: Assume the last day of the month; 
x DD-UKN-YYYY/UK-UKN-YYYY: Assume 31-DEC-YYYY. 
x If missing only the month of the end date, then the day will be treated as missing and both 
month and day will be replaced according to the missing day and month logic above. 
x After imputation, if end date is after date of death, then end date is assumed to be date of 
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If the end date is not recorded on CRF then no date imputation will be performed. 
4.1. 
Sample Size 
A sample size of 448 subjects (224 subjects on each of MB09 and EU-Prolia 
[Arm 2 Prolia-MB09 and Arm 3 Prolia-Prolia pooled] at Month 12) will approximately 
achieve 85% statistical power for the demonstration of equivalence in the %CfB lumbar 
spine BMD at Month 12, based on the two one-sided 2.5% significance level and an 
equivalence margin of ± 1.45%. In this sample size calculation, the common SD is assumed 
to be 4.5% and the true mean difference of %CfB is assumed to be zero. Therefore, allowing 
for a 15% dropout, 528 subjects will be randomised 2:1:1 to the MB09-MB09, Prolia-MB09 
and Prolia-Prolia treatment arms. 
A meta-analysis of three studies (Bone et al 2008, Cummings et al 2009, and 
McClung et al 2006) gave the pooled denosumab treatment effect 5.35% (95% CI: 4.83% to 
5.87%). Based on the lower bound of the 95% CI, a 1.45% margin will preserve 70% of the 
treatment effect (0.3*4.83%). Please refer to Appendix 16.2 for further documentation on 
sample size assumptions.  
4.2. 
Randomisation, Stratification, and Blinding 
Interactive response technology will be used to administer the randomisation schedule. 
Biostatistics will generate the randomisation schedule using SAS® software Version 9.4 or 
later (SAS Institute Inc., Cary, North Carolina) for IRT, which will link sequential subject 
randomisation numbers to treatment codes. The randomisation schedule will be stratified by 
baseline BMD T-score at the lumbar spine (≤ -3.0 and > -3.0 SD), body mass index (< 25 
and ≥ 25 kg/m2), age at study entry (≥ 55 to < 68 years versus ≥ 68 to ≤ 80 years) and prior 
bisphosphonate medication use at study entry (prior use of bisphosphonates versus no prior 
bisphosphonate use). IRT system will dynamically allocate stratification combination of the 
stratification factors in order to allocate a subject to a treatment arm in a blinded manner. 
Eligible subjects will be randomised in a 2:1:1 ratio to receive MB09-MB09 (Arm 1), 
Prolia-MB09 (Arm 2), or Prolia-Prolia (Arm 3). 
Subjects who withdraw the study will not be replaced. 
Stratification 
The randomisation will be stratified by baseline BMD T-score at the lumbar spine (≤ -3.0 
and > -3.0 SD), body mass index (< 25 and ≥ 25 kg/m2), age at study entry (≥ 55 to < 68 
years versus ≥ 68 to ≤ 80 years) and prior bisphosphonate medication use at study entry 
(prior use of bisphosphonates versus no prior bisphosphonate use).  
Blinding 
This study will remain double-blinded until the end of all follow-up procedures. The 
randomisation codes will not be revealed to study subjects, investigators, or study site 


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personnel, except for delegated unblinded staff who will handle the study drug, and 
predefined unblinded mAbxience and PPD personnel, until all final clinical data have been 
entered into the database and the database is locked and released for analysis. 
The overall randomisation code will be broken only for reporting purposes. This will occur 
after database lock for data up to the end of Month 12 for all subjects. The unblinded 
personnel will be predefined and documented before breaking the study blinding. The study 
will remain blinded to the investigators, subjects, and predefined mAbxience and PPD 
blinded personnel until all subjects have completed the study and the database has been 
finalised for study closure. 
A separate unblinded project team at PPD will be unblinded after the database is locked up 
to Month 12 for the primary efficacy analysis. Datasets (and related Table, Listing, Figure 
[TLFs]) containing unblinding data will be exclusively handled by unblinded project team 
members at PPD. However, for the blinded Clinical Study Report for the primary efficacy 
analysis only cumulative summary results (Tables and Figures) that do not contain 
information about individual study treatment assignments or other unblinding data for 
individual subjects will be provided to unblinded and blinded project teams at PPD and 
mAbxience. An unblinding plan will give full details. 
Breaking the Blind Methods for Unblinding a Subject 
Under normal circumstances, the blind will not be broken. The blind will be broken only if 
specific emergency treatment that will be dictated by knowing the study drug assignment is 
required for medical management. In such cases, the investigator may, in an emergency, 
determine the identity of the study drug by using the applicable procedure in the IRT. In case 
the blind needs to be broken because of a medical emergency, the investigator may unblind 
an individual subject’s treatment allocation. 
The date, time, and reason for the unblinding must be documented in the appropriate field 
of the electronic case report form (eCRF), and the medical monitor must be informed as soon 
as possible. All calls resulting in an unblinding event will be recorded and reported by the 
IRT to the medical monitor and mAbxience personnel. Any subject for whom the blind is 
broken may continue in the study and receive the further study drug (per protocol) at the 
investigator’s discretion. 
mAbxience’s Pharmacovigilance Department will have access to the randomisation code, if 
SUSARs, which are subject to expedited reporting and will be unblinded before submission 
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4.3. 
Intercurrent Events and Estimands 
Intercurrent Events 
The following intercurrent events (ICEs) are relevant in the treatment of postmenopausal 
women with osteoporosis by subcutaneous injection of study drug (MB09 or EU-Prolia 
every 6 months): 
x Discontinuation of study drug due to any reason. 
x 
Errors or deviations in dosing: this would include incorrect dose, incorrect study 
drug, incorrect route, or a deviation in timing of the Month 6 dose (defined as being 
outside of the window (181 ± 28 days). Of note, study drug will be administered by 
the clinical staff to minimise the chance of error. 
x Administration of any prohibited therapies or other osteoporosis medications. 
x Adjustments to vitamin D or calcium supplements. 
x Formation of antidrug antibodies. 
x Death. 
Estimands 
Table 4-1 presents the primary objective with its estimands and rationale for strategies to 
address ICEs. 
Table 4-1 
Primary Objective and Estimands With Rationale for Strategies 
to Address Intercurrent Events 
 
Estimand 1a (Primary)  
Estimand 1b (Supportive) 
Estimand 
Description 
(summary 
below) 
Difference in means (MB09 minus 
EU-Prolia) in  
composite endpoint of %CfB in lumbar 
spine BMD after 52 weeks/12 months 
(where %CfB of zero is taken for anyone 
who dies)  
in postmenopausal women[1] with 
osteoporosis treated with subcutaneous 
denosumab injections every 6 months 
assuming that all women receive two 
denosumab doses without any errors or 
deviations in dosing and without receipt 
of any prohibited therapies or other 
osteoporosis medications. 
Difference in means (MB09 minus 
EU-Prolia) in  
composite endpoint of %CfB in lumbar 
spine BMD after 52 weeks/12 months 
(where %CfB of zero is taken for anyone 
who dies)  
in postmenopausal women[1] with 
osteoporosis treated with subcutaneous 
denosumab injections every 6 months 
irrespective of discontinuation of 
treatment for any reason, errors or 
deviations in dosing and whether any 
prohibited therapies or other osteoporosis 
medications are taken. 
Treatment 
Conditions of 
Interest 
MB09 versus EU-Prolia 
Target 
Population  
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Estimand 1a (Primary)  
Estimand 1b (Supportive) 
Endpoint 
Percentage change from baseline in lumbar spine bone mineral density (%CfB lumbar 
spine BMD) to Month 12 and taking %CfB value of zero for someone who dies. 
Population 
Level 
Summary 
Difference between treatments in population mean %CfB BMD at Month 12. 
ICEs and 
Strategies to 
Handle ICEs 
Hypothetical strategy for: 
• 
Discontinuation of study drug due to 
any reason (related or unrelated to 
study drug or osteoporosis). 
• 
Errors or deviations in dosing. 
• 
Administration of any prohibited 
therapies or other osteoporosis 
medications. 
Treatment policy strategy for: 
• 
Formation of antidrug antibodies. 
• 
Adjustments to calcium and 
vitamin D. 
Composite strategy for death. 
Treatment policy strategy for: 
• 
Discontinuation of study drug due to 
any reason (related or unrelated to 
study drug or osteoporosis). 
• 
Errors or deviations in dosing. 
• 
Administration of any prohibited 
therapies or other osteoporosis 
medications. 
• 
Formation of antidrug antibodies. 
• 
Adjustments to calcium and 
vitamin D. 
Composite strategy for death. 
Rationale 
It is anticipated that the occurrence of each ICE will be balanced between groups since 
the biosimilar, MB09, should have similar properties to the EU-Prolia. Note that the 
treatment policy approach in the primary Estimand 1b requires follow-up of subjects 
to measure BMD at Month 12 irrespective of whether they have taken any 
prohibited therapies or other osteoporosis medication or not received both doses. 
It should be noted that Prolia has a good safety profile, and it is anticipated that < 1% 
of subjects will have tolerability issues or die during the year after first dose.   
The hypothetical strategy of Estimand 1a will require statistical modelling to estimate 
the difference that might exist in the scenario that those ICEs do not occur.    
Note: The formation of antidrug antibodies against EU-Prolia in the first year of 
treatment is not particularly common (< 1%) and thus this ICE has not been 
specifically mentioned in the estimand and will be ignored in estimation approaches.    
[1] Women will not have been previously treated with denosumab but may have had prior treatment with 
bisphosphonates and will be co-administered calcium and vitamin D supplements. 
Abbreviations: %CfB, percentage change from baseline; BMD, bone mineral density; 
EU-Prolia, EU-sourced Prolia; ICE, intercurrent event. 
Note: The screening BMD assessment will be taken as the baseline BMD assessment 
4.4. 
Analysis Sets 
The following analysis sets will be used in the statistical analyses. 
4.4.1. 
All Enrolled Analysis Set 
The all enrolled analysis set will consist of all subjects who signed an ICF.  


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4.4.2. 
All Randomised Analysis Set 
The all randomised analysis set will include all (consenting) subjects who were randomised 
regardless of whether they actually received any study drug. Analysis will be based on 
treatment allocated at randomisation. 
4.4.3. 
Safety Analysis Set  
The safety analysis set (SAF) will consist of all randomised subjects who received at least 
one administration of study drug. The SAF will be used for all safety and immunogenicity 
analyses. In the SAF, subjects will be analysed per the actual treatment received. 
4.4.4. 
Safety Analysis Set for the Transition Period 
The SAF-TP will consist of all subjects in the SAF who progressed to receive a dose of study 
drug at Month 12, and so thereby enter the Transition Period. The SAF-TP will be used for 
all safety and immunogenicity analyses of the Transition Period (per the actual treatment 
received). 
4.4.5. 
Full Analysis Set 
The Full Analysis Set (FAS) will consist of all (consenting) randomised subjects who receive 
at least one dose of study drug. Subjects from the FAS will be analysed under the treatment 
as randomised and will be used for supportive analyses for efficacy endpoints.  
4.4.6. 
Modified Full Analysis Set 
The Modified Full Analysis set (mFAS) will consist of the subset of subjects in FAS who 
meet all eligibility criteria.  Furthermore, the mFAS term will define a set at the data point 
level which includes a data record at each time point for all eligible subjects in the FAS but 
excludes data observed after the first occurrence of those ICEs where a hypothetical strategy 
is taken (e.g., missing a dose, errors or deviations in dosing, or receipt of any prohibited 
therapies or other osteoporosis medication). Data in the mFAS will be analysed under the 
treatment as randomised and used as the primary analysis set for efficacy and PD. 
4.4.7. 
Full Analysis Set for the Transition Period 
The Full Analysis Set for the Transition Period (FAS-TP) will consist of all randomised 
subjects in the safety analysis set for the transition period (SAF-TP) who progressed to 
receive a dose of study drug at Month 12. 
4.4.8. 
Modified Full Analysis Set for the Transition Period 
The term mFAS-TP will be used to define the analysis data set with a data record at each 
time for subjects in the FAS-TP but excludes subjects who failed eligibility criteria and data 
observed after the first occurrence of ICE. 
4.4.9. 
Pharmacokinetic Analysis Sets 
The PK Concentration Sets for the Main Treatment Period (PKCS) and for the 


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Transition Period (PKCS-TP) are concentration observation-level sets which comprise all 
subjects who received at least one full dose of study drug (MB09 or EU-Prolia) in the 
respective period and exclude observations after relevant ICEs which impact PK (e.g., 
missing a dose, errors or deviations in dosing or receipt of other therapies which also contain 
denosumab). These sets will be used for summaries of concentrations and troughs. 
The PK Parameter Set (PKPS) for the Main Treatment Period comprises all subjects who 
have at least three measurable concentrations in PKCS which must include Day 11 to allow 
for reliable estimation of both Cmax and AUC0-6 months. The PK Parameter Set for the 
Transition Period (PKPS-TP) is defined similarly. 
5. Subject Disposition 
5.1. 
Disposition 
Subject disposition in the Main Treatment Period will be summarised for each treatment 
group and overall for the All Enrolled Analysis Set. Similarly, subject’s disposition in the 
Transition Period will be summarised for each treatment arm and overall for the FAS-TP. 
The number of enrolled subjects and screen failures (including re-screened subject IDs), and 
subjects who are randomised in the study to each treatment group and the count and 
percentage of subjects who completed the Main Treatment Period and the Transition Period 
(i.e., study participation until the Month 12 or Month 18/EOS visit respectively without early 
termination) will be presented. Count and percentage of subjects who are on ongoing 
treatment at data cut-off date, who discontinue study treatment with the primary reason, 
completed the study or discontinued study early, as well as the primary reason for study 
discontinuation, will also be summarised. 
The count and percentage of subjects in each analysis set will be presented in a summary 
table, separately for the Main Treatment Period and the Transition Period analysis sets. 
Percentages will be calculated out of the number of subjects in the All Randomised and FAS-
TP for the Main Treatment Period and the Transition Period, respectively. 
Subject disposition data including reason for individual unblinding, analysis sets, and 
randomisation data will be presented in data listings. Screen failure data will be summarised 
and will be presented in data listings.  
5.2. 
Major Protocol Deviations 
Major protocol deviations are a subset of protocol deviations deemed to impact critical data 
and lead to exclusion from efficacy analyses (based on Modified Full Analysis Set). Major 
protocol deviations rules associated with eligibility criteria will be developed, documented 
in the study deviation rules document, and finalised in a blinded manner before database 
lock.  


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The number and percentages of subjects with each major protocol deviation type will be 
provided separately for the Main Treatment Period and the Transition Period by treatment 
(arm) and overall, using the SAF and SAF-TP, respectively.  
A listing of major protocol deviations and a separate listing for COVID-19 related protocol 
deviations will be provided for two periods (Main treatment period and Transition period), 
using the SAF analysis set. 
6. Demographics and Baseline Characteristics 
6.1. 
Demographics 
The following demographic and baseline disease characteristics will be summarised 
separately for the Main Treatment Period and the Transition Period, using the SAF and 
SAF-TP analysis sets, respectively: 
x Age (years) 
x Age group (age 55 to 67, 68 to 80) as per eCRF 
x Sex (female) 
x Smoking status (Current Smoker, Former Smoker, Never-smoker) 
x Race (White, Black or African American, Asian, American Indian Or Alaska 
Native, Native Hawaiian Or Other Pacific Islander, Not to be collected as per 
regulations, Other, Multiple [if more than one race category is selected]) 
x Ethnicity (Hispanic or Latino, Not Hispanic Or Latino) 
x Height (cm) 
x Weight (kg) 
x BMI (kg/m2) 
x BMI Group (>= 25 kg/m2, < 25 kg/m2) as per eCRF  
x BMD T-score at the lumbar spine (<= -3 SD, > -3 SD) as per eCRF 
x Lumbar spine BMD (g/cm2)  
x Total hip BMD (g/cm2) 
 
x Femur neck BMD (g/cm2) 
 
x Menopause duration (years) defined as (randomization date-date of menopause 
+1)/365. In case date of menopause is incomplete, only the year will be used for 
calculation. 
x Osteoporosis duration (years) defined as (randomization date-osteoporosis 
diagnosis date +1) /365. In case date of menopause is incomplete, only the year 
will be used for calculation.   


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x Prior use of bisphosphonates (yes, no) as per eCRF 
x Fracture history (yes, no) 
x History of vertebrae fractures (yes, no) 
Summaries for the mFAS analysis set will be also provided if SAF and mFAS are not 
concordant for more than 5% of the subjects. Summary table (cross-tabulation) by treatment 
for stratification factor will be provided to show any discrepancy between what was reported 
through IRT vs. clinical database at baseline. This summary will be performed based on All 
Randomised analysis set. 
Demographic and baseline characteristics data will be listed for two periods (Main treatment 
period and Transition period) using the All Randomised analysis set. 
6.2. 
Medical History 
Medical history will be classified by system organ class (SOC) and preferred term (PT) using 
MedDRA (Version 24.1 or higher) and summarised by SOC and PT for each treatment group 
and overall for the Main Treatment Period and Transition Period using the SAF analysis set. 
Medical history will be presented in a data listing for subjects in the All Randomised analysis 
set. 
6.3. 
Inclusion and Exclusion Criteria 
A listing, based on the All Enrolled analysis set, will be included displaying which protocol 
version each subject was recruited under, and whether the subject met and/or did not meet 
the inclusion and exclusion criteria.  
7. Treatments and Medications 
7.1. 
Prior and Concomitant Medications 
Any prior and concomitant medication used during the study will be recorded and coded 
using WHODRUG (Version B3 dated September 2021 or higher). Summaries of all 
medications by drug class (ATC Level 4 coding) and PT will be provided separately for prior 
medications and concomitant medications. 
For the Main Treatment Period, prior medications are those with the stop date prior to the 
first dose of the Main Treatment Period. Concomitant medications are those with start dates 
prior to the first dose of the Main Treatment Period and continuing after the first dose of the 
Main Treatment Period or with start dates between the first dose of the Main Treatment 
Period and the first dose of the Transition Period. 
For the Transition Period, concomitant medications are those with start dates prior to Day 1 
of the Transition Period and continuing after Day 1 of the Transition Period or with start 
dates on or after Day 1 of the Transition Period. 


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Prior and concomitant medications will be summarised and listed for both the Main 
Treatment Period and the Transition Period. For the Main Treatment Period, prior and 
concomitant medications will be summarised separately using the SAF analysis set. For the 
Transition Period, concomitant medications will be summarised using the SAF-TP analysis 
set. 
For the purpose of inclusion in prior and concomitant medication tables, incomplete 
medication start and stop dates will be imputed as described in Section 4. 
If start date is completely missing and end date is after the first study drug dose or completely 
missing, then the medication will be classified as both prior and concomitant. If the start date 
is completely missing and the end date is prior to the first dose of study drug, then the 
medication will be classified as prior. If the end date is missing and the start date is after first 
study drug dose, then the medication will be considered as ongoing and classified as 
concomitant. If the end date is missing and the start date is before first study drug dose, then 
the medication will be considered as ongoing and classified as both prior and concomitant. 
Prior and concomitant medications for two periods (Main treatment period and Transition 
period) will be presented in a listing for the SAF analysis set presenting information 
collected under the “Prior and Concomitant Medications” and “Bisphosphonates” eCRF 
forms. 
For concomitant medications only, any that are reporting Vitamin D or Calcium will not be 
summarised or listed.  
7.2. 
Prohibited Concomitant Medications 
Prohibited concomitant therapy will be summarised separately for the Main Treatment 
Period and the Transition Period using the SAF and SAF-TP, respectively. 
 
For this study, prohibited concomitant therapy will be defined as the bundle of medication 
compound, indication, dose, frequency and duration of the therapy, or any other 
consideration which impacts on bone metabolism, BMD and/or denosumab mechanism of 
action. To select the prohibited therapies, the same medication compounds that were 
considered to have an impact on bone metabolism for eligibility were analysed. After 
flagging them in an excel file report taken from CM SDTM, medical assessment was 
performed to conclude whether that therapy was to be prohibited or not. The medical 
assessment was performed case by case considering therapy as a bundle of factors including 
dose, frequency, indication and duration of medication. In cases where applies, also 
cumulative dose was considered, as well as any other potential impact on bone metabolism, 
BMD or denosumab mechanism of action.  
Before primary and final data cut-off date, mAbxience team will flag prohibited medications 
in an excel file report taken from CM SDTM. Prohibited medications flagged will be loaded 
back in CM SDTM to be used in the statistical analysis. This process is documented in a 


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Data Import Agreement document. 
In addition, time to first prohibited or other osteoporosis medication will be presented by 
treatment (MB09 or Prolia) using a Kaplan-Meier curve on the SAF whereby the first dose 
date of prohibited or other osteoporosis medication will be the event date. Subjects who have 
not had an event will be censored at the earliest of data cut-off date and EOS visit date. 
7.3. 
Vitamin D and Calcium Supplementation 
Vitamin D and calcium supplementation compliance will be summarised separately for the 
Main Treatment Period using the SAF and for the Transition Period and throughout the study 
using the SAF-TP and SAF respectively.  
Compliance (%) = (total number of scheduled visits when supplement was taken/total 
number of scheduled visits performed) × 100. 
Summary statistics for vitamin D and calcium supplementation compliance percentages and 
compliance categories (<25, ≥25 - <50, ≥50 - <75, ≥75 - <100, 100) will be summarised.  
All vitamin D and calcium supplementation administration data for two periods (Main 
Treatment Period and Transition Period) will be presented in a data listing using the SAF 
analysis set. 
7.4. 
Study Treatments 
Study treatments will be summarised separately for the Main Treatment Period and the 
Transition Period using the SAF and SAF-TP, respectively. The count and percentage of 
subjects receiving each dose, and reason if dose is not administered. 
In addition, time to treatment discontinuation will be presented by treatment (MB09 or 
Prolia) using a Kaplan-Meier curve on the SAF whereby the last visit date will be the event 
date for those subjects who are off study treatment. Subjects who have not had an event will 
be censored at the earliest of data cut-off date and EOS visit date. 
All study drug administration data for two periods (Main treatment period and Transition 
period) will be presented in a data listing using the SAF analysis set. 


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8. Efficacy Analysis 
8.1. 
Overview of Statistical Methods: Estimation of Estimands and Sensitivity Analyses 
Table 8-1 presents a summary of statistical methods including sensitivity analyses. 
Table 8-1 
Summary of Statistical Methods, Including Sensitivity Analyses 
Estimand 
Label 
Estimand Description 
Main Estimation 
Sensitivity Analysis 
Analysis Set 
Imputation/Data/ 
Censoring Rules 
Analysis Model/Method 
Estimand 1a 
(Primary) 
Difference in means 
(MB09 minus EU-Prolia) in  
composite endpoint of %CfB 
in lumbar spine BMD after 
52 weeks/12 months 
(where %CfB of zero is taken 
for anyone who dies)  
in postmenopausal women[1] 
with osteoporosis treated 
with subcutaneous 
denosumab injections every 6 
months assuming that all 
women receive two 
denosumab doses without 
any errors or deviations in 
dosing and without receipt of 
any prohibited therapies or 
other osteoporosis 
medications. 
mFAS 
The composite endpoint 
defines any deaths as 
zero. 
mFAS removes data 
occurring after ICEs for 
which the hypothetical 
strategy is used (keeping 
all eligible subjects in the 
FAS). 
For sensitivity [i], MI 
under MAR [ii] delta 
applied to imputation in 
the tipping point 
approach. 
MMRM of %CfB BMD at 
Month 6 and Month 12 
including terms for visit 
by treatment, baseline 
BMD (as a covariate), and 
classification variables 
for: age, body mass index 
and prior use of 
bisphosphonates. The 
estimated mean difference 
in %CfB will be presented 
with 95% CI at each time 
point. The 95% CI for the 
mean difference at Month 
12 in %CfB BMD will be 
compared to margins of 
[-1.45, 1.45]. 
(See Section 8.2.1 for 
further details). 
[i] MI under MAR approach will 
be applied to the mFAS 
(see Section 8.2.2.1 for further 
details).  
%CfB BMD at Month 12 from 
each multiple imputed data set 
will be analysed by MMRM and 
results pooled using Rubin’s 
method.  
[ii] A tipping point analyses will 
be performed. First, MI under 
MAR will be used to impute 
missing data where a penalty will 
be added to the imputed %CfB 
values. The same penalty (delta) 
will be applied to anyone who 
dies. The tipping point will 
consider delta1 and delta2 for the 
Prolia and MB09, respectively in a 
matrix of delta so that tipping 
points for both the upper and 
lower margins are considered (see 
Section 8.2.2.2 for further details). 
Supplementary: MMRM analysis 
of log transformed data (see 
Section 8.2.5 for further details). 


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Estimand 
Label 
Estimand Description 
Main Estimation 
Sensitivity Analysis 
Analysis Set 
Imputation/Data/ 
Censoring Rules 
Analysis Model/Method 
Estimand 2a 
Similarly for lumbar spine 
BMD at 6 months 
mFAS 
As above 
As above 
As above for [i] MI under MAR, 
and supplementary MMRM on log 
data. 
Estimand 1b 
(Supportive) 
Difference in means 
(MB09 minus EU-Prolia) in  
composite endpoint of %CfB 
in lumbar spine BMD after 
52 weeks/12 months 
(where %CfB of zero is taken 
for anyone who dies)  
in postmenopausal women[1] 
with osteoporosis treated 
with subcutaneous 
denosumab injections every 
6 months irrespective of 
discontinuation of treatment 
for any reason, errors or 
deviation in dosing and 
whether any prohibited 
therapies or other 
osteoporosis medications are 
taken.  
FAS 
The composite endpoint 
defines %CfB of zero for 
anyone who dies. 
For the main analysis, MI 
under MAR  with offset 
applied to “treatment 
failures” (not receiving 
the 2nd dose) to be centred 
around baseline.  %CfB-
TF will define %CfB after 
applying offset for 
treatment failures (see 
Section 8.2.3.1). 
ANCOVA of %CfB-TF 
BMD at Month 12 for 
each multiply imputed 
dataset and including 
terms for treatment, 
baseline BMD (as a 
covariate), and 
classification variables 
for: age, body mass index 
and prior use of 
bisphosphonates. Results 
will be pooled using 
Rubin’s method 
The estimated mean 
difference in %CfB BMD 
will be presented with 
95% CI (see Section 8.2.3 
for further details).  
 
The same tipping point approach 
used for Estimand 1a will be 
performed.  A penalty will be 
added to the imputed %CfB-TF 
values. The tipping point will 
consider delta1 and delta2 for the 
Prolia and MB09, respectively in a 
matrix of delta so that tipping 
points for both the upper and 
lower margins are considered 
(Section 8.2.2.2 and 8.2.4). 
Supplementary: ANCOVA 
analysis of untransformed and log 
transformed data in FAS without 
imputation (see Section 8.2.5 for 
further details). 
Estimand 2b 
(Supportive) 
Similarly for lumbar spine 
BMD at 6 months. 
FAS 
The composite endpoint 
defines any deaths as zero. 
Observed data will be 
analysed without any 
imputation. 
ANCOVA of %CfB BMD 
at Month 6 as above. 
Supplementary: ANCOVA 
analysis of log transformed data 
(see Section 8.2.5 for further 
details). 


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Estimand 
Label 
Estimand Description 
Main Estimation 
Sensitivity Analysis 
Analysis Set 
Imputation/Data/ 
Censoring Rules 
Analysis Model/Method 
Estimand 
3a-4a 
Difference in means (MB09 
minus EU-Prolia) in  
composite endpoint of %CfB 
(zero is taken for anyone who 
dies) in  
x (3a) hip BMD after 
6 and 12 months. 
x (4a) femur neck BMD 
after 6 and 12 months. 
In postmenopausal women[1] 
with osteoporosis treated 
with subcutaneous 
denosumab injections every 
6 months assuming that all 
women receive scheduled 
denosumab dose(s) without 
any errors or deviations in 
dosing and without receipt of 
any prohibited therapies or 
other osteoporosis 
medications are taken. 
mFAS 
The composite endpoint 
defines %CfB of zero for 
anyone who dies. 
The mFAS removes data 
occurring after ICEs for 
which the hypothetical 
strategy is used (keeping 
all subjects in the mFAS). 
As per Estimand 1a and 
2a for lumbar spine BMD, 
MMRMs will be fitted to 
hip BMD and to femur 
neck %CfB BMD at 
Month 6 and Month 12 
and these will be of the 
same form including 
terms for visit by 
treatment, baseline BMD 
and strata as classification 
variables. 
(See Section 8.3.1 for 
further details). 
None. 
Estimand 
3b-4b 
Difference in means 
(MB09 minus EU-Prolia) in  
x (3b) hip BMD after 
6 and 12 months. 
x (4b) femur neck BMD 
after 6 and 12 months. 
(where %CfB of zero is taken 
for anyone who dies)  
in postmenopausal women[1] 
with osteoporosis treated 
with scheduled denosumab 
FAS 
The composite endpoint 
defines any deaths as zero. 
Observed data will be 
analysed without any 
imputation. 
 
ANCOVA of %CfB BMD 
for each endpoint by 
time point and including 
terms for treatment, 
baseline BMD, and strata 
as classification variables. 
The estimated mean 
difference in %CfB will 
be presented with 95% CI. 
(See Section 8.3.2 for 
further details). 
None. 


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Estimand 
Label 
Estimand Description 
Main Estimation 
Sensitivity Analysis 
Analysis Set 
Imputation/Data/ 
Censoring Rules 
Analysis Model/Method 
dose(s) every 6 months 
irrespective of 
discontinuation of treatment 
for any reason, errors or 
deviations in dosing and 
whether any prohibited 
therapies or other 
osteoporosis medications are 
taken. 
Estimand 5 
Ratio of geometric means 
(MB09/EU-Prolia) in sCTX 
AUEC0-6 months 
in postmenopausal women[1] 
with osteoporosis treated 
with subcutaneous 
denosumab injections every 
6 months assuming all 
women receive their first 
denosumab dose without any 
errors in dosing and without 
receipt if any prohibited 
therapies or other 
osteoporosis medications up 
to 6 months after the first 
dose. 
Additional summary: Mean 
difference in sCTX at 
11 days; 1, 3 and 6 months 
after the first dose; and 
6 months after the second 
dose of study drug. 
mFAS 
Interpolation/extrapolation 
will be used to calculate 
AUEC but will require at 
least baseline and 
three post-dose time 
points. 
ANCOVA model on log 
transformed data 
including log transformed 
baseline sCTX as a 
continuous covariate with 
stratification variables 
included as classification 
factors. Back 
transformation of mean 
differences will give the 
ratio of geometric means 
(MB09/EU-Prolia) with 
95% CI. (See Section 10.1 
for further details). 
Supplementary: MMRM on the 
unlogged sCTX allowing for 
different variability at each 
time point up to Month 12. The 
least square means and differences 
with 95% CI will be plotted over 
time. An estimate statement will 
be used to calculate a weighted 
average across the scheduled 
time points where the weights 
correspond to the weights used in 
calculating AUEC. Thus this will 
give an estimate of mean AUEC 
and difference between mean 
AUEC with 95% CI. 
(See Section 10.1 for further 
details). 
[1] Women will not have been previously treated with denosumab but may have had prior treatment with bisphosphonates and will be co-administered 
calcium and vitamin D supplements. 


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Abbreviations: %CfB, percentage change from baseline; %CfB-TF, percentage change from baseline for treatment failure; ANCOVA, analysis of 
covariance; AUEC, area under the effect curve; AUEC0-6 months, area under the effect curve from zero to 6 months; BMD, bone mineral density; CI, 
confidence interval; EU-Prolia, EU-sourced Prolia; FAS, Full Analysis Set; ICE, intercurrent event; MAR, missing at random; mFAS, Modified Full 
Analysis Set; MI, multiple imputation; MMRM, mixed model for repeated measures; sCTX, serum carboxy-terminal cross-linking telopeptide of type 
I collagen. 
Note: The screening BMD assessment will be taken as the baseline BMD assessment. 
 


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8.2. 
Primary Efficacy Endpoint 
8.2.1. 
Main Estimation of Estimand 1a (Primary) 
The centralized independent and blinded reading and analysis of DXA scans will be used to 
assess BMD. Uncorrected subject BMD results will be sent to PPD, and if and when 
corrections are determined as they are all retrospective, the corrected data will be sent as 
well. These are corrections for longitudinal drift, cross-calibration, and machine equivalence 
(scanner upgrades). Efficacy analysis will be based on the corrected data if corrections are 
applied.  
Unadjusted total lumbar spine BMD results will include lumbar vertebrae from L1 to L4 and 
will be sent to PPD. Due to fracture, artifact such as hardware or other issues individual 
vertebral levels may be excluded retrospectively from all visits with the total spine BMD 
calculated based on the evaluable vertebral levels. If and when adjustment in vertebral levels 
occurs, the adjusted data will be sent as well. Efficacy analysis will be based on the adjusted 
total spine BMD results. 
The statistical hypothesis associated with the difference in treatments for the primary 
efficacy analysis of %CfB in lumbar spine BMD at Month 12 is:  
H0: (μMB09 - μProlia ≤ -1.45%) or (μMB09 - μProlia ≥ +1.45%)  
H1: -1.45% < μMB09 - μProlia < +1.45%  
where μMB09 and μProlia denotes the true mean %CfB in lumbar spine BMD at Month 12 for 
MB09 and EU-Prolia, respectively. 
For the primary efficacy analysis, a MMRM will be fitted to the composite %CfB lumbar 
spine BMD at Month 6 and Month 12 on the mFAS. The MMRM will include terms for visit 
by treatment, with stratification variables (age, body mass index and prior use of 
bisphosphonates) included as classification factors and baseline BMD included as a 
continuous covariate. Note: Baseline BMD at the lumbar spine is included as a covariate 
rather than including BMD T-score as a classification factor. Subject will be included as a 
random effect.  
The estimated treatment LS means will be presented at each time point. Due to potential 
imbalances in stratification covariates treatment LS means will be computed for the two 
weighting schemes: 
1. The standard weighting scheme with equal coefficients across stratification 
covariates. 
2. Weighting scheme with coefficients that are proportional to those found in the data 
(using SAS OM option). 


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The estimated mean difference in %CfB lumbar spine BMD will be presented with 95% CI 
at each time point. 
The estimated mean difference in %CfB lumbar spine BMD at Month 12 will be presented 
with 95% CI and equivalence will be concluded if this falls within the predefined 
equivalence margins of [ -1.45%, 1.45%]. 
Of note, the main analysis method is on the mFAS and, therefore, does not use data after any 
errors or deviation in dosing and without receipt of any prohibited therapies or other 
osteoporosis medications. 
All efficacy data will be presented in listings. 
8.2.2. 
Sensitivity Analysis of Primary Efficacy Endpoint 
Two sensitivity approaches will be performed: 
1. 
A multiple imputed data set produced under MAR, as explained below in 
Section 8.2.2.1, will be applied to the mFAS. In each multiple imputed data set, all 
eligible subjects in the FAS (i.e. mFAS) will have complete data and an indicator 
variable will be derived to indicate if data are observed or imputed. The composite 
%CfB lumbar spine BMD will be calculated as a post processing step from BMD 
values. 
 
2. 
“Sensitivity using tipping point” will assess the robustness of results in both of the 
one-sided hypotheses by adding penalties in both directions to all missing data (see 
Section 8.2.2.2). 
8.2.2.1. 
Multiple Imputation Model Under Missing at Random 
The multiple imputation approach will be tested on blinded data and thus should be 
confirmed, and any changes documented before database lock in the blinded review. Any 
post-unblinding modifications to the multiple imputation model or approaches to address 
missing data due to unexpected data issues after unblinding treatment will be described in 
the Clinical Study Report. 
Data Pre-processing 
Data will be transposed to give a single record per subject (FAS or mFAS) at each relevant 
scheduled timepoint (Screening, Month 6, and Month 12). Actual values rather than changes 
from baseline will be included as input into the imputation model. 
Imputation Model Step 1 
The multiple imputation process will be used with 30 imputations so that 30 complete 
multiple imputed datasets are produced using SAS 9.4 (or higher) PROC MI.  


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The first step is to impute any intermittent missing data at Month 6 (i.e., where Screening 
and Month 12 data are available) using a Markov Chain Monte Carlo (MCMC) method with 
single chain, non-informative prior, 200 burn-in iterations, 30 iterations between imputations 
in a chain and Expectation-Maximization algorithm (using mcmc chain=single 
impute=monotone prior = jeffreys options) and seed of 8749102 (this seed has been 
randomly generated). 
The imputation model will be fitted by treatment (MB09 or Prolia) and analysis set (mFAS 
or FAS) and include the following terms in this specific order with terms included in 
chronological order (i.e. all baseline terms are first and all Month 12 terms are last): 
x Age (continuous) 
x BMI at baseline (continuous) 
x Total number of doses received 
x Prior use of bisphosphonates (0, 1) 
x Baseline sCTX 
x Lumbar spine BMD at Baseline 
x sCTX at Day 11, Month 1, Month 3, Month 6 
x Lumbar spine, hip, femur BMD at Month 6 
x sCTX at Month 12 
x Lumbar spine, hip, femur BMD at Month 12 
In the event that the model does not converge then removal of some of the later sCTX terms 
will be considered first.  
 
Imputation Model Step 2 
The output data set from Imputation Model Step 1 (MI1) will be the input for Step 2 using 
Monotone Regression. The second imputation model will generate one imputation for each 
of previous multiple imputed datasets of MI1 (i.e., by _Imputation_ and analysis set) and a 
seed of 293654.  
The model will include the same variables and in the same specific order as above with the 
additional first term for Randomised treatment (MB09 or Prolia). 
In the event that the model does not converge then removal of some of the later sCTX terms 
will be considered first.  
Data Post-Processing 


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The output dataset from the multiple imputation model requires post-processing. In 
particular, the composite endpoint of %CfB lumbar spine BMD will be derived.  
Note that the %CfB lumbar spine BMD is defined as zero for anyone who dies, and any 
imputed values will be replaced at this step. 
Additionally, %CfB-TF will be calculated for FAS as defined in Section 8.2.3.1 to achieve 
a return to baseline imputation at Month 12 of those who only received a single dose. 
Multiple Imputation: Analysis Phase 
For Estimands 1a and 2a (mFAS) a MMRM model of %CfB lumbar spine BMD at Month 6 
and Month 12 will be run on each of the 30 multiple imputed datasets. The MMRM model 
(as per Estimand 1a) will comprise terms for visit by treatment, baseline lumbar spine BMD 
(as a covariate), and classification variables for: age, body mass index and prior use of 
bisphosphonates.  
For Estimands 1b and 2b (FAS) an ANCOVA model of %CfB (%CfB-TF for Month 12 
FAS) lumbar spine BMD at Month 6 and Month 12 will be run on each of the 30 multiple 
imputed datasets. The ANCOVA model (as per Estimand 1b) will comprise terms for 
treatment, baseline lumbar spine BMD (as a covariate), and classification variables for: age, 
body mass index and prior use of bisphosphonates. 
Datasets will be produced comprising a record for each imputation of the difference in means 
(MB09 minus EU-Prolia) with corresponding 95% CI. 
Multiple Imputation: Combining Phase 
Difference in means with corresponding 95% CI from MMRM (for Estimand 1a) and 
ANCOVA (for Estimand 1b) of the multiply imputed datasets will be pooled using PROC 
MIANALYZE to produce an overall estimate (the mean of the 30 estimates) based on 
Rubin’s formula with corresponding 95% CI. 
8.2.2.2. 
Sensitivity Using Tipping Point 
Multiple imputation under MAR should produce results close to MMRM and ANCOVA 
analysis of observed data. The tipping point approach tests the robustness of results from MI 
assuming MAR by adding a penalty. 
A tipping point penalty will be added to the Month 12 imputed %CfB lumbar spine BMD 
values (but not to data observed). The same penalty (delta) will be applied to anyone who 
dies for related reasons. The tipping point will add penalties of delta1 and delta2 to %CfB 
BMD values for EU-Prolia and MB09, respectively, in a matrix of values (delta1 = -6 to 6 
by delta2 = -6 to 6 in steps of 1.5). For each combination of delta values, ANCOVA is 
performed for each multiply imputed dataset and then result pooled using Rubin’s method. 
Of note, both positive and negative values of delta will be tested in order to evaluate the 


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tipping point of where the 95% CI for the mean difference in %CfB BMD fails to meet each 
of the lower and upper bounds of the equivalence margins of [-1.45, 1.45]. 
8.2.3. 
Main Estimation of Estimand 1b (Supportive) 
The supportive Estimand 1b requires that study conduct has made a good effort to follow-up 
on subjects particularly after ICEs. 
In order to estimate Estimand 1b an ANCOVA will be fitted to the composite %CfB lumbar 
spine BMD at Month 12 to each multiple imputed data set on the FAS where a treatment 
failure offset penalty is applied to missing values of those not receiving the 2nd dose (see 
Section 8.2.3.1 for details).  The ANCOVA will include terms for treatment, with 
stratification variables (age, body mass index and prior use of bisphosphonates) included as 
classification factors and baseline BMD included as a continuous covariate. Of note, baseline 
BMD at the lumbar spine is included as a covariate rather than including BMD T-score as a 
classification factor. 
The estimated mean difference in %CfB lumbar spine BMD results will be pooled using 
Rubin’s method and will be presented with 95% CI.   
8.2.3.1. 
Return to Baseline Multiple Imputation using Treatment-Failure 
Penalty 
MI under MAR approach will be applied to the FAS (see Section 8.2.2.1) and then an offset 
penalty applied where Month 6 doses was not received.  Subjects will be assumed 
“treatment-failure” if they have missing data at Month 12 and only received the baseline 
dose (did not receive Month 6 treatment for any reason).  It is assumed that these “treatment 
failure” subjects would return to around baseline levels rather than benefit from any 
improvement that may have been expected following Month 6 dose administration. In order 
to allow for a reasonable level of uncertainty in the Month 12 imputed values, the Month 12 
imputed BMD data from the MI under MAR will be adjusted by an individual offset so that 
%CfB BMD values for a subject considered as treatment failure will be centred around zero. 
Thus, an alternative %CfB-TF will be calculated defined as %CfB minus offset where offset 
is calculated for each individual as the mean of that individual’s %CfB values (imputed 
under MAR) for subjects classified as treatment failures. No offset (i.e. offset = 0) is applied 
to: 
x any observed data (treatment policy approach uses data as observed);  
x any missing Month 6 BMD data (since at Month 6 everyone will have only received 
a single dose) 
x deaths (deaths have composite %CfB BMD defined as zero); 
x subjects who receive both baseline and Month 6 treatment.  
  
An ANCOVA is performed on %CfB-TF for each multiply imputed dataset and then results 
pooled using Rubin’s method in order to present the difference in mean %CfB with 95% CI. 


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8.2.4. 
Tipping Point Sensitivity Analysis of Estimand 1b (Supportive) 
The main estimation method for Estimand 1b is ANCOVA on Month 12 imputed %CfB 
lumbar spine BMD values where a multiple imputation approach with treatment failure 
offset is used and thus the dependent variable is defined as %CfB-TF (see Section 8.2.3.1). 
The same approach will be taken as for the primary estimand tipping point (see Section 
8.2.2.2).   A tipping-point penalty (delta) will be added to all imputed %CfB-TF above (but 
not to data observed).  This penalty will be applied regardless of the reason for missingness 
and even if the treatment failure offset penalty has already been applied.  In the case of any 
deaths, the penalty will be applied to anyone who dies for related reasons but for unrelated 
deaths zero change from baseline is assumed (the same approach as per Section 8.2.2.2). 
The tipping point will add penalties of delta1 and delta2 to %CfB-TF BMD Month 12 values 
for EU-Prolia and MB09, respectively, in a matrix of values (delta1 = -6 to 6 by delta2 = -6 
to 6 in steps of 1.5). For each combination of delta values, ANCOVA is performed for each 
multiply imputed dataset and then results pooled using Rubin’s method.  
8.2.5. 
Supplementary Analysis of Primary Efficacy Endpoint 
In order to investigate assumptions of normality, the log transformed BMD as a ratio of 
baseline will be analysed in a similar MMRM model to the main analysis but with baseline 
covariate as the log BMD (using the mFAS). The least squares means and difference will be 
back-transformed to present geometric mean ratios of baseline, and 95% CI for the ratio of 
geometric means (MB09/EU-Prolia). Note: For anyone who dies, no change from baseline 
will be assumed (BMD ratio of baseline of 1). Residual plots will be produced and compared 
to the main analysis. 
Similarly, the ANCOVA analysis on the FAS (without multiple imputation) will be 
performed on non-transformed and log transformed data as supplementary analysis for 
Estimand 1b.  Geometric mean ratios of baseline at Month 12, and 95% CI for the ratio of 
geometric means (MB09/EU-Prolia) will be presented. 
Residual plots from these analyses on untransformed and log-transformed data will be 
visually inspected. 
8.3. 
Analysis of Key Secondary Efficacy Endpoints 
8.3.1. 
Main Estimation of Hypothetical Estimand 2a-4a 
MMRM as per the main analysis of the primary endpoint (see Section 8.2.1) will be used to 
analyse composite endpoint of %CfB (zero is taken for anyone who dies) on the mFAS in: 
x Lumbar spine BMD after 6 months.  
x Hip BMD after 6 and 12 months. 


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x Femur neck BMD after 6 and 12 months. 
8.3.2. 
Main Estimation of Treatment Policy Estimand 2b-4b 
An ANCOVA (see Section 8.2.3) on the FAS (without any multiple imputation methods) 
will be used to analyse the composite endpoint of %CfB (zero is taken for anyone who dies) 
in:  
x Lumbar spine BMD after 6 months.  
x Hip BMD after 6 and 12 months. 
x Femur neck BMD after 6 and 12 months. 
8.4. 
Subgroup Analyses 
Subgroup analyses will be conducted for the primary estimand 1a and the secondary 
estimand 2a in the mFAS and the below subgroups will be examined. Other exploratory 
subgroups that may have implications on the treatment effect may be examined as well. 
Difference in means (MB09 minus EU-Prolia) will be estimated using the same analysis 
model as described in Section 8.1.  
x Baseline lumbar spine BMD T-score (as per Clario) (≤ -3.0 versus > -3.0 SD). 
x Body mass index at baseline (< 25 versus ≥ 25 kg/m2). 
x Age at study entry (≥ 55 to < 68 years versus ≥ 68 to ≤ 80 years). 
x Prior bisphosphonate medication use at study entry 
(prior use of bisphosphonates versus no prior bisphosphonate use). 
x Body weight at baseline (≥ 50 to < 70 kg versus ≥ 70 to ≤ 99.9 kg). 
x Smoker (Yes/No). 
x Region (Latin America/Europe) 
A forest plot of difference in means at Month 6 and 12 will be produced. The number and 
percentage of subjects in each subgroup level, difference in means and corresponding 95% 
CI will be provided.  
9. Safety Analysis 
Safety assessments include vital sign assessments, ECG, physical examination, clinical 
laboratory analyses, adverse events (AEs), serious adverse events (SAEs), adverse events of 
special interest (AESIs) and deaths. 
All safety measurements will use all available data for analyses (listings only), including 
data from unscheduled visits. 


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Main Treatment Period and the Transition Period will be analysed on SAF and SAF-TP, 
respectively. Analysis in the Main Treatment Period will be tabulated by MB09-MB09 
(Arm 1) and combined treatment group of Prolia-MB09 (Arm 2) and Prolia-Prolia (Arm 3). 
Analysis in the Transition Period will be tabulated by Prolia-MB09 (Arm 2) and 
Prolia-Prolia (Arm 3). Additionally, cumulative safety data throughout the study (Baseline 
to the end of Transition Period [Month 18]) will be analysed for MB09-MB09 (Arm 1) and 
Prolia-Prolia (Arm 3) as described in section 4. 
In the Transition Period, changes from Month 12 and changes from baseline (Day 1) in 
selected laboratory parameters will be of interest (see Section 9.2). 
9.1. 
Adverse Events 
An AE is defined as any untoward medical occurrence in a subject enrolled into this study 
regardless of its causal relationship to the study drug.  
Any new condition noted at or after screening up to baseline (i.e., before administration of 
the first dose of the study drug) will be regarded as an AE, but not a treatment emergent 
adverse event (TEAE), see Section 9.1.1 for further details on TEAE.  
Anticipated day-to-day fluctuations of pre-existing diseases or conditions present or 
detected at the start of the study that do not worsen are not considered AE. Laboratory results 
of disease/disorders being studied, medical/surgical procedures are not an AE but rather the 
condition/event that leads to it are defined as an AE. 
Any abnormal laboratory test results (haematology, clinical chemistry, coagulation or 
urinalysis) or other safety assessments (eg, ECGs, radiological scans, vital sign 
measurements), including those that worsen from baseline or are clinically significant in the 
medical and scientific judgement of the investigator will be recorded as AE or SAE if they 
fulfil the following: 
x Results in discontinuation from the study. 
x Requires treatment or any other therapeutic intervention. 
x Requires further diagnostic evaluation (excluding a repetition of the same procedure 
to confirm the abnormality). 
x Are clinically significant as evaluated by the investigator. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, will not be reported as AE or SAE. Disease progression of 
postmenopausal osteoporosis will not be recorded as an AE or SAE; however, any new 
fractures confirmed by the central imaging vendor will be recorded as AE or SAE. 
Medical intervention such as surgery, diagnostic procedures, and therapeutic procedures are 
not AEs but the action taken to treat the medical condition. They will be recorded as 


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treatment(s) of the AEs. The event term of primary cause will be recorded and reported 
instead of the term of surgery, diagnostic procedure, or therapeutic procedure. 
AEs experienced by the subjects will be collected throughout the entire study and will be all 
listed and coded using the MedDRA (version 24.1 or higher). 
9.1.1. 
Treatment Emergent Adverse Events 
A TEAE is defined as any event not present before exposure to the study drug or any event 
already present that worsens in intensity after exposure to the study drug. This includes any 
occurrence that is new in onset or aggravated in severity from the baseline condition. 
For the Main Treatment Period, TEAE is an event observed after first administration of study 
drug on Day 1 until Month 12 and no more than 6 months after last administration of study 
drug in case of early treatment discontinuation unless the TEAE is considered as related to 
the drug by investigator. 
For the Transition Period, TEAE is an event observed after third dose of study drug at Month 
12 until Month 18. 
For the cumulative safety data analysis at Month 18, TEAE is an event that is classified as 
either Main Treatment Period TEAE or Transition Period TEAE. 
Imputed AE data will be summarised, but all the original collected AE data will be presented 
in a listing. TEAEs will be flagged in all the AE listings and will be summarised. 
In the case of missing or partially missing AE onset dates, the rules described in Section 4 
will be applied. 
9.1.2. 
Incidence of Adverse Events 
Summaries of the total number of TEAEs and the number and percentage of subjects with 
at least one TEAE will be provided by treatment (arm). The number and percentage of 
subjects and the number of events will also be presented by SOC and PT. At each level of 
subject summarisation, a subject will be counted once if the subject reported one or more 
events. Percentages will be calculated out of the number of subjects in the SAF and SAF-TP 
for the Main Treatment Period and the Transition Period respectively. Cumulative safety data 
analysis will be calculated out of the number of subjects in the SAF. 
. The number of events at each level of SOC and PT will also be summarised.  
The summary of TEAEs will be presented in descending order of frequency of SOC and PT 
in the specified treatment (arm) (that is, MB09-MB09 arm (Arm 1) for the Main Treatment 
Period, Prolia-MB09 arm (Arm 2) for the Transition Period, and MB09-MB09 arm (Arm 1) 
and Prolia- Prolia (Arm 3) for cumulative safety data analysis. If the incidence for two or 
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The number and percentage of subjects and the number of events will also be categorised by 
PT only and will be presented in descending order of incidence. 
9.1.3. 
Relationship of Adverse Events to Study Drug 
The investigator will provide an assessment of the relationship of the event to the study drug. 
The possible relationships are “Unrelated”, “Possibly Related”, “Probably Related” and 
“Definitely Related”. "Unrelated” AEs will be categorised as “Not Related”. All other AEs: 
“Possibly Related”, “Probably Related” and “Definitely Related” will be categorised as 
“Related”. TEAEs that are missing a relationship will be presented in the summary table as 
“Related” but will be presented in the data listing with a missing relationship. The TEAE 
data will be categorised and presented by SOC, PT, and relationship (i.e., “Related” and “Not 
Related”) similarly to that described in Section 9.1.2. Percentages will be calculated out of 
the number of subjects in the SAF and SAF-TP for the Main Treatment Period and the 
Transition Period respectively. Cumulative safety data analysis will be calculated out of the 
number of subjects in the SAF. 
9.1.4. 
Severity of Adverse Event 
The assessment of severity, or intensity, of an TEAE will be made using the following 
CTCAE grading criteria Version 5.0: 
Grade 1: 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2: 
Moderate: minimal, local or non-invasive intervention indicated; limited 
age-appropriate instrumental activities of daily living. 
Grade 3: 
Severe: medically significant but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; limited 
self-care activities of daily living. 
Grade 4: 
Life-threatening consequences: urgent intervention indicated. 
Grade 5: 
Death related to adverse event. 
A summary of TEAEs by severity will be presented in a table. The severity that will be 
presented represents the most extreme severity captured on the CRF page. In the TEAE 
severity table, if a subject reported multiple occurrences of the same TEAE, only the most 
severe will be presented. TEAEs that are missing severity will be presented in table as 
“Grade 3” but will be presented in the data listing with a missing severity. Percentages will 
be calculated out of the number of subjects in the SAF and SAF-TP for the Main Treatment 
Period and the Transition Period respectively. Cumulative safety data analysis will be 
calculated out of the number of subjects in the SAF.  
The TEAE data will be categorised and presented by SOC, PT and severity in a manner 
similar to that described in Section 9.1.2. In addition, a summary presented by SOC, PT, 
severity and relationship will be provided similarly to that described in Section 9.1.3. 


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9.1.5. 
Serious Adverse Events 
The seriousness of an AE should be assessed by the investigator independently from the 
severity of the AE. A serious AE (SAE) is any untoward medical occurrence that at any dose 
results in death, is immediately life threatening, requires inpatient hospitalisation or 
prolongation of existing hospitalisation, results in persistent or significant disability or 
incapacity, is a congenital anomaly or birth defect. Medical and scientific judgement will be 
exercised in deciding whether expedited reporting is appropriate in other situations, such as 
important medical events that may not be immediately life-threatening or result in death or 
hospitalisation but may jeopardise the subject or may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition above. 
AEs to be treated as SAEs by the investigator are AEs associated with hospitalisation (over 
24 hours) or prolongation of hospitalisation. Admission also includes transfer within the 
hospital to an acute/intensive care unit (e.g., from the psychiatric wing to a medical floor, 
from medical floor to a coronary care unit, from neurological floor to a tuberculosis unit).  
Hospitalisation or prolongation of hospitalisation in the absence of a precipitating clinical 
AE is not in itself a SAE. 
For missing dates, the rules stated in Section 4 will be followed.  
Serious TEAEs will be categorised presented by SOC and PT in a manner similar to that 
described in Section 9.1.2. The number and percentage of subjects and the number of events 
will also be categorised by PT only and will be presented in descending order of incidence. 
In addition, a summary of serious TEAEs presented by SOC, PT, and severity will be 
provided similarly to that described in Section 9.1.4. 
All SAEs will be presented in a listing. 
9.1.6. 
Serious Adverse Events, Related to Study Drug 
The drug-related serious TEAE data will be categorised and presented by SOC and PT in a 
manner similar to that described in Section 9.1.2. 
9.1.7. 
Adverse Events of Special Interest 
Adverse events of special interests (AESIs) are defined as AEs of scientific or medical 
concern.  
The following AEs are considered as AESIs: injection site reaction, drug-related 
hypersensitivity/allergic reaction, infection, hypocalcaemia, osteonecrosis of the jaw, 
dermatologic reaction and atypical femoral fracture. 
A summary of AESIs will be presented by severity, SOC and PT similar to that described in 
Section 9.1.4. 


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All AESIs will be presented in a listing. 
9.1.8. 
Serious Adverse Events of Special Interest 
A summary of serious AESIs will be categorised and presented by SOC, PT, in a manner 
similar to that described in Section 9.1.2. 
9.1.9. 
Adverse Events Leading to Treatment Discontinuation 
A summary of TEAEs with a study drug action taken of “Drug Withdrawn” will be 
presented in a table in a similar manner to that described in Section 9.1.2. 
All TEAEs leading to treatment discontinuation will be presented in a listing. 
9.1.10. 
Adverse Events Leading to Death 
A summary of TEAEs where the answer to “Outcome” is “Fatal” will be presented in a table 
in a similar manner to that described in Section 9.1.2.  
All subjects who have an AE with an outcome of “Fatal” will be presented in a listing. 
9.1.11. 
Death 
Deaths and reasons for death will be presented in the AE overview summary table and will 
be presented in a listing. 
9.1.12. 
Overview summary 
An overview summary of the number and percentage of subjects with any TEAE, study 
drug-related TEAE, serious TEAE, study drug-related serious TEAE, AESI, serious AESI, 
TEAE leading to treatment discontinuation, AE leading to death, and all deaths will be 
provided by treatment (arm).  
9.1.13. 
Summary of Non-Traumatic Fractures 
A summary of non-traumatic fractures will be presented in a table in a similar manner to that 
described in Section 9.1.2.  
9.2. 
Clinical Laboratory Evaluations 
All summaries will be based on SI units. Blood and urine samples collected for clinical 
laboratory values (haematology, clinical chemistry, coagulation and urinalysis) will be 
analysed by the central laboratory.  
Clinical chemistry and haematology are collected at screening, baseline (Day 1), Day 11, 
Month 1, Month 3, Month 6, Month 9, Month 12 (End of Treatment), Transition Period 
Day 11, Transition Period Month 3, and Transition Period Month 6 (End of Study) visits. 
Coagulation and urinalysis are collected at screening, baseline (Day 1), Month 6, Month 12 
(End of Treatment), and Transition Period Month 3. 


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In the Main Treatment Period, a summary table presenting observed values and changes 
from baseline will be presented for clinical chemistry (PTH parameter) only with numeric 
values. Change from baseline to each scheduled post-baseline visit will be presented.  
The following graphics will also be provided for selected clinical laboratory tests 
(albumin-corrected calcium only): 
x A plot showing baseline and worst post-baseline in clinical laboratory values. 
x A boxplot of values per visit. 
x A spaghetti plot of values per visit. 
Shift tables summarising the baseline and post-baseline timepoints for analysis ranges of 
clinical laboratory tests will be displayed in cross-tabulations. Additionally, the worst 
post-baseline result categorized based on analysis range will be presented. 
A summary table presenting the worst post-baseline CTCAE grade for the albumin-adjusted 
total serum calcium will be provided. Results will be programmatically graded according to 
CTCAE v5.0. 
In the Transition Period, summary tables and graphics will be presented for all laboratory 
parameters described in sections 9.2.1 to 9.2.4, except changes will be presented from 
Month 12 instead of baseline (Day 1). Additionally, changes from baseline (Day 1) to each 
scheduled visit in the Transition Period will be presented for selected clinical laboratory 
tests: albumin-corrected calcium.  
For the cumulative safety data analysis at Month 18, summary tables and graphics will be 
presented for all laboratory parameters described in sections 9.2.1 to 9.2.4, except data will 
be analysed for armMB09-MB09 (Arm 1) and Prolia-Prolia (Arm 3) and all assessments up 
to Month 18 will be included. 
Listings of clinical laboratory data will be provided separately for two periods (Main 
treatment period and Transition period) using the SAF analysis set.  
9.2.1. 
Haematology 
The following laboratory tests will be included: haemoglobin, haematocrit, red blood cell 
count, white blood cell count with differential count, absolute neutrophil count, absolute 
lymphocyte count, and platelet count. Summary tables and listings will be presented as 
described in Section 9.2. 
9.2.2. 
Clinical Chemistry 
The following laboratory tests will be included: albumin-adjusted total serum calcium, 
alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, total 
cholesterol, creatinine, creatine clearance estimation, gamma-glutamyl transferase, glucose, 
triglycerides, magnesium, phosphorus, PTH, potassium, sodium, total bilirubin direct 
bilirubin, protein, thyroid-stimulating hormone and serum 25-OH vitamin D. Summary 
tables and listings will be presented as described in Section 9.2. 


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Albumin-adjusted total serum calcium level will be calculated using the following formula: 
Corrected calcium (mg/dL) = measured total calcium (mg/dL) + 0.8 (4.0 − serum albumin 
[g/dL]), where 4.0 represents the average albumin level. 
If the albumin-adjusted total serum calcium level is calculated using mg/dL unit, it will be 
adjusted for SI units using the following formula: Corrected calcium (mmol/L) = total 
calcium (mmol/L) + 0.02 (40 – serum albumin [g/L]). 
9.2.3. 
Coagulation 
The following laboratory tests will be included: INR, aPTT and PT. Summary tables and 
listings will be presented as described in Section 9.2. 
9.2.4. 
Urinalysis 
The following laboratory tests will be included: colour, pH, specific gravity, glucose, 
ketones, leukocytes, nitrite, protein, bilirubin, urobilinogen, occult blood, and microscopic 
examination (only if urinalysis dipstick results are abnormal). Summary tables and listings 
will be presented as described in Section 9.2. 
9.3. 
Vital Sign Measurements 
Vital signs (including systolic and diastolic blood pressures, heart and respiratory rates, and 
body temperature) will be measured once at pre-dose and once at post-dose for Day 1, 
Month 6, and Month 12 visits; and once for all other visits. Actual values, and changes from 
Month 12 in the Transition Period for systolic and diastolic blood pressures will be 
summarised by scheduled visit, timepoint (pre-dose and post-dose) on days of study drug 
administration, and by treatment (arm), for the Transition Period.  
The following graphics will also be provided for systolic and diastolic blood pressures, 
separately for the Transition Period. 
x A plot showing baseline and worst post-baseline in vital signs. 
x A boxplot of values per visit. 
For the cumulative safety data analysis at Month 18, summary tables and graphics will be 
presented as described for the Transition Period, except data will be analysed for arm 
MB09-MB09 (Arm 1) and Prolia-Prolia (Arm 3) and all assessments up to Month 18 will 
be included. 
All vital signs measurements for two periods (Main treatment period and Transition period) 
will be presented in a data listing using the SAF analysis set. 
9.4. 
Physical Examination 
Physical examination will be collected on the CRF: a complete physical examination will be 
collected at the screening, baseline (Day 1), Month 6, Month 12 and Transition Period Month 


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6 (End of Study) visits. A symptom-specific physical examination will be collected for other 
visits. 
Both complete and symptom-specific physical examination results will be presented in a 
listing together with abnormality specification when provided for two periods (Main 
treatment period and Transition period) using the SAF analysis set. 
9.5. 
Electrocardiogram 
A 12-lead ECG will be performed after the subject has rested in a supine position for at least 
5 minutes at the screening, baseline (Day 1), Month 3, Month 6, Month 12, and Transition 
Period Month 3 visits. Each scheduled visit captures ECG interpretation results as Normal, 
Abnormal NCS, Abnormal CS. 
In the Main Treatment Period, changes from baseline (Day 1) in ECG interpretation results 
will be presented in a shift table by visit for the following categories: Normal, Abnormal 
NCS, Abnormal CS. Similarly, in the Transition Period, changes from Month 12 will be 
presented by visit. 
For the cumulative safety data analysis at Month 18, summary tables will be presented as 
described for the Main Treatment Period, except data will be analysed for arm MB09-MB09 
(Arm 1) and Prolia-Prolia (Arm 3) and all assessments up to Month 18 will be included. 
All ECG interpretation results will be presented in a listing together with abnormality 
specification when provided for two periods (Main treatment period and Transition period) 
using the SAF analysis set. 
9.6. 
Other Safety Data 
9.6.1. 
Injection Site Reaction 
Injection site reactions will be assessed up to 1 hour (± 10 minutes) after the End of Study 
drug administration, as specified in the Schedule of Events (Appendix 16.1). Injection site 
reactions will be graded per FDA guidance (DHHS 2007) as shown in Table 9-1. 
 
 
 
 
 
 


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Table 9-1 
Local Reactions to Injected Study Drug 
Local Reaction to 
Injected Study Drug 
None 
(Grade 0) 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life-Threatening 
(Grade 4) 
Pain 
None 
Does not 
interfere 
with 
activity 
Repeated use 
of non-narcotic 
pain reliever 
>24 hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents 
daily activity 
Emergency room 
visit or 
hospitalisation 
Tenderness 
None 
Mild 
discomfort 
to touch 
Discomfort 
with 
movement 
Significant 
discomfort at 
rest 
Emergency room 
visit or 
hospitalisation 
Erythema/Redness* 
None 
2.5 to 5 cm 
5.1 to 10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling** 
None 
2.5 to 5 cm 
and does 
not 
interfere 
with 
activity 
5.1 to 10 cm or 
interferes with 
activity 
>10 cm or 
prevents 
daily activity 
Necrosis 
*In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable. 
**Indurations/swelling should be evaluated and graded using the functional scale as well as the actual 
measurement. 
All injection site reactions data will be presented in a data listing for two periods (Main 
treatment period and Transition period) using the SAF analysis set. 
9.6.2. 
Hypersensitivity/Allergic Reaction 
Hypersensitivity/allergic reactions monitoring will be assessed before the start of the study 
drug administration (within 15 minutes) and at 1 hour (± 10 minutes) after the end of the 
study drug administration at baseline (Day 1), Month 6, and Month 12 (End of Treatment) 
visits. 


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All hypersensitivity/allergic reactions data will be presented in a data listing for two periods 
(Main treatment period and Transition period) using the SAF analysis set. 
10. Pharmacokinetics and Pharmacodynamics 
10.1. 
Pharmacokinetics 
Blood samples for the determination of serum concentrations of denosumab will be collected 
from subjects in the Main Treatment Period and Transition/Safety Follow-Up Period at the 
time points specified in the Schedule of Events (Appendix 16.1) and as follows: during the 
main treatment period, PK samples will be collected on Day 1 (0 pre-dose), Day 11 and at 
Month 1 (Day 36), Month 3 (Day 90), Month 6 (Day 182, pre-dose) and Month 12 (Day 
365) (for those subjects entering the Transition Period, this sample should be taken prior to 
the third dose of the study drug). During the Transition/Safety Follow-Up Period, additional 
PK samples will be taken at 10 days, 5 weeks, 3 months and 6 months after the administration 
of the third dose of study drug (i.e., Transition Period Day 11, Transition Period Month 1, 
Transition Period Month 3 and Transition Period Month 6).  
The serum concentration-time data for denosumab will be listed and summarised by 
treatment, treatment-induced ADA (TI-ADA) status (where data permits), and time point 
using the PK Concentration Set (PKCS) for the Main Treatment Period and by arm, TI-ADA 
status (where data permits), and time point using the PK Concentration Set for the Transition 
Period (PKCS-TP). Samples whose concentrations are assessed as BLQs (Below Limit of 
Quantification) will be treated as half of LLOQ (lower limit of quantification) value for 
summary statistics. Individual serum denosumab concentration versus actual time data will 
be presented graphically on linear and semilogarithmic scales. Mean serum concentration 
versus nominal time of denosumab data on linear and semilogarithmic scales will also be 
provided.  
If baseline predose concentrations are above the lower limit of quantification, the subject’s 
data (without any adjustments) will be included in all PK tables and statistical evaluations 
where the pre-dose concentration is < 5% of Cmax for the affected subject profile. If the pre-
dose value is > 5% of Cmax, the subject will be flagged in all associated data listings and 
the affected profile will be excluded from all PK summaries and statistical evaluation. 
The pharmacokinetic parameters including Cmax, AUC0-6 months and Ctrough as defined below 
will be generated for each individual subject if data permit by the non-compartmental 
analysis using Phoenix® Win-Nonlin® software Version 8.3 (Certara USA, Inc, Princeton, 
NJ) or SAS software Version 9.4. Actual dose and collection time will be used in the 
calculation of PK parameters. For non-compartmental analysis the following conventions 
will be utilized for BLQ samples: for time points prior to first measurable concentration, 
concentrations BLQs will be treated as zero whereas, embedded BLQ concentrations will be 
treated as missing and terminal BLQ concentrations will be treated as half of LLOQ. 
Individual PK parameters will be listed and summarised by treatment, arm, and TI-ADA 
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Parameter 
Definition 
Cmax 
Observed maximum serum concentration after administration 
AUC0-6 months 
Area under the concentration-time curve from time zero to 6 months, 
calculated using the linear trapezoidal linear interpolation method 
Ctrough 
Trough (pre-dose) serum concentration 
Additional PK parameters, such as truncated AUCs or AUCs over a common time period 
across all subjects, may be calculated as required. 
To assess the denosumab PK profile of MB09 compared with EU-Prolia, Cmax and 
AUC0-6 months will be analysed on the log scale by ANCOVA. The model will include 
treatment and stratification variables (baseline BMD T-score at the lumbar spine (≤ -3.0 and 
> -3.0 SD), body mass index (< 25 and ≥ 25 kg/m2), age at study entry (≥ 55 to < 68 years 
versus ≥ 68 to ≤ 80 years) and prior bisphosphonate medication use at study entry (prior use 
of bisphosphonates versus no prior bisphosphonate use as fixed effects. The estimated mean 
difference with 95% CI will be back-transformed to give the ratio of geometric means 
(MB09/EU-Prolia) with 95% CI following the first dose in the Main Treatment Period. 
Similarly, parameters derived in the Transition Period will be analysed and comparisons will 
be made (Arm 2 Prolia-MB09/Arm 3 Prolia-Prolia and Arm 1 MB09 MB09/Arm 3 Prolia-
Prolia). Ctrough may also be compared at Month 6 and Month 12 in the Main Treatment Period 
and at Month 6 in the Transition Period. 
10.2. 
Pharmacodynamics  
Concentrations of the bone turnover marker (sCTX) will be measured from fasting serum 
samples in the Main Treatment Period and Transition/Safety Follow-Up Period at the time 
points specified in the Schedule of Events (Appendix 16.1). The sCTX concentration and 
percent change from baseline (% CFB) data will be listed and summarised by treatment, 
ADA status (where data permits), and time point using the Modified Full Analysis Set 
(mFAS) for the Main Treatment Period, and by arm, ADA status (where data permits), and 
time point using the Modified Full Analysis Set for Transition Period (mFAS-TP). Samples 
whose concentrations are assessed as BLQs will be treated as half of LLOQ (lower limit of 
quantification) value for summary statistics. Individual original sCTX concentration and 
%CFB in sCTX concentration versus actual time data will be presented graphically on linear 
scale. Mean original sCTX concentration and %CFB in sCTX concentration versus nominal 
time data on linear scale by study period, treatment or arm, and ADA status (where data 
permits) will also be provided. The %CFB will be determined by subtracting each postdose 
sCTX concentration from the D1 predose concentration divided by the D1 predose 
concentration X 100. 
 
All PD parameters will be calculated for each individual subject if data permit by the non-
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Inc, Princeton, NJ). AUEC0-6months will be estimated for sCTX using absolute sCTX 
concentrations. The following PD parameters will be estimated for sCTX using %CFB in sCTX 
values: Imax (the maximum % inhibition), TImax (the time of occurrence of the maximum % 
inhibition) and AUIC0-6months (area under the % inhibition curve from time zero to month 6 
using %CFB data). 
 
AUEC0-6 months and AUIC0-6months will be calculated by the linear trapezoidal method provided 
there are at least baseline, and three post-dose time points between Day 11 and Month 6, 
inclusive. Interpolation or extrapolation will be used if the last time point is not at exactly 
Day 182 whereby concentrations are estimated based on the slope of elimination.If the slope 
cannot be characterized and the Month 6 sample is missing the AUEC0-6 months or AUIC0-
6 months will not be reported.  In such cases, additional PD parameters, such as truncated 
AUECs or AUICs over a common time period across all subjects, may be calculated as required. 
Individual sCTX AUIC0-6 months will be listed and summarised by treatment, arm, period, and 
ADA status (as data permits).  
 
As sCTX is highly variable and can be influenced by many factors (food, circadian rhythm, 
sample handling and processing etc.) (Szulc et al 2017) which might affect in particular the 
baseline CTX values, in order to standardise the PD analysis of equivalence will be 
conducted using the %CFB.  
 
If sCTX baseline values are close to the LLOQ of the sCTX assay the effect of denosumab 
on sCTX in terms of %CFB cannot be measured and will lead to unreliable %CFB values 
(ie, within the assay precision of 16.3% for LLOQ level). Therefore, for baseline PD values 
of <1.163 fold the LLOQ, the AUIC of %CFB in serum CTX will still be calculated, but 
excluded from further analysis. 
 
The individual PD parameters will be presented in data listings and summarized by treatment 
using the following descriptive statistics: number of subjects, arithmetic mean, SD, CV, 
median, minimum, maximum, geometric mean and geometric CV. 
To assess the denosumab sCTX PD profile of MB09 compared with EU-Prolia, 
AUEC0-6 months and AUIC0-6 months will be analysed on the log scale by ANCOVA. The 
geometric least squares means, ratios of the geometric least squares means (MB09 compared 
with EU-Prolia), and corresponding 90% CIs for the ratios will be computed by taking the 
antilog of the least squares means from the ANCOVA model on the natural logarithms of 
the corresponding PD parameters including log transformed baseline sCTX as a continuous 
covariate with treatment and stratification variables (baseline BMD T-score at the lumbar 
spine (≤ -3.0 and > -3.0 SD), body mass index (< 25 and ≥ 25 kg/m2), age at study entry (≥ 
55 to < 68 years versus ≥ 68 to ≤ 80 years) and prior bisphosphonate medication use at study 
entry (prior use of bisphosphonates versus no prior bisphosphonate use) as fixed effects. 
Biosimilarity will be concluded if the 90% CIs for the test (MB09) to reference (EU-Prolia) 
ratios of the geometric least square means is entirely contained within the [80.00%, 
125.00%] interval for AUEC and AUIC.  


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If deemed necessary by the sponsor, a supplementary analysis may be performed to assess 
the impact of missing data. A mixed model for repeated measures (MMRM) will be fitted to 
the unlogged sCTX (mFAS) allowing for different variability at each time point (up to Month 
12). The model will include fixed effect terms for visit by treatment, baseline sCTX and 
classification factors for each stratum. The least squares means and differences with 95% CI 
will be plotted over time. An estimate statement will be used to calculate a weighted average 
across the scheduled visits where the weights correspond to the weights used in calculating 
AUEC. Thus, this will give an estimate of mean AUEC and difference between mean AUEC 
with 95% CI. 
 Descriptive statistics of sCTX concentrations for TP will be presented. 
11. Immunogenicity Assessments  
The immunogenicity of MB09 and EU-Prolia will be analysed in the Main Treatment Period 
by treatment (i.e MB09-MB09 (Arm 1) and combined treatment group of Prolia-MB09 (Arm 
2) and Prolia-Prolia (Arm 3)), in the Transition Period by treatment arms: MB09-MB09 
(Arm 1), Prolia-MB09 (Arm 2),  and Prolia-Prolia (Arm 3). Additionally, immunogenicity 
data throughout the study (Baseline to the end of Transition Period (Month 18)) will be 
analysed for MB09-MB09 (Arm 1) and Prolia-Prolia (Arm 3). 
Analysis of immunogenicity data will be based on ADA evaluable subjects defined as all 
SAF or SAF-TP subjects with baseline and at least one post-baseline immunogenicity 
assessment within the Main Treatment Period or the Transition Period/whole study period, 
respectively. 
The formation of ADAs against MB09 or EU-Prolia will be assessed in blood samples 
(Day 1, Month 6 and Month 12) up to 30 minutes before the study drug administration. All 
other samples will be collected as close as possible to the scheduled time point within 
windows as specified in the schedule of events (Appendix 16.1). 
ADA test methods enable characterization of samples into ADA positive vs. ADA negative. 
Each sample is categorized based on the following definitions: 
x Baseline ADA positive: ADA is detected in the sample before initiation of 
treatment 
x Baseline ADA negative: ADA is not detected in the sample before initiation of 
treatment or no evaluable ADA assessment before initiation of treatment 
x ADA positive sample during main treatment period: treatment induced or 
treatment boosted ADA positive sample 
o Treatment induced ADA (TI-ADA) positive sample: After initiation of 
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subject for whom ADA is not detected at baseline (ADA negative or no 
evaluable ADA assessment at baseline)  
o Treatment boosted ADA (TB-ADA) positive sample: After initiation of 
treatment and during main treatment period, an ADA detected sample with 
ADA titer to be at least n-fold or greater than baseline positive titer, where n 
represents twice the dilution level applied for titration (i.e., at least 4-fold 
increase in ADA titer is considered a positive TB-ADA sample when a 2-
fold serial dilution is applied for titration). 
x ADA negative sample: After initiation of treatment and during main treatment 
period, ADA not positive sample relative to baseline 
 
Subject ADA status is defined based on the sample ADA status as follows: 
x Baseline ADA positive subject: A subject with baseline ADA positive sample 
x Baseline ADA negative subject: A subject with baseline ADA negative sample 
x ADA positive subject: A subject with at least one ADA positive sample relative to 
baseline during main treatment period after initiation of treatment 
x Nab positive subject: At least one ADA positive sample with neutralising 
antibodies detected post-baseline during main treatment period. 
x ADA negative subject: A subject with no ADA positive sample after initiation of 
treatment during main treatment period. 
For analyses based on transition period, ADA positive and ADA negative will consider all 
data after initiation of treatment at week 52 for all three arms. For the analyses thought the 
study, definitions will consider all data after initiation of treatment at Day 1.  
Number and percentage of subjects by subject ADA status will be provided. 
Number and percentage of subjects at each timepoint with positive sample ADA status and 
positive Nab status will be provided. ADA titre data at each timepoint will be summarised 
using summary statistics.  
Effect of immunogenicity on safety will be explored by examining the frequency of AEs. 
Overall AE summary table by subject ADA status will be provided. 
Effect of immunogenicity on efficacy will also be explored similarly. Summary of %CfB in 
lumbar spine BMD by visit and subject ADA status will be provided. 
Association between PK parameters CL and AUC0-6m and TI-ADA status may be explored, 
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All ADA and NAb data will be listed. 
12. COVID-19 Remote Visits 
Visits and assessments completed remotely due to COVID-19 will be listed for the All 
Randomized analysis set. 
13. Interim Analysis 
There will be no formal interim analysis. Safety data will be generated for approximately 
seven DSMB review meetings. In accordance with the protocol, the first formal data review 
meeting will be conducted 3 months after first subject in. After the first data review meeting 
has occurred meetings will be held regularly to evaluate safety during main treatment period. 
14. Changes in the Analysis 
14.1. 
Changes from the Protocol in the Planned Analysis  
The following changes in methods or additional details to those given in Protocol 
Amendment 1 (07 November 2022) are listed below.  Note that these are all made prior to 
data base lock and breaking the study blind. 
 
FAS Definition (Section 4.4.1).  The requirement to strictly meet all eligibility criteria has 
been removed from FAS.  Thus, FAS will be used to compare treatments using an intent-to-
treat philosophy and including all randomised subjects receiving at least one dose.  However, 
it should be noted that some ineligible subjects dosed in error were discontinued from the 
study at W26 as per the original protocol.  After Protocol Amendment 1 (07 November 
2022), at the investigator discretion, subjects who did not meet all eligibility criteria were 
allowed to remain in the study when there was considered to be a potential clinical benefit 
without safety concerns.    
 
mFAS Definition (Section 4.4.6).   
Note that the text of the mFAS definition has been updated due to the change above in the 
FAS but the intent of mFAS remains unchanged from the protocol.  This comprises the 
subset of subjects in FAS who are in the target population of interest defined as meeting all 
eligibility criteria.  This set is used for the primary estimation of Estimand 1a in order to 
achieve a sensitive comparison to test equivalence of the groups for the primary analysis. 
 
FAS-TP Definition (Section 4.4.7).  Similar to FAS above, eligibility criteria have been 
removed so that set is as wide as possible to give information on the 3rd transition dose. 
 
Multiple Imputation Model Terms (Section 8.2.2.1)  
The protocol specified full details of terms in the MI model would be specified in the SAP.  
sCTX has been included as a term in the MI model since this is an important PD biomarker 
which may provide useful information to inform the imputation and data may be available 
at Day 11, Month 1 and Month 3 even if missing at Month 6.   


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The number of doses has been removed as a term; it is not required for the hypothetical 
Estimand 1a (mFAS) as imputation should be as though both doses received.  For estimation 
of the treatment policy Estimand 1b (FAS), there is only a small amount of Month 12 
observed data available for those receiving 1 administration only and so rather than build 
this term into the imputation model and risk convergence issues and inflated variability, the 
treatment failure offset will be applied to resulting imputations (Section 8.2.3.1) to achieve 
a return to baseline imputation.  
 
Main Estimation of Estimand 1b (Section 8.2.3).  This main estimation approach will use 
multiple imputation and a return to baseline assumption on those who only received a single 
dose so as to not over-estimate the benefit of treatment.   
The original ANCOVA without imputation on FAS is retained as a supportive approach 
(Section 8.2.5).   
 
Return to Baseline Multiple Imputation using Treatment Failure Penalty (Section 
8.2.3.1).   This approach to achieve a return to baseline level MI on those who only have 
received a single dose is moved from sensitivity to be the main estimation method of 
Estimand 1b (treatment policy).   An offset penalty to shift imputations to return to baseline 
levels will apply to withdrawn subjects who only received a single dose administration and 
discontinued treatment for any reason (not just those related to study drug or osteoporosis).   
%CfB-TF is defined as the endpoint with treatment failure offset applied where applicable.  
This is aligned to the assumption that we are interested in the treatment policy estimand and 
any benefit of the initial dose of treatment will be gone by Month 12.  The requirement to 
also apply a penalty for those who take any prohibited therapies or other osteoporosis 
medication is removed as the assumption that they would have returned to baseline does not 
seem reasonable.   
 
Tipping Point Sensitivity Analysis of Estimand 1b (Section 8.2.4)  A tipping point 
approach will be used for Estimand 1b (not just Estimand 1a) to explore the robustness of 
conclusions to missing data imputations.  MI under MAR is used as the initial step of the 
main imputation process and removed as a standalone sensitivity. 
 
ICE – dosing window (Section 4.3) As part of blinded data review meeting, an ICE 
definition in Section 4.3 was relaxed slightly so that a window of 28 days rather than 10 
days around the Month 6 dose would be used as cut off.  This cut off was chosen based on 
clinical evidence that a dosing deviation of up to 4 weeks was considered to not clinically 
impact either the primary endpoint of BMD (Lyu, Zhau et al 2020) or fracture risk (Lyu, 
Yoshida et al 2020) and thus by definition, such minor deviations should not be considered 
an ICE.  The impact of this extended window is that in the primary analysis method, it will 
allow for the use of observed Month 12 BMD data for approximately 29 patients who have 
a Month 6 dosing deviation above 10 and up to 28 days that would otherwise be removed 
and imputed.   The inclusion of these data may benefit study power.   
 


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14.2. 
Changes from the Prior SAP version  
The following changes were made in V2.0 of the SAP compared to V1.0: 
1. Implementation of the changes from the planned analyses in the protocol as 
detailed in the section above.  
2. Updates based on the mAbxience review of TLFs as part of dry-run delivery. 
3. Inclusion of relevant documentation for sample size estimation, in Appendix 16.2, 
and prohibited medications, in Section 7.2. 
4. PK/PD updates based on latest agreements as specified in Section 10. 
5. IMM analysis is updated including the descriptive analysis of the Prolia-MB09 
(Arm 2). 
15. References 
Clinical study protocol MB09-C-01-19 v1.0 EudraCT 2021-003609-24 
Clinical study protocol MB09-C-01-19 Version 2.0 (Amendment 1) EudraCT 2021-
003609-24 
Prolia (denosumab) [package insert]. Amgen Inc. One Amgen Center Drive Thousand 
Oaks, California 91320-1799; May 2021. Available from: https://www.pi.amgen.com/-
/media/Project/Amgen/Repository/pi-amgen-com/prolia/prolia_pi.pdf 
Prolia (denosumab) [Summary of product characteristics]. Amgen Europe B.V., Minervum 
7061, 4817 ZK Breda, The Netherlands; 16 January 2020. Available from: 
https://www.ema.europa.eu/en/documents/product-information/prolia-epar-product-
information_en.pdf 
Cummings SR, San Martin J, McClung MR et al. Denosumab for prevention of fractures in 
postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756-65. 
Bone HG, Bolognese MA, Yuen CK et al. Effects of denosumab on bone mineral density 
and bone turnover in postmenopausal women. J Clin Endocrinol Metab. 2008;93(6):2149-
57. 
McClung MR, Lewiecki EM, Cohen SB et al. Denosumab in postmenopausal women with 
low bone mineral density. N Engl J Med. 2006;345(8):8:821-31. 
Lyu H, Yoshida K, Zhao SS, Wei J, Zeng C, Tedeschi SK, Leder BZ, Lei G, Tang P, 
Solomon DH. Delayed Denosumab Injections and Fracture Risk Among Patients With 
Osteoporosis : A Population-Based Cohort Study. Ann Intern Med. 2020 Oct 
6;173(7):516-526. doi: 10.7326/M20-0882. Epub 2020 Jul 28. PMID: 32716706.  
 


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Lyu H, Zhao SS, Yoshida K, Tedeschi SK, Xu C, Nigwekar SU, Leder BZ, Solomon DH. 
Delayed Denosumab Injections and Bone Mineral Density Response: An Electronic Health 
Record-based Study. J Clin Endocrinol Metab. 2020 May 1;105(5):1435–44. doi: 
10.1210/clinem/dgz321. PMID: 31894244; PMCID: PMC7089847 
 


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16. Appendices 
16.1. 
Schedule of Events 
Study Period 
 
Main Treatment Period 
Transition/Safety Follow-Up Period 
 
Visit Number* 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Visit Label 
Screenin
g 
Baseline 
D11 
M1 
M3 
M6 
M9 
M12 
EOT 
TP 
D11 
TP M1  TP 
M3 
TP  
M6 EOS 
Visit Day  
-28 to -1 
1 
11 
36 
90 
182 
270 
365 
M12 
+10 d
ays 
M12 
+5 wee
ks 
456 
547 
Window (±days) 
 
 
±3 
±5 
±7 
±10 
±10 
±10 
±3 
±5 
±10 
±10 
Written informed consenta 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibilityb 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demography data 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
Xc 
 
 
 
 
 
 
 
 
 
 
NYHA Functional 
Classification 
X 
 
 
 
 
 
 
 
 
 
 
 
Lateral spine X-rayd 
X 
 
 
 
 
 
 
 
 
 
 
 
HBV, HCV and HIV-1/HIV-2e 
X 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2f 
X 
As required 
Follicle-stimulating hormone 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomisationg 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical examinationh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs weight, height, and 
body mass indexi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGj 
X 
X 
 
 
X 
X 
 
X 
 
 
X 
 
Haematologyk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Coagulationl 
X 
X 
 
 
 
X 
 
X 
 
 
X 
 
Clinical chemistrym 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Urinalysisn 
X 
X 
 
 
 
X 
 
X 
 
 
X 
 
Drug administrationg 
 
X 
 
 
 
X 
 
X 
 
 
 
 
Hypersensitivity, allergic 
reaction, injection site reaction 
monitoringo 
 
X 
 
 
 
X 
 
X 
 
 
 
 


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Study Period 
 
Main Treatment Period 
Transition/Safety Follow-Up Period 
 
Visit Number* 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Visit Label 
Screenin
g 
Baseline 
D11 
M1 
M3 
M6 
M9 
M12 
EOT 
TP 
D11 
TP M1  TP 
M3 
TP  
M6 EOS 
Visit Day  
-28 to -1 
1 
11 
36 
90 
182 
270 
365 
M12 
+10 d
ays 
M12 
+5 wee
ks 
456 
547 
Vitamin D and calcium 
supplement administration 
 
Daily 
Review of vitamin D and 
calcium intake 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BMD assessed with DXAp 
X 
 
 
 
 
X 
 
X 
 
 
 
 
Pharmacodynamics 
sCTXq 
 
X 
X 
X 
X  
X  
 
X 
X 
X 
X 
X 
Pharmacokineticsr 
 
X  
X 
X 
X  
X 
 
X 
X 
X 
X 
X 
Immunogenicitys 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Prior and concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventst 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Radiographyu 
As required 
Abbreviations: 25-OH vitamin D, 25-hydroxy vitamin D; aPTT, activated partial thromboplastin time; BMD, bone mineral density; COVID-19, 
coronavirus disease 19; D, Day; DXA, dual-energy X-ray absorptiometry; ECG, electrocardiogram; EOS, end of study; EOT, end of treatment; HBV, 
hepatitis virus B; HCV, hepatitis virus C; HIV-1/HIV-2, human immunodeficiency virus subtypes 1 and 2; ICF, informed consent form; INR, 
International Normalised Ratio; M, month; NYHA, New York Heart Association; PD, pharmacodynamic(s); PK, pharmacokinetic(s); PT, prothrombin 
time; SARS-CoV-2, severe acute respiratory coronavirus 2; sCTX, serum carboxy-terminal telopeptide cross-linked type 1 collagen; TP, Transition 
Period. 
* 
In the case when site visits are not possible or the subject does not wish to visit the site, remote visits (by means of phone calls or video calls) or 
home visits (as a last option) may be allowed for visits that do not include study drug administration or BMD assessments. Even if a study visit 
cannot be made, possible data will be continuously collected via a telephone call and during the next visit, if applicable. The investigator will keep 
following up with subjects regarding any safety issues (adverse events, concomitant medication) by telephone call before the subjects visit the 
study site. Note: All remote activities depend on site- and country-specific requirements. 
a. 
Informed consent must be obtained before any study-related procedures are performed. 
b. The inclusion and exclusion criteria will be checked at screening and confirmed at baseline. 
c. 
Review medical history and ensure that the subject remains qualified for the study. 
d. An X-ray of the lateral spine will be performed at screening. This assessment may be also performed as required for confirmation of suspected 
new vertebral fractures. Radiographs will be assessed by quantitative grading at a central imaging centre. 


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e. 
At the screening visit, subjects will be screened for HBV surface antigen, HCV antibody and HIV-1/HIV-2 antibody. If a positive surface antigen 
test result is obtained for hepatitis B, a confirmatory test is required. In the case of a positive HCV test, an HCV viral RNA load test will be 
performed as a confirmatory test. In the case of a positive HIV-1/HIV-2 test result, a confirmatory test will be performed. Hepatitis B virus, HCV 
and HIV-1/HIV-2 analyses will be performed at the central laboratory. 
f. 
At the screening visit, a COVID-19 test will be performed. Subjects who have a COVID-19 infection will be allowed to be rescreened on the basis 
that they have a confirmatory negative COVID-19 test result and have completely recovered from COVID-19 before being entered into the study. 
In the case that a subject is required to be rescreened within 28 days of the initial screening no additional tests are required to be performed. In the 
case that the subject is required to be rescreened after 28 days from the initial screening, all screening procedures/tests are required to be repeated 
(with the exception of DXA scans performed at screening, which will have a validity period of 3 months, provided the investigator considers the 
data from the DXA scan to be relevant [ie, the same DXA instrument will be used for the study and data on total hip, femoral neck and lumbar 
spine are available]). In the event the investigator deems the DXA scan invalid, a repeat DXA scan should be performed for the subject who has 
been re-examined. Systematic COVID-19 screening tests will be performed locally based on the site guidelines and on the investigator’s 
discretion throughout the study period. If COVID-19 is confirmed after randomisation, the investigator will discuss case-by-case with mAbxience 
and the medical monitor. If the subject has contact with COVID-19 infected patients within 14 days following any site visit, the investigator will 
re-assess the visit schedule following the site and/or local regulatory guidelines. 
g. On Day 1, during the Main Treatment Period, all subjects will be randomised in a 2:1:1 ratio to receive MB09-MB09, Prolia-MB09 or 
Prolia-Prolia. Subjects will receive one subcutaneous injection (60 mg/mL) of study drug on Day 1 and at Month 6, and Month 12. At Month 12, 
after all efficacy and safety assessments have been performed, the subject will enter the Transition/Safety Follow-Up Period and will receive the 
third dose of study drug. Subjects assigned to the MB09-MB09 arm (Arm 1) will receive MB09 on Day 1, and at Month 6, and at Month 12. 
Subjects assigned to the Prolia-MB09 arm (Arm 2) will receive EU-Prolia on Day 1 and at Month 6, and MB09 at Month 12. Subjects assigned to 
the Prolia-Prolia arm (Arm 3) will receive EU-Prolia on Day 1, at Month 6, and at Month 12. All subjects will be followed up to Transition Period 
Month 6. 
h. A complete physical examination will be performed at the screening, baseline (Day 1), Month 6, Month 12, and Transition Period Month 6 (End 
of Study) visits. A symptom-specific physical examination will be completed for other visits.  
i. 
Vital signs (including systolic and diastolic blood pressures, heart rate, respiratory rate, and body temperature) will be measured after 5 minutes of 
rest (sitting) (once at pre-dose and once at post-dose for Day 1, Month 6 and Month 12 visits, and once for all other visits). 
j. 
Subjects are required to rest in a supine position for at least 5 minutes prior to recording of 12-lead ECG.  
k. Haematology tests include haemoglobin, haematocrit, red blood cell count, white blood cell count with differential count, absolute neutrophil 
count, lymphocyte count, and platelet count.  
l. 
Coagulation tests include INR and aPTT. 
m. Clinical chemistry tests include albumin, albumin-adjusted total serum calcium, alkaline phosphatase, alanine aminotransferase, aspartate 
aminotransferase, bicarbonate, blood urea nitrogen, calcium, chloride, total cholesterol, high-density lipoprotein cholesterol, creatine kinase, 
creatine kinase-myocardial band isoenzyme, creatine phosphokinase, creatinine, gamma-glutamyl transferase, glucose, lactate dehydrogenase, 
triglycerides, magnesium, phosphate, potassium, sodium, total bilirubin, direct bilirubin, total protein, uric acid, troponin I, thyroid-stimulating 
hormone, parathyroid hormone (intact) and serum 25-OH vitamin D. Clinical monitoring of albumin-adjusted total serum calcium, serum 25-OH 
vitamin D and mineral levels (magnesium, phosphate) will be performed. Any sign and symptoms of hypocalcaemia will be closely sought and 
adequately treated at the investigator’s discretion. Serum 25-OH vitamin D will be re-tested within the Screening Period. Clinical monitoring of 
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two weeks after the initial dose of study drug. If any subject presents with suspected symptoms of hypocalcaemia during study drug treatment, 
albumin-adjusted total serum calcium levels should be measured during an unscheduled visit. After each administration of study drug at Day 1 
and Month 12, albumin-adjusted total serum calcium levels will be monitored as part of the clinical chemistry panel on Day 11 and Transition 
Period Day 11, respectively. Note: Serum 25-OH vitamin D levels will also be measured at the unscheduled visit, if required. 
n. Urinalysis tests include colour, pH, specific gravity, glucose, ketones, leukocytes, nitrite, protein, bilirubin, urobilinogen, occult blood, and 
microscopic examination (only if urinalysis dipstick results are abnormal). 
o. Subjects will be closely monitored by the investigator and/or subinvestigator for signs of injection site reactions or hypersensitivity/allergic 
reactions during the administration of the study drug and up to 1 hour (± 10 minutes) after the administration of study drug. Vital signs including 
blood pressure, heart and respiratory rates and temperature (within 15 minutes prior to and at 1 hour ± 10 minutes after every injection) to monitor 
for possible hypersensitivity reactions. Hypersensitivity/allergic reactions will be also monitored by routine continuous clinical monitoring, 
including subject-reported signs and symptoms. Study drug will be administered at a location with immediate access to emergency support. The 
clinical team at the site facility should be prepared and qualified to conduct emergency care. In the case of anaphylaxis, the investigator must 
follow national and/or international recommendations of the specific treatment. Anaphylaxis with necessary therapeutic interventions will be 
reported as serious adverse events. In case of hypersensitivity, emergency equipment, such as adrenaline, antihistamines, corticosteroids and 
respiratory support including inhalational therapy, oxygen and artificial ventilation must be available and any types of ECG can be performed. 
Injection site reactions will be assessed 1 hour (± 10 minutes) after the end of administration of the study drug. In the case that the subject 
experiences an adverse event on the day of study drug administration, they are to call the site or get immediate help. 
p. Bone mineral density will be assessed by DXA at screening, and at Month 6 and Month 12, using validated instruments. Assessment of lumbar 
spine, total hip and femoral neck BMD assessments will be performed using the same DXA instrument for each subject throughout the study 
period. Note: The screening BMD assessment will be taken as the baseline BMD assessment. Note: A DXA scan taken up to 3 months of the 
screening DXA scan will be accepted as a rescreening DXA scan, provided the investigator considers the data from the DXA scan to be relevant 
(ie, the same DXA instrument will be used for the study and that data on total hip, femoral neck and lumbar spine are available). In the event the 
investigator deems the DXA scan invalid, a repeat DXA scan should be performed for the subject who has been re-examined. 
q. Samples for PD testing (sCTX) will be taken in the morning after fasting overnight for 8 hours prior to assessment, and the subjects have to 
refrain from intense exercise the day prior to PD assessment. During the Main Treatment Period, PD assessments will be performed on Day 1 
(0 pre-dose), Day 11 and at Month 1, Month 3, Month 6 (pre-dose) and Month 12 (for those subjects entering the Transition Period, this sample 
should be taken prior to the third dose of the study drug). During the Transition/Safety Follow-Up Period, PD assessments will be performed at 
Month 12 (pre-dose) and 10 days, 5 weeks, 3 months, and 6 months after the administration of the third dose of study drug (i.e., Transition Period 
Day 11, Transition Period Month 1, Transition Period Month 3 and Transition Period Month 6). 
r. 
Samples for PK testing will be collected up to 30 minutes prior to dosing of the study drug if study drug is administered on the same visit. Other 
samples may be taken at any time during a scheduled visit. During the Main Treatment Period, PK assessments will be performed on Day 1 
(0 pre-dose), Day 11 and at Month 1, Month 3, Month 6 (pre-dose) and Month 12 (for those subjects entering the Transition Period, this sample 
should be taken prior to the third dose of the study drug). During the Transition/Safety Follow-Up Period, PK assessments will be performed at 
Month 12 (pre-dose) and 10 days, 5 weeks, 3 months, and 6 months after the administration of the third dose of study drug (i.e., Transition Period 
Day 11, Transition Period Month 1, Transition Period Month 3, and Transition Period Month 6). 
s. 
Samples for immunogenicity testing will be collected up to 30 minutes prior to dosing of the study drug. Other samples may be taken at any time 
during a scheduled visit. Immunogenicity (antidrug antibody and neutralising antibody) will be performed on Day 1 (0 predose), Day 11 and at 
Month 1, Month 3, Month 6 (predose) and Month 12 (for those subjects entering the Transition Period, this sample should be taken prior to the 


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third dose of the study drug) during the Main Treatment Period. During the Transition/Safety Follow-Up Period, immunogenicity assessments will 
be performed at Month 12 (predose) and 10 days, 5 weeks, 3 months, and 6 months after the administration of the third dose of study drug (ie, 
Transition Period Day 11, Transition Period Month 1, Transition Period Month 3, and Transition Period Month 6). If any additional 
immunogenicity samples are required to be taken if immune-related adverse events occur, the investigator is to seek prior advice from PPD 
medical monitor and mAbxience before performing the additional sampling. 
t. 
Adverse events will be assessed from the date that the ICF is signed until the End of Study visit (Transition Period Month 6 visit), regardless of 
the relationship to the study drug. The related adverse events will be followed until resolution or improvement to baseline, relationship reassessed 
as unrelated, confirmed by the investigator that no further improvement could be expected, no more collection of clinical or safety data, or final 
database closure. 
u. Lateral spine radiographs will be performed at screening only (per footnote d). Radiographs will be performed only as required for confirmation 
of suspected new clinical fractures. Radiographs will be assessed by quantitative grading at a central imaging centre. 
 
 
 


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16.2. 
Sample size assumptions and calculation MB09 
 
In order to gain an understanding of the clinical effect of the reference treatment, Prolia®, a meta-analysis has been conducted 
to ascertain the expected %CFB for the reference arm, including the following references: (Bone et al 2008, Cummings et al 
2009, and McClung et al 2006).  
 
a) Standard deviation selection 
 
A 
standard 
deviation 
of 
4.5% 
was 
chosen 
based 
on 
the 
publication 
McClung 
et 
al 
2006.
 
 


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Based on 60 mg Denosumab 6-monthly BMD to M12 in Lumbar Spine, SE was 0.5 and so SD based on this paper is 
approximately 3.4. However, the calculated sample size based on this estimated SD value to 4.5 for the calculation of sample 
size to increase the chance of demonstrating equivalence. 
 
b) Margin derivation of %CfB in LS-BMD 
 
These references were chosen due to achieving the following criteria:  
x Study of denosumab 60mg vs Placebo; 
x Evaluation using BMD, with results available at 12-month (52-week) timepoint (weighted mean difference); 
x PMO indication; 
x Lumbar spine outcome. 
 
The results of this meta-analysis, StatsDirect3 software, are as follows: 
 
Study 
Mean difference 
Variance of mean difference 
Weight 
FREEDOM (Cummings et al 
2009) 
5.5 
0.1308 
7.6479 
McClung et al 2006 
5.35 
0.4519 
2.2131 
DEFEND (Bone et al 2008) 
5.1 
0.2209 
4.5269 
Overall weighted average 
5.35 
0.0695 
 
 
Therefore, the point estimate of the difference in treatment effects is 5.35% with 95% CI (4.83%, 5.87%).  
 
The lower bound of the 95% CI is used to justify an appropriate margin. A margin of 1.45% retains at least 70% of the minimum 
treatment effect.  
 
A meta-analysis of three studies (Bone et al 2008, Cummings et al 2009, and McClung et al 2006) gave the pooled denosumab 
treatment effect 5.35% (95% CI: 4.83% to 5.87%). Based on the lower bound of the 95% CI, a 1.45% margin will preserve 
70% of the treatment effect (0.3*4.83%). 
 


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As state in the clinical study protocol, Section 7.3, a sample size of 448 subjects (224 subjects on each of MB09 and EU-Prolia 
(Arm 2 Prolia-MB09 and Arm 3 Prolia-Prolia pooled) at Month 12) will achieve 85% statistical power for the demonstration 
of equivalence in the %CfB lumbar spine BMD at Month 12, based on the two one-sided 2.5% significance level and an 
equivalence margin of ± 1.45%. In this sample size calculation, the common SD is assumed to be 4.5% and the true mean 
difference of %CfB is assumed to be zero. Therefore, allowing for a 15% dropout, 528 subjects will be randomised 2:1:1 to the 
MB09-MB09, Prolia-MB09 and Prolia-Prolia treatment arms.