Conditions: Healthy Volunteers
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 257
Healthy volunteers: yes

Brief summary:
Randomized, double blind, parallel group, single dose, 3 arm study to investigate and compare the PK, PD, safety and immunogenicity profile of MB09 with EU/US-Xgeva® in healthy male subjects.

During the course of the study, the similarity in pharmacokinetics will be assessed by sampling the levels of drug in the blood, and by comparing these levels among the different administration arms. Pharmacodynamics, safety, tolerability, and immunologic response to the administered drugs will also be evaluated throughout.

Detailed description:
The primary PK parameter endpoints are AUC0-last and Cmax for denosumab. The secondary PK endpoints will include all other PK parameters for denosumab, including AUC0-∞, Tmax, CL and t1/2.

For the primary PK Analysis, an analysis of variance (ANOVA) model with treatment and stratification factors as fixed effects will be performed on the natural log transformed values of Cmax, AUC0 last, and AUC0-∞.

Estimates of geometric mean ratios together with the corresponding 90% confidence intervals (CI) will be derived for the comparisons of the PK parameters as follows:

* MB09 versus EU-Xgeva®
* MB09 versus US-Xgeva®
* EU-Xgeva® versus US-Xgeva®

Bioequivalence will be concluded if the 90% CIs for the test to reference ratios of the geometric least square means for AUC0-last and Cmax are entirely contained within the \[80%, 125%\] interval.

For the PD Analysis, an analysis of covariance (ANCOVA) model with treatment and stratification factors as fixed effects and logged pre-dose sCTX concentrations fitted as a covariate will be performed on the natural log-transformed values of AUEC0 253 and AUIC0 253.

Adverse events will be coded using MedDRA Version 24. All AE data will be presented in a data listing. Treatment-emergent AEs will be summarised by treatment and overall, as well as by severity and relationship to study drug. Serious AEs and AEs leading to discontinuation of study drug will also be presented in the data listings and summarised by treatment and overall.

The incidence of ADA to denosumab and the neutralizing potential and titre of positive ADAs will be reported. All immunogenicity data will be presented in the data listings.

Arms:
arm 1: Sterile vial 120mg/1.7mL, Single dose, 35mg SC arm 2: Sterile vial 120mg/1.7mL, Single dose, 35mg SC arm 3: Sterile vial 120mg/1.7mL, Single dose, 35mg SC

Interventions: intervention 1: MB09 intervention 2: US-sourced Xgeva intervention 3: EU-sourced Xgeva
Intervention descriptions: intervention 1: Single dose of 35mg SC administered intervention 2: Single dose of 35mg SC administered intervention 3: Single dose of 35mg SC administered

Protocol document:
Prot_000.pdf: 
Protocol Title: 
A Randomised, Double Blind, Three Arm, 
Single Dose, Parallel Study to Compare the 
Pharmacokinetics, Pharmacodynamics, Safety, 
and Immunogenicity Profile of MB09 
(Proposed Denosumab Biosimilar) and EU/US 
sourced Xgeva® in Healthy Male Volunteers
NCT Number: 
NCT05299073
Protocol version 
date: 
Version 2.0, 30 November 2021


 
 
CLINICAL STUDY PROTOCOL 
2021-003290-54 
 
A RANDOMISED, DOUBLE-BLIND, THREE-ARM, SINGLE-DOSE, 
PARALLEL STUDY TO COMPARE THE PHARMACOKINETICS, 
PHARMACODYNAMICS, SAFETY, AND IMMUNOGENICITY 
PROFILE OF MB09 (PROPOSED DENOSUMAB BIOSIMILAR) AND 
EU/US-SOURCED XGEVA® IN HEALTHY MALE VOLUNTEERS 
 
MB09-A-01-19 
Sponsor: 
mAbxience Research S.L. 
 
 
 
. 
Sponsor Contact: 
 
Clinical Project Manager 
 
 
Medical Monitor: 
 
Medical Advisor 
 
 
Version of Protocol: 
2.0 
Date of Protocol:  
 
 
CONFIDENTIAL 
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed, 
written consent of mAbxience. 
The study will be conducted according to the International Council for Harmonisation 
Guideline E6(R2): Good Clinical Practice. 
 


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SIGNATURE PAGE 
 
PROTOCOL TITLE: 
A Randomised, Double-Blind, Three-Arm, Single-Dose, 
Parallel Study to Compare the Pharmacokinetics, 
Pharmacodynamics, Safety, and Immunogenicity Profile of 
MB09 (Proposed Denosumab Biosimilar) and 
EU/US-sourced Xgeva® in Healthy Male Volunteers 
PROTOCOL NUMBER: 
MB09-A-01-19 
 
 
 
 
 
 
 
 
Medical Advisor 
 
 
Date 
 
 
 
 
 
 
 
Clinical Project Manager 
 
 
Date 


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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
I agree to conduct the study as outlined in the protocol titled “A Randomised, Double-Blind, 
Three-Arm, 
Single-Dose, 
Parallel 
Study 
to 
Compare 
the 
Pharmacokinetics, 
Pharmacodynamics, Safety, and Immunogenicity Profile of MB09 (Proposed Denosumab 
Biosimilar) and EU/US-sourced Xgeva® in Healthy Male Volunteers” in accordance with the 
guidelines and all applicable government regulations. I have read and understand all sections 
of the protocol. 
 
 
 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 


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TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................... 1 
SIGNATURE PAGE ............................................................................................................... 2 
INVESTIGATOR PROTOCOL AGREEMENT PAGE ..................................................... 3 
TABLE OF CONTENTS ........................................................................................................ 4 
1. 
INTRODUCTION ............................................................................................... 7 
1.1 
BACKGROUND ................................................................................................7 
1.2 
RATIONALE FOR STUDY ..............................................................................7 
1.3 
RATIONALE FOR DOSE SELECTION...........................................................8 
2. 
STUDY OBJECTIVES ........................................................................................ 8 
2.1 
PRIMARY OBJECTIVE ....................................................................................8 
2.2 
SECONDARY OBJECTIVES ...........................................................................9 
3. 
STUDY DESIGN .................................................................................................. 9 
3.1 
SCHEDULE OF EVENTS ...............................................................................10 
4. 
STUDY POPULATION..................................................................................... 12 
4.1 
INCLUSION CRITERIA .................................................................................12 
4.2 
EXCLUSION CRITERIA ................................................................................13 
4.3 
WITHDRAWAL CRITERIA ...........................................................................15 
4.4 
SUBJECT REPLACEMENT ...........................................................................15 
5. 
STUDY TREATMENTS ................................................................................... 15 
5.1 
TREATMENTS ADMINISTERED .................................................................15 
5.2 
INVESTIGATIONAL PRODUCTS ................................................................15 
5.2.1 
Study Drug Preparation and Storage ............................................................16 
5.2.2 
Study Drug Accountability ...........................................................................16 
5.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS .........16 
5.4 
BLINDING .......................................................................................................17 
5.4.1 
Blinding Procedures .....................................................................................17 
5.4.2 
Breaking the Blind ........................................................................................17 
6. 
STUDY PROCEDURES ................................................................................... 17 
6.1 
PHARMACOKINETIC ASSESSMENTS AND ENDPOINTS ......................18 
6.1.1 
Pharmacokinetic Sample Collection .............................................................18 
6.1.2 
Pharmacokinetic Sample Analysis................................................................18 
6.2 
PHARMACODYNAMIC ASSESSMENTS AND ENDPOINTS ...................18 
6.2.1 
Pharmacodynamic Sample Collection ..........................................................18 
6.2.2 
Pharmacodynamic Sample Analysis .............................................................19 
6.3 
IMMUNOGENICITY ASSESSMENTS AND ENDPOINTS .........................19 
6.3.1 
Immunogenicity Sample Collection .............................................................19 


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6.3.2 
Immunogenicity Sample Analysis ................................................................19 
6.4 
SAFETY ASSESSMENTS AND ENDPOINTS ..............................................19 
6.4.1 
Adverse Events .............................................................................................20 
6.4.2 
Clinical Laboratory Assessments .................................................................20 
7. 
STATISTICAL ANALYSIS PLANS ................................................................ 21 
7.1 
SAMPLE SIZE CALCULATIONS..................................................................21 
7.2 
ANALYSIS SETS ............................................................................................21 
7.3 
STATISTICAL ANALYSES ............................................................................21 
7.3.1 
Pharmacokinetic Analyses ............................................................................22 
7.3.2 
Pharmacodynamic Analyses .........................................................................23 
7.3.3 
Safety and Immunogenicity Analyses ..........................................................23 
7.4 
HANDLING OF MISSING DATA ..................................................................24 
7.5 
INTERIM ANALYSES ....................................................................................24 
8. 
REFERENCE LIST........................................................................................... 25 
9. 
APPENDICES .................................................................................................... 27 
9.1 
APPENDIX 1: LIST OF ABBREVIATIONS ..................................................27 
9.2 
APPENDIX 2: STANDARD PROCEDURES .................................................29 
9.2.1 
Removal of Subjects From Therapy or Assessment .....................................29 
9.2.1.1 
General Criteria for Withdrawal .............................................................. 29 
9.2.1.2 
Handling of Withdrawals ......................................................................... 29 
9.2.2 
Prior and Concomitant Medications and Therapies and Other Study 
Restrictions ...................................................................................................30 
9.2.2.1 
Prior Medications ..................................................................................... 30 
9.2.2.2 
Concomitant Medications ........................................................................ 30 
9.2.3 
Treatment Compliance..................................................................................31 
9.3 
APPENDIX 3: ADVERSE EVENT DEFINITIONS AND REPORTING ......32 
9.3.1 
Adverse Event Definitions ...........................................................................32 
9.3.2 
Eliciting and Documenting Adverse Events .................................................34 
9.3.3 
Reporting Adverse Events ............................................................................34 
9.3.4 
Assessment of Severity .................................................................................35 
9.3.5 
Assessment of Causality ...............................................................................36 
9.3.6 
Follow-up of Adverse Events .......................................................................36 
9.3.7 
Reporting Serious Adverse Events ...............................................................36 
9.3.8 
Reporting of Suspected Unexpected Serious Adverse Reactions .................37 
9.4 
APPENDIX 4: STUDY GOVERNANCE .......................................................39 
9.4.1 
Data Quality Assurance ................................................................................39 
9.4.2 
Investigator Obligations ...............................................................................39 
9.4.2.1 
Confidentiality ......................................................................................... 39 


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9.4.2.2 
Ethics Committee Review ....................................................................... 40 
9.4.2.3 
Subject Consent ....................................................................................... 40 
9.4.2.4 
Study Reporting Requirements ................................................................ 41 
9.4.2.5 
Financial Disclosure and Obligations ...................................................... 41 
9.4.2.6 
Investigator Documentation ..................................................................... 41 
9.4.2.7 
Study Conduct ......................................................................................... 42 
9.4.2.8 
Case Report Forms and Source Documents ............................................ 42 
9.4.2.9 
Adherence to Protocol ............................................................................. 43 
9.4.2.10 
Reporting Adverse Events ....................................................................... 43 
9.4.2.11 
Investigator’s Final Report ...................................................................... 43 
9.4.2.12 
Records Retention .................................................................................... 43 
9.4.2.13 
Publications .............................................................................................. 44 
9.4.3 
Study Management .......................................................................................44 
9.4.3.1 
Monitoring ............................................................................................... 44 
9.4.3.2 
Management of Protocol Amendments and Deviations .......................... 45 
9.4.3.3 
Study Termination .................................................................................... 46 
9.4.3.4 
Final Report ............................................................................................. 46 
 


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1. 
INTRODUCTION 
1.1 
BACKGROUND 
Denosumab, the active substance of Xgeva® manufactured and marketed by Amgen in the EU 
and US, is a human mAb (IgG2) that targets and binds with high affinity and specificity to 
RANKL. It prevents the RANKL/RANK interaction from occurring, thus resulting in reduced 
osteoclast numbers and function, thereby decreasing bone resorption and cancer-induced bone 
destruction. 
MB09 is a medicinal product containing mAb denosumab as the active substance, developed 
by mAbxience as a biosimilar product to Xgeva. In a preliminary assessment, MB09 and 
Xgeva were proven to be analytically similar in terms of the physicochemical (structure, 
conformation, post-translational modifications including charge variants and glycosylation 
profile, and product purity), and biological attributes, using an exhaustive panel of 
state-of-the-art orthogonal and complementary analytical methods. The objective of 
developing MB09 is to obtain a biosimilar product to Xgeva in all aspects, ie, not only 
analytical characteristics evaluated in vitro, but also in terms of clinical results. 
Further information on the study drugs can be found in the investigator’s brochure 
(mAbxience 2021). 
1.2 
RATIONALE FOR STUDY 
mAbxience is using a similarity-by-design approach for development of the proposed 
biosimilar, MB09. Following the principles laid out in the current international regulatory 
guidelines (DHHS 2015a, 2015b, 2019; EMA 2012, 2013, 2014a, 2014b), mAbxience has 
designed an overall development program to establish similarity between MB09 and Xgeva, 
tailoring the design of the studies to focus on the molecule’s mode of action and analytical 
similarity between reference medicinal product and MB09. There is no specific target group in 
the clinical development of a denosumab biosimilar, MB09 as the indications will comprise 
both males and females. As per the biosimilar development guidelines (DHHS 2016; EMA 
2014), it is expected that the safety and efficacy of MB09 would be extrapolated to all 
indications when such biosimilar comparability to the reference medicinal product is 
demonstrated by thorough physicochemical and structural analyses as well as by in vitro 
functional tests, complemented with clinical data (efficacy, safety, and/or PK/PD) in 1 
therapeutic indication. 


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This study planned in healthy male volunteers is part of the clinical development program for 
MB09 (which will also include a clinical trial in postmenopausal women), and is designed to 
assess the bioequivalence of MB09 compared with EU- and US-sourced Xgeva. 
1.3 
RATIONALE FOR DOSE SELECTION 
Denosumab displays nonlinear PK due to target-mediated drug elimination at lower doses 
(>20 mg and <60 mg). However, for doses of 60 mg and above, approximately 
dose-proportional increases in exposure are seen (linear nontarget-mediated drug disposition). 
The use of a subtherapeutic dose is considered more sensitive to detect PK differences between 
MB09 and Xgeva. A lower dose would also limit the exposure and therefore be considered 
safer for administration in healthy volunteers. 
This study is foreseen as part of the clinical development plan to demonstrate PK 
bioequivalence, and similar PD, immunogenicity and safety profiles of MB09 and Xgeva. 
When used in the same way as Xgeva, following the same warnings and precautions, it is 
anticipated that MB09 will provide the same benefits with no difference in risks. 
Further information on dose selection, the known and expected benefits and risks, and 
reasonably anticipated AEs of MB09 may be found in the investigator’s brochure 
(mAbxience 2021). 
2. 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objectives of this study are to assess the bioequivalence of single SC doses in 
healthy subjects of: 
• MB09 versus EU-sourced Xgeva 
• MB09 versus US-sourced Xgeva 
• EU-sourced Xgeva versus US-sourced Xgeva 


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2.2 
SECONDARY OBJECTIVES 
The secondary objectives of this study are: 
• To evaluate and compare the derived PK and PD of single SC doses of MB09 and 
EU-sourced Xgeva and MB09 and US-sourced Xgeva in healthy subjects 
• To evaluate the safety, tolerability, and immunogenicity of single SC doses of MB09, 
EU-sourced Xgeva, and US-sourced Xgeva in healthy subjects 
3. 
STUDY DESIGN 
This is a Phase 1, double-blind, randomised, single-dose, bioequivalence study to compare the 
PK, PD, safety, and immunogenicity of MB09 and EU/US-sourced Xgeva in 3 parallel arms. 
Healthy male volunteers who meet all inclusion and none of the exclusion criteria will be 
randomly assigned to receive either 35 mg of MB09 SC (Study Arm 1) or 35 mg of EU-sourced 
Xgeva SC (Study Arm 2) or 35 mg of US-sourced Xgeva SC (Study Arm 3) in 1:1:1 ratio. The 
subjects will be stratified based on their body weight. 
The study will consist of a screening period (Days -30 to -2), check-in (Day -1), treatment 
period (Day 1), follow-up period (Days 2 to 252) and an EOS visit (Day 253). 
The PK, PD, safety, and immunogenicity endpoints will be evaluated in this study. 
Subjects will be confined to the clinical unit from Day -1 until discharge on Day 2. The 
duration of the study, excluding screening, is approximately 36 weeks.




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(g) A full physical examination will be performed at screening (at minimum, assessment of skin, head, oral cavity, ears, eyes, nose, throat, neck, thyroid, lungs, heart, cardiovascular, abdomen, lymph nodes, 
and musculoskeletal system/extremities). A brief physical examination will be performed at check-in, Day 225, and EOS (at minimum, assessment of oral cavity, skin, lungs, cardiovascular system, and 
abdomen [liver and spleen]). Interim physical examinations may be performed at the discretion of the investigator, if necessary, to evaluate AEs or clinical laboratory abnormalities. 
(h) To be performed by dentist and otolaryngologist, respectively at screening only. 
(i) Vital signs will include systolic and diastolic blood pressure, respiratory rate, pulse rate, and tympanic temperature and will be measured after the subject has been in the supine position for at least 
5 minutes. Tympanic temperature will be measured at screening, Days 2, 22, 225, and EOS. Vital signs will be measured within 15 minutes prior to study drug dosing on Day 1. 
(j) Single 12-lead ECG recordings will be made after the subject has been in the supine position for at least 5 minutes. A single repeat measurement is permitted at screening for eligibility determination. 
Measurements of the following intervals will be reported: RR interval, PR interval, QRS width, QT interval, and QTcF. Assessments should include comments on whether the tracings are normal or 
abnormal; rhythm; presence of arrhythmia or conduction defects; morphology; any evidence of myocardial infarction; or ST-segment, T-wave, and U-wave abnormalities. 
(k) A complete list of assessments is provided in Section 6.4.2. Blood and urine samples will be collected after overnight fasting for 10 hours and prepared per the clinic’s standard procedures. The same visit 
windows will apply for safety laboratory sample collection as for PK (refer to footnote (o)). 
(l) The clinic will follow standard procedures and/or local guidelines with respect to COVID-19 testing at screening and any other timepoints during the study, if deemed necessary by the investigator. 
(m) Randomisation should be done on Day -1 or Day 1 prior to initiating any study procedures. 
(n) The time of study drug dosing will be called “0” hour and is denoted with grey shading. A single SC dose of 35 mg of the study drug will be administered in the upper arm to each subject. Subjects will 
remain semi-supine for the first 4 hours after administration unless moving is medically necessary, requires procedures, or means going to the washroom. 
(o) Blood samples for PK analysis of the study drug (MB09 or Xgeva) in plasma and PD analysis of area under the effect curve will be collected up to 2 hours prior to study drug dosing and after dosing at 8 and 
16 hours (± 2 hours), 24, 48, and 72 hours (± 4 hours), Days 6, 8, and 11 (± 1 day), Days 15, 22, and 29 (± 2 days), Days 43, 57, 71, 85, 99, 113, 141, 169, 197, 225, and 253 (± 3 days). At each time point, 
blood samples will be collected after overnight fasting of at least 10 hours. 
(p) Samples for immunogenicity analysis will be obtained prior to study drug dosing and at the timepoints indicated in the schedule of events. If hypersensitivity occurs after the study drug dosing, additional 
samples for immunogenicity testing may be obtained at the discretion of the investigator to determine serum sickness. 
(q) Adverse events and SAEs will be assessed from the time of signing the ICF until EOS and should be followed until they are resolved, stable, or judged by the investigator to be not clinically significant. 
 


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4. 
STUDY POPULATION 
Adequate number of healthy male subjects will be screened and enrolled at selected centres in 
Poland to have 204 evaluable subjects. 
4.1 
INCLUSION CRITERIA 
Each subject must meet all of the following criteria to be enrolled in this study: 
1. The subject is a male of any race, between 28 and 55 years of age, inclusive, at 
screening. 
2. The subject has a BMI between 18.5 and 29.9 kg/m2, inclusive, (total body weight 
between 60 and 95 kg, inclusive) at screening and check-in. 
3. The subject is considered by the investigator to be in good general health as determined 
by medical history, clinical laboratory test results (congenital nonhaemolytic 
hyperbilirubinemia [eg, Gilbert’s syndrome] is acceptable), vital sign measurements 
(systolic BP ≥90 mm Hg and ≤140 mm Hg, diastolic BP ≥50 mm Hg and ≤90 mm Hg), 
12-lead ECG results, and physical examination findings at screening and check-in. 
4. The subject must use an adequate method of contraception (eg, condom) or be willing 
to practice sexual abstinence during the study starting from the day of dosing and for 
140 days after dosing. The subject must agree to not donating sperm during the study 
and for at least 140 days after dosing. Participating subject’s female partner of 
childbearing potential should use an additional form of contraception such as an 
intra-uterine device, barrier method with spermicide, oral contraceptive, injectable 
progesterone, or sub-dermal implant starting from the male partner’s day of dosing until 
at least 140 days after dosing. The female partner of the participating subject should be 
familiar with the use of the respective contraceptive methods. Intra-uterine devices and 
hormonal methods for contraception should be used for at least 1 menstruation cycle 
prior to the administration of study drug. 
5. The subject must be able to comprehend and willing to sign an ICF and to abide by the 
study restrictions. Subjects must have signed an ICF before any study-related procedure 
or evaluation is performed. 


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4.2 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from the study: 
1. The subject has had previous exposure to denosumab. 
2. The subject has a significant history or clinical manifestation of any metabolic, allergic, 
dermatological, hepatic, renal, haematological, cardiovascular, gastrointestinal, 
neurological, respiratory, endocrine, or psychiatric disorder, as determined by the 
investigator. 
3. The subject has a history of significant hypersensitivity, intolerance, or allergy to any 
drug compound, food, or other substance, unless approved by the investigator.  
4. The subject has any current or recent history of infections, including localised 
infections (within 2 months prior to screening for any serious infection that requires 
hospitalisation or IV anti-infective or within 14 days prior to screening for any active 
infection which requires oral treatment). 
5. The subject has a dental or jaw disease requiring oral surgery or dental surgery within 
6 months prior to study product administration or plans to have dental surgery within 
6 months after dosing. 
6. The subject has a history of osteomyelitis or osteonecrosis of the jaw requiring suturing 
within 30 days before dosing, or within 30 days after the last study visit. 
7. The subject has a medically significant dental disease or dental neglect, with signs 
and/or symptoms of local or systemic infection that would likely require a dental 
procedure during the course of the study. Standard dentistry treatments (eg, dental 
filling or prophylaxis/cleaning) are allowed. 
8. The subject has clinically relevant history of alcoholism, addiction or drug/chemical 
abuse prior to check-in, and/or positive urinary test for alcohol or drugs of abuse at 
screening or check-in. 
9. The subject has positive hepatitis panel (HBV and HCV) or positive HIV test. Subjects 
whose results are compatible with prior immunisation and not infection may be 
included at the discretion of the investigator. 


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10. The subject has participated in a clinical study involving administration of an 
investigational drug (new chemical entity), with dosing in the past 90 days prior to 
Day -1, or within 5 half-lives of the investigational drug used in the study, whichever 
is longer. 
11. The subject has used or intends to use slow-release medications/products considered to 
still be active within 30 days prior to check-in, unless deemed acceptable by the 
investigator. 
12. The subject has used or intends to use any nonprescription medications/products 
(except paracetamol [up to 2 g/day] and ibuprofen [800 mg/day]), including vitamins, 
minerals, supplements (eg, Biotin), and phytotherapeutic/herbal/plant-derived 
preparations within 7 days prior to check-in, unless deemed acceptable by the 
investigator. Vitamin C, vitamin D, and calcium in daily recommended doses 
(≤1000 mg elemental calcium and 1000 IU vitamin D based on screening levels of 
vitamin D) are allowed. 
13. The subject has received the COVID-19 vaccine within 14 days before Day 1 or plans 
to receive a COVID-19 vaccine within 12 weeks after study drug dosing or has positive 
test for COVID-19 during screening or presence of COVID-19 symptoms within 
4 weeks prior to Day -1. 
14. The subject has received a live or attenuated vaccine within 3 months prior to screening 
or has the intention to receive a vaccine during the study. The subject intends to travel 
to a region where a vaccination will be required due to endemic disease during the study. 
15. The subject has used tobacco- or nicotine-containing products within 1 year prior to 
check-in or anytime during the study, or has a positive cotinine test upon screening or 
check-in.  
16. The subject has donated blood within 60 days prior to dosing, plasma from 14 days 
prior to screening, or platelets from 42 days prior to dosing. 
17. The subject has poor peripheral venous access. 
18. Subjects who, in the opinion of the investigator, should not participate in this study. 


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4.3 
WITHDRAWAL CRITERIA 
General criteria for subject withdrawal and the handling of withdrawals can be found in 
Appendix 2. 
4.4 
SUBJECT REPLACEMENT 
At the discretion of the investigator, and after consultation with the medical monitor any 
subject who is withdrawn or discontinued from the study for reasons other than those related 
to study treatment may be replaced to retain the target of 204 evaluable subjects (68 subjects 
in each study arm). Any replacement subject will be assigned to receive the same treatment as 
the subject he is replacing. 
5. 
STUDY TREATMENTS 
5.1 
TREATMENTS ADMINISTERED 
All subjects will receive the study treatments as described in Section 3 and according to the 
SOE (Section 3.1). Additional instructions for dosing can be found in the SOE. 
5.2 
INVESTIGATIONAL PRODUCTS 
The study drugs that will be used are as follows: 
Product 
Supplied Formulation 
MB09 (Study Arm 1, test) 
Vial containing 70 mg/mL 
EU-sourced Xgeva® (Study Arm 2, reference) 
Vial containing 70 mg/mL 
US-sourced Xgeva® (Study Arm 3, reference) 
Vial containing 70 mg/mL 
 
Each of the investigational products contains the following inactive excipients: glacial acetic 
acid, sodium hydroxide (for pH adjustment - acetate buffer is formed by mixing acetic acid 
with sodium hydroxide), sorbitol (E420), polysorbate 20, and water for injection. 
Further information on the study drugs can be found in the MB09 investigator’s brochure 
(mAbxience 2021), EU-sourced Xgeva summary of product characteristics (Amgen 2020), 
and US-sourced Xgeva prescribing information (Amgen 2020). 


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5.2.1 
Study Drug Preparation and Storage 
The sponsor will provide the investigators and clinical units with adequate quantities of MB09, 
EU-sourced Xgeva, and US-sourced Xgeva vials. Unblinded clinical unit pharmacists will 
prepare the study treatments. A single 35 mg SC dose of the randomly assigned study drug will 
be administered in the upper arm by the blinded clinical unit personnel to each subject at the 
clinical unit according to the SOE (Section 3.1). 
All study drugs must be stored refrigerated between 2ºC and 8ºC according to the labeled 
instructions in a secure cabinet or room with access restricted to necessary clinic personnel. 
The sites will be required to keep a temperature log to establish a record of compliance with 
storage conditions. Refer to the pharmacy manual for further instructions on storage, 
preparation, and administration of the study drugs. 
5.2.2 
Study Drug Accountability 
The unblinded clinical unit pharmacists will maintain an inventory of the supplies, ensuring 
that the study drugs are received intact and in appropriate amounts, before completing the 
supplies receipt. The investigators will maintain accurate records of receipt of all study drugs, 
including dates of receipt. Accurate records will be kept at all times regarding when and how 
much study drug is dispensed and used by each subject in the study. Reasons for departure 
from the expected dispensing regimen must be communicated to the sponsor and recorded. 
The unblinded clinical monitor will be responsible to verify that the study drugs receipt records 
are correctly maintained by the sites. The unblinded clinical monitor may also check the study 
drug supplies inventory and records at any time during the study. At the completion of the study, 
and to satisfy regulatory requirements regarding drug accountability, all study drugs will be 
reconciled and retained or destroyed according to applicable regulations post approval from 
the sponsor. 
5.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT 
GROUPS 
PPD will generate the randomisation schedule. Subjects who meet all inclusion and none of 
the exclusion criteria will be randomly assigned to 1 of the 3 study arms. Randomisation 
numbers (in sequential order) will be assigned before the study drug is administered on Day 1. 
Randomisation will be stratified based on the subject’s body weight: 60 to <80 kg and 
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5.4 
BLINDING 
5.4.1 
Blinding Procedures 
This study will employ a double-blind study design. MB09 and Xgeva will be packed in 
identical boxes. The unblinded pharmacists will be responsible for preparing and dispensing 
the study drug in a manner consistent with maintaining the blind. 
5.4.2 
Breaking the Blind 
The sites will be responsible for maintaining the blind throughout the study. If a subject 
becomes seriously ill during the study, the blind will be broken upon the investigator’s approval 
only if knowledge of the administered study drug will affect that subject’s available treatment 
options. In the event of a medical emergency requiring identification of the study drug 
administered to an individual subject, the investigator will make every attempt to contact the 
medical monitor to explain the need for opening the code within 24 hours of opening the code. 
The mAbxience pharmacovigilance department will have access to the randomisation code, if 
SUSARs, which are subject to expedited reporting, will be unblinded before submission to the 
regulatory authorities. The unblinded personnel will be predefined and documented before 
breaking the study blind. The investigator will be responsible for documenting the time, date, 
reason for the code break, and the names of the personnel involved. Subjects who are unblinded 
can continue in the study at the investigator’s discretion. 
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. 
6. 
STUDY PROCEDURES 
Before performing any study procedures, all potential subjects will sign an ICF as outlined in 
Section 9.4.2.3. 
• Details of additional standard study procedures can be found in Appendix 2. 
• The total amount of blood collected from each subject over the duration of the study, 
including any extra assessments that may be required, will not exceed 500 mL. 


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6.1 
PHARMACOKINETIC ASSESSMENTS AND ENDPOINTS 
The following denosumab PK parameters will be calculated as MB09 and Xgeva endpoints 
using standard noncompartmental methods: 
Primary endpoints: AUC0-last and Cmax 
Secondary endpoints: AUC0-∞, Tmax, CL, t1/2 
• The timing and frequency of PK sample collection is listed in the SOE (Section 3.1).  
• Definitions of the PK parameters can be found in the list of abbreviations, Appendix 1. 
6.1.1 
Pharmacokinetic Sample Collection 
Details for the collection, processing, storage, and shipping of PK samples will be provided to 
the clinical units separately in a laboratory manual. 
6.1.2 
Pharmacokinetic Sample Analysis 
Pharmacokinetic samples will be analyzed using a validated MSD-ECL assay for denosumab 
in human plasma. Assay results and validation details will be provided in a separate 
bioanalytical report. 
6.2 
PHARMACODYNAMIC ASSESSMENTS AND ENDPOINTS 
The following plasma serum C-terminal telopeptide of Type 1 collagen (sCTX) parameter will 
be calculated as PD endpoint for determination of proposed bioequivalence between test and 
reference products: 
Secondary endpoint: AUEC0-last.  
• The timing and frequency of PD sample collection is listed in the SOE (Section 3.1). 
• Definitions of the PD parameter can be found in the list of abbreviations, Appendix 1. 
6.2.1 
Pharmacodynamic Sample Collection 
Details for the collection, processing, storage, and shipping of PD samples will be provided to 
the clinical units separately in a laboratory manual. 


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6.2.2 
Pharmacodynamic Sample Analysis 
Pharmacodynamic samples will be analyzed for sCTX using validated ELISA. Assay results 
and validation details will be provided in a separate bioanalytical report. 
6.3 
IMMUNOGENICITY ASSESSMENTS AND ENDPOINTS 
Denosumab ADA and neutralizing antibodies will be assessed by a validated MSD-ELC assay. 
• The timing and frequency of immunogenicity sample collection is listed in the SOE 
(Section 3.1).  
• Definitions of the immunogenicity parameters can be found in the list of abbreviations, 
Appendix 1. 
6.3.1 
Immunogenicity Sample Collection 
Details for the collection, processing, storage, and shipping of immunogenicity samples will 
be provided to the clinical units separately in a laboratory manual. 
6.3.2 
Immunogenicity Sample Analysis 
The analysis will involve both a screening, confirmatory, and titre assay to confirm positive 
results. Immunogenicity samples will be analyzed for anti-MB09 and neutralizing anti-MB09 
antibodies using validated MSD-ECL assay. Assay results and validation details will be 
provided in a separate bioanalytical report. 
6.4 
SAFETY ASSESSMENTS AND ENDPOINTS 
The timing and frequency of all safety assessments is listed in the SOE (Section 3.1). 
Safety and tolerability endpoints will include monitoring and recording of AEs, clinical 
laboratory test results (haematology, coagulation, serum chemistry, and urinalysis), vital sign 
measurements, 12-lead ECG results, and targeted physical examination findings. 
For all safety assessments, the investigator will determine whether results are clinically 
significant, which is defined as any variation in a result that has medical relevance and may 
result in an alteration in medical care (eg, active observation, diagnostic measures, or 
therapeutic measures). If clinical significance is noted, the result and reason for significance 
will be documented in the subject’s source document and an AE reported on the AE page of 


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the subject’s eCRF. The investigator will monitor the subject even after EOS, if need be, until 
the result has reached the reference range or the result at screening, or until the investigator 
determines that follow-up is no longer medically necessary. Refer Section 9.3 for details on 
AE definitions and reporting. 
6.4.1 
Adverse Events 
Definitions and procedures for reporting of AEs can be found in Appendix 3. For this study, 
the following contact information is to be used for SAE reporting: 
mAbxience Pharmacovigilance: 
Telephone (24 hour): 0034-689-838-874 
Fax: 0034-917-711-590 
Email: pharmacovigilance@mabxience.com 
6.4.2 
Clinical Laboratory Assessments 
The following clinical laboratory assessments will be performed: 
Haematology 
Leukocyte count and percentage and absolute differentials 
(basophils, eosinophils, lymphocytes, monocytes, neutrophils), 
haematocrit, haemoglobin, mean corpuscular haemoglobin, mean 
corpuscular haemoglobin concentration, mean corpuscular volume, 
platelet count, red blood cell count, and red blood cell distribution 
width 
Coagulation 
INR, PT, aPTT 
Serum Chemistry 
ALT, albumin, ALP, AST, bilirubin (total, direct, indirect), BUN, 
calcium, chloride, cholesterol (total, high-density lipoprotein, and 
calculated low-density lipoprotein), creatine kinase, 
gamma-glutamyltransferase, globulin, glucose, lactate 
dehydrogenase, phosphorus, potassium, sodium, total protein, 
triglycerides, uric acid, vitamin D, creatinine, and GFR 
GFR will be calculated by the MDRD equation: 
175 × (standardized serum creatinine/88.4)-1.154 × (age)-0.203 × (1.212 if black) 
Urinalysis 
Appearance, bilirubin, colour, glucose, ketones, leukocyte esterase, 
reflex microscopy (performed if protein or blood/erythrocytes are 
detected and reported as abnormal on dipstick; and includes 
bacteria, casts, crystals, epithelial cells, red blood cells, and white 
blood cells), nitrites, occult blood, pH, protein, specific gravity, 
turbidity, and urobilinogen 
Serology 
Hepatitis B surface antigen, anti-hepatitis B core antigen, 
anti-hepatitis B surface antigen, hepatitis B DNA test (optional), 
HCV antibody, and HIV antibody types 1 and 2 (screening only) 


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Other analyses 
All subjects: COVID-19 test, alcohol test (urine/breath), urine drug 
screen (amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine metabolites, cotinine, methamphetamines, 
tricyclic antidepressants, and opiates) 
 
 
• The clinical laboratory that performs the tests will provide the reference ranges for all 
clinical laboratory parameters. 
• Clinical laboratory tests should not be repeated unless deemed necessary by the 
investigator; re-evaluation may be allowed once for assessment of inclusion and exclusion 
criteria or evaluation of clinical laboratory abnormalities.  
7. 
STATISTICAL ANALYSIS PLANS 
7.1 
SAMPLE SIZE CALCULATIONS 
The sample size for this study is based on a statistical power calculation. A CV value of 33% 
was estimated for AUC parameter (which showed the highest variability) based on previous 
PK studies conducted at a dose of 60 mg or 1 mg/kg. Assuming a ratio of AUC and Cmax 
between 0.95 and 1.05, 68 PK-evaluable subjects per arm would be required to provide at least 
90% power to conclude bioequivalence of MB09 and Xgeva. Thus, 204 evaluable subjects will 
be required in all. 
Assuming a 20% dropout rate, approximately 255 subjects are planned to be enrolled in this 
study. Enrollment could be stopped when the target of having 204 evaluable subjects is 
achieved. Subjects will be randomly assigned to 1 of 3 study arms in a 1:1:1 ratio. 
7.2 
ANALYSIS SETS 
The analysis populations are as follows: 
• The PK population will include subjects who receive the study drug, who do not have major 
protocol deviations, and have sufficient data to calculate primary PK endpoints. 
• The safety population will include all subjects who receive the study drug. 
7.3 
STATISTICAL ANALYSES 
Details of all statistical analyses will be described in a separate statistical analysis plan. All 
data collected will be presented in data listings. Data from subjects excluded from an analysis 


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population will be presented in the data listings, but not included in the calculation of summary 
statistics. 
For categorical variables, frequencies and percentages will be presented. Continuous variables 
will be summarised using descriptive statistics (number of subjects, mean, median, SD, 
minimum, and maximum). 
Baseline demographic and background variables will be summarised overall for all subjects. 
The number of subjects who enroll in the study and the number and percentage of subjects who 
complete the study will be presented. Frequency and percentage of subjects who withdraw or 
discontinue from the study and the reason for withdrawal or discontinuation will also be 
summarised. 
7.3.1 
Pharmacokinetic Analyses 
Individual plasma concentration and time deviation data will be presented in a data listing. 
Plasma concentration data will be summarised by time point for each treatment using the 
following descriptive statistics: number of subjects, arithmetic mean, SD, CV, geometric mean, 
geometric CV, median, minimum, and maximum. Individual and mean plasma concentration 
versus scheduled time profiles will be presented in figures on both linear and semilogarithmic 
scales. 
The PK parameters of MB09 and Xgeva will be analyzed based on the actual sampling times. 
All parameters will be calculated using the latest version of Phoenix® WinNonlin® (Certara 
USA Inc., Princeton, New Jersey) or SAS® (SAS Institute Inc., Cary, North Carolina). The 
individual PK parameters will be presented in data listings and summarised by treatment using 
the following descriptive statistics: number of subjects, mean, SD, CV, median, minimum, and 
maximum. Geometric means will be included for Cmax, AUC0-last, and AUC0-∞. 
An ANOVA model with fixed effects for treatment will be performed on the natural 
log-transformed values of Cmax, AUC0-last, and AUC0-∞ to assess the relative bioequivalence of 
the test drug (MB09) to the reference drugs (EU/US-sourced Xgeva), as well as for comparing 
EU-sourced Xgeva to US-sourced Xgeva. The geometric least squares means and 
corresponding 90% CIs will be computed for Cmax, AUC0-last, and AUC0-∞ by taking the antilog 
of the least squares means from the linear mixed-effect model on the natural logarithms of the 
corresponding PK parameters. A 90% CI for the ratio will be constructed as the antilog of the 
confidence limits of the mean difference. No adjustment will be made for multiplicity. 


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Bioequivalence will be concluded if the 90% CIs for the test to reference ratios of the geometric 
least square means for AUC0-last and Cmax are entirely contained within the [80%, 125%] 
interval. 
Nonparametric methods will be used to examine difference in medians of Tmax for MB09 and 
Xgeva. 
7.3.2 
Pharmacodynamic Analyses 
Individual observed concentrations of sCTX and time deviation data will be presented in a data 
listing. Observed concentrations of sCTX will be summarised by time point for each treatment 
using the following descriptive statistics: number of subjects, arithmetic mean, SD, CV, 
geometric mean, geometric CV, median, minimum, and maximum. Individual and mean 
observed concentrations of sCTX versus scheduled time profiles will be presented in figures 
on linear scales. 
The PD parameters of MB09 and Xgeva will be analyzed based on the actual sampling times. 
All parameters will be calculated using the latest version of Phoenix® WinNonlin® (Certara 
USA Inc., Princeton, New Jersey) or SAS® (SAS Institute Inc., Cary, North Carolina) without 
baseline adjustment. The individual PD parameters for sCTX will be presented in data listings 
and summarised by treatment using the following descriptive statistics: number of subjects, 
mean, SD, CV, median, minimum, and maximum. Geometric means will be included for 
AUEC0-last. 
An ANOVA model with fixed effects for treatment will be performed on the natural 
log-transformed values of area under the effect versus time curve (AUEC) to compare between 
the test drug (MB09) to the reference drugs (EU/US-sourced Xgeva). The geometric least 
squares means and corresponding 90% CIs will be computed for AUEC by taking the antilog 
of the least squares means from the linear mixed-effect model on the natural logarithms of the 
corresponding PD parameters. A 90% CI for the ratio will be constructed as the antilog of the 
confidence limits of the mean difference. No adjustment will be made for multiplicity.  
Bioequivalence in PD biomarker will be reported as the test to reference ratio of geometric 
means and its corresponding 90% CI for AUEC PD parameter. 
7.3.3 
Safety and Immunogenicity Analyses 
Adverse events will be coded by preferred term and system organ class using MedDRA 
Version 24. All AE data will be presented in a data listing. Treatment-emergent AEs will be 


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summarised by treatment and overall, as well as by severity and relationship to study drug. 
Serious AEs and AEs leading to discontinuation of study drug will also be presented in the data 
listings and summarised by treatment and overall. 
Actual values and changes from baseline for clinical laboratory test results, vital sign 
measurements, and 12-lead ECG results will be summarised by treatment at each time point 
using descriptive statistics (number of subjects, mean, SD, median, minimum, and maximum). 
Shift tables will be generated for clinical laboratory test results. Physical examination findings 
will be presented in a data listing. 
The incidence of ADA to denosumab and the neutralizing potential and titre of positive ADAs 
will be reported. All immunogenicity data will be presented in the data listings. 
7.4 
HANDLING OF MISSING DATA 
Plasma denosumab concentrations that are below limit of quantification (BLQ) will be treated 
as zero for descriptive statistics; mean BLQ concentrations will be presented as BLQ, and the 
SD and CV will be reported as not applicable. Missing concentrations will be excluded from 
the calculation of concentration summary statistics. 
For the PK analysis, denosumab BLQ values will be treated as zero with the exception that a 
BLQ value between 2 quantifiable concentrations will be set as missing. Missing 
concentrations will be treated as missing from the PK parameter calculations. If consecutive 
BLQ concentrations are followed by quantifiable concentrations in the terminal phase, those 
concentrations after BLQ concentrations will be treated as missing. 
For the PD analysis, sCTX concentrations that are BLQ will be treated as zero for descriptive 
statistics; mean BLQ concentrations will be presented as BLQ, and the SD and CV will be 
reported as not applicable. Missing sCTX concentrations will be excluded from the calculation 
of concentration summary statistics. 
For the PD analysis, all sCTX BLQ values will be treated as one-half the lower limit of 
quantification for the estimation of PD parameters, and missing sCTX concentrations will be 
treated as missing. 
7.5 
INTERIM ANALYSES 
No formal interim analyses will be performed in this study. 


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8. 
REFERENCE LIST 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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9. 
APPENDICES 
9.1 
APPENDIX 1: LIST OF ABBREVIATIONS 
Abbreviation 
Term 
ADA 
anti-drug antibodies 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC0-last 
area under the plasma concentration versus time curve from time 0 
to the last quantifiable concentration 
AUC0-∞ 
area under the plasma concentration versus time curve from time 0 
extrapolated to infinity 
AUEC 
area under the effect versus time curve 
AUEC0-last 
area under the effect versus time curve from time 0 to the last 
quantifiable concentration 
BLQ 
below limit of quantification 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL 
clearance 
Cmax 
maximum observed plasma concentration 
COVID-19 
coronavirus disease 2019 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
end of study 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 


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Abbreviation 
Term 
IgG 
immunoglobulin G 
INR 
international normalised ratio 
IV 
intravenous 
mAb 
monoclonal antibody 
MDRD 
modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSD-ELC 
Meso Scale Discovery-electrochemiluminescence 
NCI 
National Cancer Institute 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PT 
prothrombin time 
RANK 
Receptor Activator of Nuclear Factor Kappa-B (NFκB) 
RANKL 
Receptor Activator of Nuclear Factor Kappa-B (NFκB) Ligand 
SAE 
serious adverse event 
SC 
subcutaneous(ly) 
SD 
standard deviation 
sCTX 
serum C-terminal telopeptide of Type 1 collagen 
SOE 
schedule of events 
SUSAR 
suspected unexpected serious adverse reaction 
Tmax 
time to reach maximum observed serum concentration 
t1/2 
terminal half-life 
USA 
United States of America 
 


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9.2 
APPENDIX 2: STANDARD PROCEDURES 
9.2.1 
Removal of Subjects From Therapy or Assessment 
9.2.1.1 
General Criteria for Withdrawal 
Subjects can withdraw consent and discontinue from the study at any time including prior to 
study drug administration, for any reason, without prejudice to further treatment. 
The investigator may withdraw a subject from the study if the subject meets any of the 
following criteria: 
1. Protocol deviation of concern occurs (eg, protocol deviations that may affect study 
objectives, or it is discovered that the subject has entered the study in violation of the 
protocol) 
2. Experiences an SAE or intolerable AE(s) that, in the investigator’s opinion, requires 
withdrawal from the study 
3. Requests early discontinuation for any reason 
The investigator can also withdraw subjects if the sponsor terminates the study. If withdrawal 
is considered because of an SAE or intolerable AE, the investigator will confer with the sponsor. 
If a subject is discontinued because of an AE, the event will be followed until it is resolved, 
stable, or judged by the investigator to be not clinically significant. If a subject withdraws 
prematurely after dosing, he will be asked to return to the clinical unit and will undergo all 
EOS (ie, Day 253) assessments. 
At the discretion of the investigator, and after consultation with the medical monitor, any 
subject who withdraws for reasons other than those related to study treatment, before 
completing the study may be replaced to retain the target of 204 evaluable subjects. Any 
replacement subject will be assigned to receive the same treatment as the subject he is replacing. 
9.2.1.2 
Handling of Withdrawals 
When a subject withdraws from the study, the reason(s) for withdrawal shall be recorded by 
the investigator on the relevant page of the eCRF. Whenever possible, any subject who 
prematurely withdraws from the study will undergo all EOS assessments. Any subject who 
fails to return for final assessments will be contacted by the site in a reasonable attempt to have 


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them comply with the protocol. The status of subjects who fail to complete final assessments 
will be recorded in the respective subject’s source document and transferred into the eCRF. 
Eligible subjects who meet all inclusion/exclusion criteria but are unable to participate in the 
study due to a scheduling conflict may be rescreened. A subject who has failed screening may 
be rescreened at the discretion of the investigator and sponsor. In these cases, a new screening 
number must be assigned for each subject who is rescreened, and a new ICF must be signed. 
9.2.2 
Prior and Concomitant Medications and Therapies and 
Other Study Restrictions 
Subjects should abstain from alcohol, caffeine-, xanthine-containing beverages or food (eg, 
coffee, tea, chocolate, and caffeinated sodas, colas), grapefruit juice, Seville orange containing 
products (eg, marmalade), or products containing any of these, from 48 hours prior to study 
drug dosing and throughout the duration of the study. Subjects should also abstain from 
strenuous activity/exercise or contact sports within 24 hours before the first dose of study drug 
and throughout the duration of the study, including 7 days before nonresidential visits, and will 
otherwise maintain their normal level of physical activity during this time (ie, will not begin a 
new exercise program nor participate in any unusually strenuous physical exertion). 
Restrictions for prior and concomitant medications and therapies are provided in Sections 4.1 
and 4.2. Prior and concomitant medications and therapies will be coded using the latest version 
of the World Health Organization Drug Dictionary. 
Other restrictions as described in the study protocol also apply. 
9.2.2.1 
Prior Medications 
Information regarding prior medications taken by the subject within the 30 days before signing 
the ICF will be recorded in the subject’s source document and transferred into the eCRF. 
9.2.2.2 
Concomitant Medications 
Any concomitant medication deemed necessary for the welfare of the subject during the study 
may be given at the discretion of the investigator. If a concomitant medication is taken, except 
for those specified in the protocol, a joint decision will be made by the investigator and the 
sponsor to continue or discontinue the subject based on the time the medication was 
administered, its pharmacology and PK, and whether the use of the medication will 
compromise the safety of the subject or the interpretation of the data. The investigator is 


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responsible for ensuring that details regarding the medication are adequately recorded in the 
eCRF. 
9.2.3 
Treatment Compliance 
All subjects will receive the study drug dose in the clinical unit under direct observation of 
clinic personnel. Clinic personnel will confirm that the subject has received the entire dose of 
study drug. 
The date and time of study drug dosing will be recorded in the subject’s source document and 
transferred into the appropriate page of the eCRF. If a subject is not administered the study 
drug dose, the reason will be recorded in the source document and transferred into the 
appropriate page of the eCRF, and the subject will be withdrawn from the study. 


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9.3 
APPENDIX 3: ADVERSE EVENT DEFINITIONS AND 
REPORTING 
The investigator is responsible for ensuring that all AEs and SAEs are recorded in the eCRF 
and reported to the sponsor, regardless of their relationship to study drug or clinical 
significance. If there is any doubt as to whether a clinical observation is an AE, the event should 
be reported. 
9.3.1 
Adverse Event Definitions 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. Subjects will be instructed to contact the 
investigator at any time after randomisation if any symptoms develop. 
A treatment-emergent AE is defined as any event not present before exposure to study drug or 
any event already present that worsens in intensity or frequency after exposure. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the study 
drug caused the AE. For the purposes of investigational new drug safety reporting, “reasonable 
possibility” means that there is evidence to suggest a causal relationship between the study 
drug and the AE. A suspected adverse reaction implies a lesser degree of certainty about 
causality than an adverse reaction. 
An adverse reaction is any AE caused by a study drug. Adverse reactions belong to a subset of 
all suspected adverse reactions and indicate that there are reasons to conclude that the study 
drug caused the event. 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator’s brochure or if it occurs with specificity or severity that has not been previously 
observed with the study drug being tested; or, if an investigator’s brochure is not required or 
available, the AE or suspected adverse reaction is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. For 
example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the investigator’s brochure referred only to elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue 
of greater specificity) if the investigator’s brochure listed only cerebral vascular accidents. 
“Unexpected,” as used in this definition, also refers to AEs or suspected adverse reactions that 
are mentioned in the investigator’s brochure as occurring with a class of drugs or as anticipated 


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from the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation. 
An AE or suspected adverse reaction is considered an SAE/SUSAR if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: 
• Death 
• Life-threatening AE 
• Inpatient hospitalisation (other than that for the study drug administration) or prolongation 
of existing hospitalisation 
• Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
• Congenital anomaly or birth defect 
Hospitalisation is to be considered as an overnight admission, except for the following reasons:  
• Hospitalisation for diagnostic investigations (eg, scans, endoscopy, sampling for laboratory 
tests, bone marrow sampling) that are not related to an AE 
• Prolonged hospitalisation for technical, practical, or social reasons, in absence of an AE 
• Hospitalisation for a procedure that was planned before study participation (ie, before 
registration or randomisation). This should be recorded in the source documents. Prolonged 
hospitalisation due to a complication of such procedures remains a reportable SAE. 
• Hospitalisation for ≤24 hours in an emergency room 
Other events subject to immediate notification (within 24 hours), include but are not limited 
to: 
• Pregnancy of partner study subject or breastfeeding cases via a pregnancy report form 
• Medication errors, namely overdose, leading to a suspected adverse reaction 
Important medical events that may not result in death, be life threatening, or require 
hospitalisation may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 


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one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalisation, or the development of 
drug dependency or drug abuse. 
An AE or suspected adverse reaction is considered “life threatening” if, in the view of either 
the investigator or sponsor, its occurrence places the subject at immediate risk of death. It does 
not include an AE or suspected adverse reaction that might have caused death if it had been 
more severe. 
9.3.2 
Eliciting and Documenting Adverse Events 
Subjects will be asked a standard question to elicit any medically related changes in their 
well-being. They will also be asked if they have been hospitalised, had any accidents, or used 
any new medications, or changed concomitant medication regimens (both prescription and 
over-the-counter medications). 
In addition to subject observations, AEs will be documented from any data collected on the AE 
page of the eCRF (eg, laboratory values, physical examination findings, and ECG changes) or 
other documents that are relevant to subject safety. 
9.3.3 
Reporting Adverse Events 
All AEs and SAEs (including partner pregnancy after study drug dosing) will be assessed from 
the time of signing the ICF until EOS. Any AE or SAE reported or observed during the study 
will be recorded on the AE page of the eCRF. Information to be collected includes drug 
treatment, type of event, time of onset, dosage, investigator-specified assessment of severity 
and relationship to study drug, time of resolution of the event, seriousness, any required 
treatment or evaluations, and outcome. Any AEs resulting from concurrent illnesses, reactions 
to concurrent illnesses, reactions to concurrent medications, or progression of disease states 
must also be reported. A paper partner pregnancy form will be used to inform the sponsor in 
case the subject’s partner becomes pregnant anytime during the study. The form to be used and 
completion instructions will be provided to the clinical units separately. The subject’s partner 
should read and sign the partner pregnancy ICF, prior to collecting any pregnancy related 
information. The partner may or may not agree to share all medical records for follow-up. All 
AEs will be followed until they are resolved, stable, or judged by the investigator to be not 
clinically significant. The MedDRA Version 24 – 01 March 2021 will be used to code all AEs. 


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Any medical condition that is present at the time that the subject is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates at any time during the 
study, it should be recorded as an AE. 
Any AE that is considered serious by the investigator or which meets SAE criteria 
(Section 9.3.1) must be reported to the sponsor immediately (within 24 hours after the 
investigator has confirmed the occurrence of the SAE). The investigator will assess whether 
there is a reasonable possibility that the study drug caused the SAE. The sponsor will be 
responsible for notifying the relevant regulatory authorities of any SAE. 
Contact information to be used for SAE reporting can be found in Section 6.4. 
9.3.4 
Assessment of Severity 
All AEs will be graded for intensity according to the CTCAE, Version 5.0 – November 2017 
(DHHS 2017). 
All other laboratory and clinical AEs not outlined in the CTCAE that occur in a subject will be 
assessed (graded) for intensity and then classified into 1 of 5 clearly defined categories as 
follows: 
• Grade 1 (Mild): Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Grade 2 (Moderate): Minimal, local, or noninvasive intervention indicated; limits 
age-appropriate instrumental activities of daily living (eg, preparing meals, shopping for 
groceries or clothes, using the telephone, managing money). 
• Grade 3 (Severe): Medically significant but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; limits self-care 
activities of daily living (eg, bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden). 
• Grade 4 (Life-threatening): Urgent intervention indicated. 
• Grade 5 (Death). 


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Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of intensity to be performed. An AE characterized as intermittent 
requires documentation of onset and duration of each episode. 
9.3.5 
Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study drug is part of the 
documentation process but is not a factor in determining what is or is not reported in the study. 
The investigator will assess causality (ie, whether there is a reasonable possibility that the study 
drug caused the event) for all AEs and SAEs. The relationship will be classified as follows: 
• Not related: There is not a reasonable possibility of relationship to study drug. The AE does 
not follow a reasonable temporal sequence from study drug administration or can be 
reasonably explained by the subject’s clinical state or other factors (eg, disease under study, 
concurrent diseases, and concomitant medications). This category will include AEs 
unrelated to the study drugs. 
• Related: There is a reasonable possibility of relationship to study drug. The AE follows a 
reasonable temporal sequence from study drug administration and cannot be reasonably 
explained by the subject’s clinical state or other factors (eg, disease under study, concurrent 
diseases, or concomitant medications), represents a known reaction to the study drug or 
other drugs in its class, is consistent with the known pharmacological properties of the 
study drug, and/or resolves with discontinuation of the study drug (and/or recurs with 
re-challenge, if applicable). This category will include AEs that may be definitely, 
probably, or possibly related to the study drugs. 
9.3.6 
Follow-up of Adverse Events 
All AEs must be reported in detail in the subject’s source document and transferred into the 
appropriate page of the eCRF and followed until they are resolved, stable, or judged by the 
investigator to be not clinically significant. 
9.3.7 
Reporting Serious Adverse Events 
Prompt notification of SAEs by the investigator to the sponsor is essential so that the sponsor 
can meet its regulatory reporting obligations for the study. If the investigator does not have all 
of the details regarding the SAE, he/she will not wait until this information becomes available 
before making the initial report to the sponsor. Contact details are in Table 9-1. 




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a case and that relevant follow up information is communicated within additional 8 days. All 
other SUSARs will be reported to the relevant competent authorities and IEC within 15 days 
after knowledge by the sponsor of such a case. 
All investigators should follow up SUSARs until resolution or until, in the opinion of the 
investigator, the events are stabilized or determined to be chronic. 


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9.4 
APPENDIX 4: STUDY GOVERNANCE 
9.4.1 
Data Quality Assurance 
This study will be conducted using the quality processes described in applicable procedural 
documents. The quality management approach to be implemented will be documented and will 
comply with current ICH guidance on quality and risk management. All aspects of the study 
will be monitored for compliance with applicable government regulatory requirements, current 
GCP, the protocol, and standard operating procedures. The monitor will maintain current 
personal knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the investigator and staff. 
Electronic CRFs and electronic data capture will be utilized. The electronic data capture system 
is validated and compliant with the applicable regulatory requirements. Each person involved 
with the study will have an individual identification code and password that allows for record 
traceability. 
Important protocol deviations, should they occur during the study, will be presented in 
Section 10.2 of the clinical study report. 
9.4.2 
Investigator Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study and may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the IEC 
but will not result in protocol amendments. 
9.4.2.1 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure storage 
area with limited access. Clinical information will not be released without the written 
permission of the subject (or the subject’s legal guardian), except as necessary for monitoring 
and auditing by the sponsor, its designee, the EMA / FDA or any other regulatory agency, or 
the IEC. 
The investigators and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study, any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 


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study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
9.4.2.2 
Ethics Committee Review 
Local regulations and ICH guidelines require that approval be obtained from an IEC before 
participation of human subjects in research studies. Before study onset, the protocol, ICF, 
advertisements to be used for the recruitment of study subjects, and any other written 
information regarding this study that is to be provided to the subject must be approved by the 
IEC. Documentation of all IEC approvals and of the IEC compliance with the ICH harmonised 
tripartite guideline E6(R2): Good Clinical Practice will be maintained by the sites and will be 
available for review by the sponsor or its designee. 
All IEC approvals should be signed by the IEC chairman or designee and must identify the 
IEC name and address, the clinical protocol by title or protocol number or both, and the date 
approval or a favorable opinion was granted. 
9.4.2.3 
Subject Consent 
Written informed consent in compliance with the applicable regulatory requirements, GCP and 
ICH shall be obtained from each subject before he enters the study or before performing any 
unusual or nonroutine procedure that involves risk to the subject. If any institution-specific 
modifications to study-related procedures are proposed or made by the sites, the consent should 
be reviewed by the sponsor or its designee or both before IEC submission. Once reviewed, the 
investigator will submit the ICF to the IEC for review and approval before the start of the study. 
If the ICF is revised during the course of the study, all active participating subjects must sign 
the revised form. 
Before recruitment and enrollment, each prospective subject will be given a full explanation 
of the study and will be allowed to read the approved ICF. The investigator or designated 
personnel will inform the subject of the objectives, methods, anticipated benefits, and potential 
risks and inconveniences of the study. The subject will be given every opportunity to ask for 
clarification of any points he does not understand and, if necessary, ask for more information. 
At the end of the interview, the subject will be given ample time to consider the study. Once 
the investigator is assured that the subject understands the implications of participating in the 
study, the subject will be asked to give his or her consent to participate in the study by signing 
and dating the ICF. After signatures are obtained, the ICF will be archived by the investigator 
in the investigator’s study file. A copy of the ICF will be provided to the subject. 


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It will be emphasized that the subject may refuse to enter the study or to withdraw from the 
study at any time, without consequences for their further care or penalty or loss of benefits to 
which the subject is otherwise entitled. Subjects who refuse to give or who withdraw written 
informed consent will not be included or continue to participate in the study. The investigators 
will be responsible for ensuring that no subject undergoes any study related examination or 
procedure before he has signed the informed consent to participate in the study. 
9.4.2.4 
Study Reporting Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the timeline and method outlined in this protocol. In addition, the investigator agrees that PPD 
will submit annual reports to the IEC as appropriate, on the investigator’s behalf. 
9.4.2.5 
Financial Disclosure and Obligations 
The investigator is required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required under EMA, 
FDA, or any other regulatory agency and to comply with ICH E6(R2) Section 8.2. In addition, 
the investigator must provide to the sponsor a commitment to promptly update this information 
if any relevant changes occur during the course of the investigation and for 1 year following 
the completion of the study. 
Neither the sponsor nor PPD is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the sponsor nor PPD is financially responsible for 
further treatment of the disease under study. 
9.4.2.6 
Investigator Documentation 
Prior to beginning the study, the investigators will be asked to comply with ICH 
E6(R2) Section 8.2, US Title 21 of the CFR and all other applicable regulatory requirements 
by providing essential documents, including but not limited to, the following: 
• IEC approval 
• An original investigator-signed investigator agreement page of the protocol 
• Curriculum vitae for the principal investigators and each subinvestigator. Current licensure 
must be noted on the curriculum vitae. Curriculum vitae will be signed and dated by the 


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principal investigators and subinvestigators at study start-up, indicating that they are 
accurate and current. 
• Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required under EMA, FDA, or any other regulatory 
agency and to comply with ICH E6(R2) Section 8.2. In addition, the investigators must 
provide to the sponsor a commitment to promptly update this information if any relevant 
changes occur during the course of the investigation and for 1 year after the completion of 
the study. 
• An IEC-approved ICF, samples of site advertisements for recruitment for this study, and 
any other written information about this study that is to be provided to the subject 
• Laboratory certifications and reference ranges for any local laboratories used by the site, 
in accordance with the applicable regulatory requirements 
9.4.2.7 
Study Conduct 
The investigators agree to perform all aspects of this study in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki, ICH E6(R2): Good Clinical 
Practice; the protocol; and all national, state, and local laws or regulations. 
9.4.2.8 
Case Report Forms and Source Documents 
Site personnel will maintain source documentation, enter subject data into the eCRF as 
accurately as possible, and will rapidly respond to any reported discrepancies. 
Electronic CRFs and electronic data capture will be utilized. The electronic data capture system 
is validated and compliant with the applicable regulatory requirements. Each person involved 
with the study will have an individual identification code and password that allows for record 
traceability. Thus, the system, and any subsequent investigative reviews, can identify 
coordinators, investigators, and individuals who have entered or modified records, as well as 
the time and date of any modifications. There may be an internal quality review audit of the 
data and additional reviews by the clinical monitor. 
Each eCRF is presented as an electronic copy, allowing data entry by site personnel, who can 
add and edit data, add new subjects, identify and resolve discrepancies, and view records. This 
system provides immediate direct data transfer to the database, as well as immediate detection 


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of discrepancies, enabling site coordinators to resolve and manage discrepancies in a timely 
manner. 
Paper copies of the eCRFs and other database reports may be printed and signed by the 
investigator. This system provides site personnel, monitors, and reviewers with access to 
hardcopy audits, discrepancy reviews, and investigator comment information. Following all 
data validation steps, the investigator (or designee) will electronically sign the completed 
electronic data prior to database lock. 
9.4.2.9 
Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol, in accordance with 
ICH E6(R2) and all applicable guidelines and regulations. 
9.4.2.10 
Reporting Adverse Events 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the timeline and method outlined in this protocol. In addition, the investigator agrees that PPD 
will submit annual reports to the IEC as appropriate, on the investigator’s behalf. The 
investigator also agrees that PPD will provide the sponsor with an adequate report, if applicable, 
shortly after completion of the investigator’s participation in the study. 
9.4.2.11 
Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the institution; 
the investigator/institution should provide the IEC with a summary of the study’s outcome and 
the sponsor and regulatory authorities with any reports required. 
9.4.2.12 
Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study drug. These documents should be retained 
for a longer period, however, if required by applicable regulatory requirements or by an 
agreement 
with 
the 
sponsor. 
The 
sponsor 
is 
responsible 
for 
informing 
the 
investigator/institution when these documents no longer need to be retained. 


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Records and documents including the signed ICF, pertaining to the conduct of this study must 
be retained and archived at the study site for at least 25 years after the end of the study. No 
records may be destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without written notification 
to the sponsor. 
9.4.2.13 
Publications 
After completion of the study, the data may be considered for reporting at a scientific meeting 
or for publication in a scientific journal. In these cases, the sponsor will be responsible for 
these activities and will work with the investigators to determine how the manuscript is written 
and edited, the number and order of authors, the publication to which it will be submitted, and 
any other related issues. The sponsor has final approval authority over all such issues. 
Data are the property of the sponsor and cannot be published without their prior authorisation, 
but data and any publication thereof will not be unduly withheld. 
9.4.3 
Study Management 
9.4.3.1 
Monitoring 
9.4.3.1.1 
Monitoring of the Study 
The clinical monitor, as a representative of the sponsor, is obligated to follow the study closely. 
In doing so, the monitor will visit the investigators and study sites at periodic intervals in 
addition to maintaining necessary telephone and email contact. The monitor will maintain 
current personal knowledge of the study through observation, review of study records and 
source documentation, and discussion of the conduct of the study with the investigators and 
staff. 
PPD will designate a blinded and an unblinded study monitor who will be responsible for 
monitoring this clinical study. The study monitors will monitor the study conduct, eCRF and 
source documentation completion and retention, and accurate study drug accountability. To 
this end, the study monitors will visit the study sites at suitable intervals and be in frequent 
contact through verbal and written communication. It is essential that the study monitors have 
access to all documents, related to the study and the individual subjects, at any time these are 
requested. In turn, the study monitors will adhere to all requirements for subject confidentiality 
as outlined in the ICF. The investigators and investigators’ staff will be expected to cooperate 


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with the study monitors, to be available during a portion of the monitoring visit to answer 
questions, and to provide any missing information. 
All aspects of the study will be carefully monitored by the sponsor or its designee for 
compliance with applicable government regulation with respect to current ICH E6(R2) 
guidelines and standard operating procedures. 
9.4.3.1.2 
Inspection of Records 
The investigators and institutions involved in the study will permit study-related monitoring, 
audits, IEC review, and regulatory inspections by providing direct access to all study records. 
In the event of an audit, the investigators agree to allow the sponsor, their representatives, the 
FDA, EMA, or other regulatory agencies access to all study records. 
The investigators should promptly notify the sponsor and study site(s) of any audits scheduled 
by any regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 
9.4.3.2 
Management of Protocol Amendments and Deviations 
9.4.3.2.1 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent immediate 
hazard to the subject, must be reviewed and approved by the sponsor or designee. Amendments 
to the protocol must be submitted in writing to the investigator’s IEC for approval before 
subjects are enrolled into an amended protocol. 
9.4.3.2.2 
Protocol Deviations 
The investigator or designee must document and explain in the subject’s source documentation 
any deviation from the approved protocol. The investigator may implement a deviation from, 
or a change to, the protocol to eliminate an immediate hazard to study subjects without prior 
IEC approval. As soon as possible after such an occurrence, the implemented deviation or 
change, the reasons for it, and any proposed protocol amendments should be submitted to the 
IEC for review and approval, to the sponsor for agreement, and to the regulatory authorities, if 
required. 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol. An important deviation (sometimes referred to as a major 


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or significant deviation) is a subset of protocol deviations that leads to a subject being 
discontinued from the study, or significantly affects the subject’s rights, safety, or well-being 
and/or the completeness, accuracy, and reliability of the study data. An important deviation can 
include nonadherence to inclusion or exclusion criteria or nonadherence to FDA or other 
regulatory agency regulations or ICH E6(R2) guidelines. 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. The investigator will be notified in writing by the monitor of deviations. The 
IEC should be notified of all major protocol deviations, if appropriate, in a timely manner. 
9.4.3.3 
Study Termination 
Although the sponsor has every intention of completing the study, they reserve the right to 
discontinue it at any time for clinical (eg, important AEs, SAEs, SUSARs reported), ethical, or 
administrative reasons (eg, low recruitment). 
The study must be discontinued at the discretion of the investigator (or designee), sponsor, or 
sponsor’s medical monitor if any of the following criteria are met: 
• A SUSAR of the same nature (meaning an SAE considered both unexpected and at least 
possibly related to the study drug administration) occurs in more than 2 subjects. 
• A severe and clinically significant nonserious adverse reaction of the same nature (meaning 
a severe nonSAE considered at least possibly related to the study drug administration) 
occurs in more than 2 subjects. 
The end of the study is defined as the date on which the last subject completes the last visit 
(including the EOS visit and any additional long-term follow-up). Any additional long-term 
follow-up that is required for monitoring of the resolution of an AE or finding may be appended 
to the clinical study report. 
9.4.3.4 
Final Report 
Regardless of whether the study is completed or prematurely terminated, the sponsor will 
ensure that clinical study reports are prepared and provided to regulatory agency(ies) as 
required by the applicable regulatory requirement(s). The sponsor will also ensure that clinical 
study reports in marketing applications meet the standards of the ICH harmonised tripartite 
guideline E3: Structure and content of clinical study reports. 


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Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review complete study results. 
Upon completion of the clinical study report, the investigator(s) will be provided with the final 
approved clinical study report, as appropriate. 

SAP_001.pdf: 
Protocol Title: 
A Randomised, Double Blind, Three Arm, 
Single Dose, Parallel Study to Compare the 
Pharmacokinetics, Pharmacodynamics, Safety, 
and Immunogenicity Profile of MB09 
(Proposed Denosumab Biosimilar) and EU/US 
sourced Xgeva® in Healthy Male Volunteers.
NCT Number: 
NCT05299073
Statistical 
Analysis Plan 
version date: 
Version 1.0, 04 June 2022


Confidential 
mAbxience Research S.L. 
MB09-A-01-19
A Randomised, Double-Blind, Three-Arm, Single-Dose, Parallel Study to 
Compare the Pharmacokinetics, Pharmacodynamics, Safety, and 
Immunogenicity Profile of MB09 (Proposed Denosumab Biosimilar) and 
EU/US-sourced Xgeva® in Healthy Male Volunteers 
Final Statistical Analysis Plan 
Version 1.0 
Prepared by: 


 
mAbxience Research S.L. 
Final Statistical Analysis Plan, Version 1.0 
Protocol: MB09-A-01-19 
 
 
Page 2 of 26 
 
TABLE OF CONTENTS ...................................................................................................  
LIST OF ABBREVIATIONS ...................................................................................................... 4 
1. 
INTRODUCTION ............................................................................................................ 6 
2. 
OBJECTIVES, ENDPOINTS AND ENDPOINTS ........................................................ 7 
2.1 
PRIMARY OBJECTIVES AND ENDPOINTS ............................................................................ 7 
2.2 
SECONDARY OBJECTIVES AND ENDPOINTS ....................................................................... 7 
3. 
STUDY DESIGN ............................................................................................................... 7 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 8 
4.1 SAMPLE SIZE........................................................................................................................... 9 
4.2 RANDOMIZATION, STRATIFICATION, AND BLINDING............................................................... 9 
4.3 ANALYSIS POPULATIONS ........................................................................................................ 9 
5. 
SUBJECT DISPOSITION ............................................................................................. 10 
5.1 DISPOSITION ......................................................................................................................... 10 
5.2 PROTOCOL DEVIATIONS ........................................................................................................ 10 
5.3 INCLUSION AND EXCLUSION CRITERIA ................................................................................. 10 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 10 
6.1 DEMOGRAPHICS .................................................................................................................... 10 
6.2 MEDICAL HISTORY ............................................................................................................... 11 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 11 
7.1 PRIOR AND CONCOMITANT MEDICATIONS ............................................................................ 11 
7.2 MEDICAL OR SURGICAL TREATMENT PROCEDURES .............................................................. 11 
7.3 STUDY TREATMENT .............................................................................................................. 11 
8. 
PHARMACOKINETICS ............................................................................................... 11 
8.1 CHANGES FROM PROTOCOL .................................................................................................. 11 
8.2 DATA HANDLING .................................................................................................................. 11 
8.3 PLASMA CONCENTRATIONS .................................................................................................. 12 
8.4 PHARMACOKINETIC PARAMETERS ........................................................................................ 13 
8.5 STATISTICAL ANALYSIS FOR RELATIVE BIOEQUIVALENCE ................................................... 14 
8.6 ASSESSMENT OF IMPACT OF IMMUNOGENICITY ON PHARMACOKINETICS ............................. 15 
9. 
PHARMACODYNAMICS ............................................................................................ 15 
9.1 DATA HANDLING .................................................................................................................. 15 
9.2 PD BIOMARKER CONCENTRATIONS ...................................................................................... 16 
9.3 PHARMACODYNAMIC PARAMETERS ...................................................................................... 16 
10. 
SAFETY ANALYSIS ..................................................................................................... 18 
10.1 ADVERSE EVENTS ............................................................................................................... 18 
10.2 CLINICAL LABORATORY EVALUATIONS ............................................................................. 20 
10.3 VITAL SIGN MEASUREMENTS ............................................................................................. 21 
10.4 PHYSICAL EXAMINATION .................................................................................................... 21 


mAbxience Research S.L. 
Final Statistical Analysis Plan, Version 1.0 
MB09-A-01-19 
 
  
Page 3 of 26 
 
10.5 ELECTROCARDIOGRAMS ..................................................................................................... 22 
10.6 IMMUNOGENICITY ANALYSIS .............................................................................................. 22 
10.7 COVID-19 IMPACT ............................................................................................................ 22 
11. 
INTERIM ANALYSIS .................................... ERROR! BOOKMARK NOT DEFINED. 
12. 
CHANGES IN THE PLANNED ANALYSIS .............................................................. 23 
13. 
REFERENCES ................................................................................................................ 24 
14. 
SCHEDULE OF ASSESSMENTS ................................................................................ 25 
 
 
 


mAbxience Research S.L. 
Final Statistical Analysis Plan, Version 1.0 
MB09-A-01-19 
Date Issued: 04/06/2022 
  
Page 4 of 26 
 
List of Abbreviations 
 
ADA  
anti-drug antibodies  
AE  
adverse event  
ALP  
alkaline phosphatase  
ALT  
alanine aminotransferase  
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
aPTT  
activated partial thromboplastin time  
AST  
aspartate aminotransferase  
AUC  
area under the plasma concentration versus time curve  
AUC0-last  
area under the plasma concentration versus time curve from time 0 to the last 
quantifiable concentration  
AUC0-∞  
area under the plasma concentration versus time curve from time 0 
extrapolated to infinity  
%AUCext 
percentage of AUC0-∞ due to extrapolation. 
AUEC  
area under the effect versus time curve  
AUEC0-last 
area under the effect-time curve from time zero to the last quantifiable sCTX 
concentration time point using absolute data (without baseline-adjustment) 
AUEC0-253 
area under the effect-time curve from time zero to Day 253 (ie, the last planned 
sampling time) using absolute data (without baseline-adjustment) 
AUIC0-last 
area under the % inhibition curve from time zero to the last quantifiable sCTX 
concentration time point using percent change from baseline data 
AUIC0-253 
area under the effect-time curve from time zero to Day 253 (ie, the last planned 
sampling time) using percent change from baseline data 
BLQ  
below the limit of quantification  
BMI  
body mass index  
BP  
blood pressure  
BUN  
blood urea nitrogen  
CI  
confidence interval  
CK  
creatine kinase  
CL/F  
apparent total body clearance following extravascular administration 
Cmax  
maximum observed plasma concentration  
Cmin 
minimum concentration 
COVID-19  
coronavirus disease 2019  
CSR 
clinical study report 
CTCAE  
Common Terminology Criteria for Adverse Events  
CV  
coefficient of variation  
DHHS 
Department of Health and Human Services 
ECG  
electrocardiogram  
eCRF  
electronic case report form  
ELISA  
enzyme-linked immunosorbent assay  
EMA 
European Medicines Agency 
EOS 
end of study 
EU  
European Union  
FDA  
Food and Drug Administration  
GCP  
Good Clinical Practice  
GFR  
glomerular filtration rate  


mAbxience Research S.L. 
Final Statistical Analysis Plan, Version 1.0 
MB09-A-01-19 
 
  
Page 5 of 26 
 
HBV  
hepatitis B virus  
HCV  
hepatitis C virus  
HIV  
human immunodeficiency virus  
ICF 
informed consent form 
IgG  
immunoglobulin G  
Imax 
maximum % inhibition 
INR  
international normalised ratio  
IV  
intravenous  
Kel 
elimination rate constant (λz) during terminal phase 
mAb  
monoclonal antibody  
MDRD  
modification of diet in renal disease  
MedDRA  
Medical Dictionary for Regulatory Activities  
MSD-ELC  
Meso Scale Discovery-electrochemiluminescence  
NA 
not applicable 
NAb  
neutralizing antibodies  
PD  
pharmacodynamic(s)  
PK  
pharmacokinetic(s)  
PT  
preferred term 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RANK  
Receptor Activator of Nuclear Factor Kappa-B (NFκB)  
RANKL  
Receptor Activator of Nuclear Factor Kappa-B (NFκB) Ligand  
SAE  
serious adverse event  
SAP 
statistical analysis plan 
SC  
subcutaneous(ly)  
SD  
standard deviation  
sCTX  
serum C-terminal telopeptide of Type 1 collagen  
SOC 
system organ class 
SOE  
schedule of events  
TEAE 
treatment emergent adverse event 
TImax 
the time of occurrence of the maximum % inhibition 
Tmax  
time to reach maximum observed plasma concentration  
Tmin 
time of occurrence of the minimum concentration 
t1/2  
terminal phase half-life  
ULN  
upper limit of normal  
US 
United States  
Vz/F 
Apparent volume of distribution during the terminal phase following 
extravascular administration 


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1. Introduction 
Denosumab, the active substance of Xgeva® manufactured and marketed by Amgen in the EU 
and US, is a human monoclonal antibody (mAb) (IgG2) that targets and binds with high affinity 
and specificity to Receptor Activator of Nuclear Factor Kappa-B (NFκB) Ligand (RANKL). It 
prevents the RANKL/RANK interaction from occurring, thus resulting in reduced osteoclast 
numbers and function, thereby decreasing bone resorption and cancer-induced bone destruction. 
MB09 is a medicinal product containing mAb denosumab as the active substance, developed by 
mAbxience as a biosimilar product to Xgeva. mAbxience is using a similarity-by-design approach 
for development of the proposed biosimilar, MB09, and has designed an overall development 
program to establish similarity between MB09 and Xgeva, tailoring the design of the studies to 
focus on the molecule’s mode of action and analytical similarity between reference medicinal 
product and MB09. This study in healthy male volunteers is part of the clinical development 
program for MB09 and is designed to assess the bioequivalence of MB09 compared with Xgeva. 
The purpose of this statistical analysis plan (SAP) is to define the planned statistical analysis of 
the study data consistent with the study objectives. This SAP is written based on protocol aMB09-
A-01-19, version 2.0, dated 30 November 2021. 


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2. Objectives, Endpoints and Endpoints 
2.1 Primary Objectives and Endpoints 
 
Primary objective 
Endpoint description  
The primary objectives of this study are to 
assess 
the 
bioequivalence 
of 
single 
subcutaneous (SC) doses in healthy subjects 
of: 
• 
MB09 versus EU-sourced Xgeva 
• 
MB09 versus US-sourced Xgeva 
• 
EU-sourced 
Xgeva 
versus 
US-
sourced Xgeva 
• 
Pharmacokinetics: AUC0-last and Cmax 
 
2.2 Secondary Objectives and Endpoints 
Secondary objective 
Endpoint description  
The secondary objectives of this study are: 
• 
To evaluate and compare the derived 
pharmacokinetics 
(PK) 
and 
pharmacodynamics (PD) of single 
SC doses of MB09 and EU-sourced 
Xgeva and MB09 and US-sourced 
Xgeva in healthy subjects 
• 
To evaluate the safety, tolerability, 
and immunogenicity of single SC 
doses of MB09, EU-sourced Xgeva, 
and US-sourced Xgeva in healthy 
subjects 
• 
Pharmacokinetics: AUC0-∞, Tmax, 
CL, t1/2 
• 
Pharmacodynamics: AUEC of sCTX 
• 
Safety: monitoring and recording of 
adverse 
events 
(AEs), 
clinical 
laboratory test results (hematology, 
coagulation, serum chemistry, and 
urinalysis), vital sign measurements, 
12-lead electrocardiogram (ECG) 
results, 
and 
targeted 
physical 
examination findings. 
• 
Immunogenicity: Denosumab anti-
drug 
antibodies 
(ADA) 
and 
neutralizing antibodies (NAb) 
 
3. Study Design 
This is a Phase 1, double-blind, randomized, single-dose, bioequivalence study to compare the PK, 
PD, safety, and immunogenicity of MB09 and EU/US-sourced Xgeva in 3 parallel arms. 
Healthy male volunteers who meet all inclusion and none of the exclusion criteria will be randomly 
assigned to receive either 35 mg of MB09 SC (Study Arm 1) or 35 mg of EU-sourced Xgeva SC 
(Study Arm 2) or 35 mg of US-sourced Xgeva SC (Study Arm 3) in 1:1:1 ratio. The subjects will 
be stratified based on their body weight. Adequate number of healthy male subjects will be 
screened and enrolled at selected centers in Poland to have 204 evaluable subjects (68 subjects in 
each study arm). 


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The study will consist of a screening period (Days -30 to -2), check-in (Day -1), treatment period 
(Day 1), follow-up period (Days 2 to 252) and an EOS visit (Day 253). 
The PK, PD, safety, and immunogenicity endpoints will be evaluated in this study. 
Subjects will be confined to the clinical unit from Day -1 until discharge on Day 2. The duration 
of the study, excluding screening, is approximately 36 weeks. 
Schedules of assessments can be found in Section 14. 
4. General Statistical Considerations 
All statistical analyses will be conducted using statistical analysis system SAS® Version 9.4 or 
higher (SAS Institute, Cary, NC).  
Descriptive statistics for continuous variables will include number of subjects, mean, standard 
deviation (SD), median, minimum, and maximum, unless otherwise noted. For categorical 
variables, frequencies and percentages will be presented.  
All tables, listings, and figures will be presented by treatment. The treatments below will be used 
for presentations: 
• 
MB09 
• 
EU Xgeva 
• 
US Xgeva 
 
All data listings will be sorted by treatment and subject number. 
No algorithm for imputation of missing data will be employed. 
Study days are calculated with respect to the first dose date as below: 
If the assessment/observation date is on or after the first dose date, then Study Day = 
Assessment/Observation Date – First Dose Date + 1; 
Otherwise, Study Day = Assessment/Observation Date – First Dose Date 
Baseline will be defined as the last non-missing assessment (including repeated and unscheduled 
assessments) before the first dose of study drug administration, unless otherwise specified. 
For summary of safety assessments, if there are repeated measurements at a time point, the first 
non-missing assessment at that time point will be used in the summary tables.  
Unscheduled results will not be included in the summary tables, except for determining Baseline, 
but will be presented in data listings. 
The methodology and data handling specifications for PK data are detailed in Section 8. 


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4.1 Sample Size 
The sample size for this study is based on a statistical power calculation. A CV value of 33% was 
estimated for AUC parameter (which showed the highest variability) based on previous PK studies 
conducted at a dose of 60 mg or 1 mg/kg. Assuming a ratio of AUC and Cmax between 0.95 and 
1.05, 68 PK-evaluable subjects per arm would be required to provide at least 90% power to 
conclude bioequivalence of MB09 and Xgeva. Thus, 204 evaluable subjects will be required in all. 
Assuming a 20% dropout rate, approximately 255 subjects are planned to be enrolled in this study. 
Enrollment could be stopped when the target of having 204 evaluable subjects is achieved. 
Subjects will be randomly assigned to 1 of 3 study arms in a 1:1:1 ratio. 
4.2 Randomization, Stratification, and Blinding 
PPD will generate the randomization schedule. Subjects who meet all inclusion and none of the 
exclusion criteria will be randomly assigned to 1 of the 3 study arms. Randomization numbers (in 
sequential order) will be assigned before the study drug is administered on Day 1. Randomization 
will be stratified based on the subject’s body weight: 60 to <80 kg and 80 to 95 kg. 
This study will employ a double-blind study design. MB09 and Xgeva will be packed in identical 
boxes. The unblinded pharmacists will be responsible for preparing and dispensing the study drug 
in a manner consistent with maintaining the blind. 
The sites will be responsible for maintaining the blind throughout the study. If a subject becomes 
seriously ill during the study, the blind will be broken upon the investigator’s approval only if 
knowledge of the administered study drug will affect that subject’s available treatment options. 
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 finalized 
for study closure. 
At the discretion of the investigator, and after consultation with the medical monitor, any subject 
who withdraws for reasons other than those related to study treatment, before completing the study 
may be replaced to retain the target of 204 evaluable subjects. Any replacement subject will be 
assigned to receive the same treatment as the subject he is replacing. 
4.3 Analysis Populations 
The safety population will include all subjects who receive the study drug. 
The PK population will include subjects who receive the study drug, who do not have major 
protocol deviations*, and have sufficient data to calculate primary PK endpoints. 
 
The PD population will include subjects who receive the study drug, who do not have major 
protocol deviations*, and have sufficient data to calculate secondary PD endpoints. 
 


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* Each subject’s data (e.g., dosing records, sample collection records, protocol deviations, 
concomitant medications, etc.) will be reviewed and assessed, and subjects may be excluded 
from the PK or PD populations on a case-by-case basis at the discretion of the 
Pharmacokineticist. It is assumed that such deviations are equally likely to occur in each of the 3 
treatment groups. 
5. Subject Disposition 
5.1 Disposition 
The following will be summarized overall for all subjects: 
• The number of subjects who enrolled in the study 
• The number of subjects who received each treatment  
• The number of subjects who completed the study 
• The number of subjects who did not complete the study (both overall and according to 
reasons for discontinuation from the study) 
• The number of subjects in each analysis population 
Subject disposition data will be presented in a data listing. Subjects who were unblinded by the 
site will be presented in a listing. Screen failure subjects and reasons for screen failure will be 
presented in a separate listing. 
5.2 Protocol Deviations 
Significant protocol deviations will be summarized by treatment. All protocol deviations will be 
presented in a data listing.  
5.3 Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria deviations will be presented in a data listing. 
6. Demographics and Baseline Characteristics 
6.1 Demographics 
Demographic information collected at screening will be presented in a data listing. 
Descriptive statistics will be calculated for the following continuous demographic characteristics:  
- 
Age (years) 
- 
Weight (kg) 
- 
Height (cm) 
- 
Body mass index (BMI) (kg/m2) 
Frequency counts and percentages will be tabulated for the categorical variables: 
- 
Race 
- 
Ethnicity 
The summaries will be presented by treatment and overall for the safety population. 


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6.2 Medical History 
The medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, version 24.0) and presented in a data listing. 
7. Treatments and Medications 
7.1 Prior and Concomitant Medications 
Medications that stop prior to the first dose of study drug will be classified as prior medication. 
Medications that start on or after the first dose of study drug will be classified as concomitant. If 
a medication starts before the first dose of study drug and stops on or after the first dose of study 
drug, then the medication will be classified as both prior and concomitant. 
All prior and concomitant medications will be coded according to the World Health Organization 
Drug Dictionary (WHODrug Global March 2022) and presented in a data listing. 
7.2 Medical or Surgical Treatment Procedures 
Medical or surgical treatment procedures will be presented in a data listing. 
7.3 Study Treatment 
The study drug administration and drug accountability data as collected on eCRF will be 
presented in the data listings. 
8. Pharmacokinetics 
8.1 Changes from Protocol 
Only a PK population was defined in the protocol (Protocol Section 7.2). A PD population 
definition was therefore defined for the purposes of the PD analysis. 
 
Rather than use an analysis of variance (ANOVA) approach to determine comparability for PD 
parameters (as specified in Protocol Section 7.3.2), given the parallel design it was deemed more 
appropriate to use an analysis of covariance (ANCOVA) to account for stratification factors (i. e. 
Body Weight) in the comparison of PD data, and to account for baseline sCTX levels when 
comparing PD data between treatments.  
 
8.2 Data Handling 
PK listings will be presented using the safety population; all summaries and analyses of PK data 
will be based on the PK population. 
 
The following procedures will be used for plasma concentration data of denosumab below the limit 
of quantification (BLQ) and missing values: 
- 
Concentration values that are BLQ will be reported as provided by the bioanalytical 
data in the PK data listings. 


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- 
Plasma concentration values that are BLQ will be treated as zero at individual time 
points for the calculation of summary statistics (e.g., mean, standard deviation [SD], 
etc.). 
- 
Mean concentrations will be reported as BLQ if all concentration values are BLQ, and 
SD and CV will be reported as not applicable (NA). 
- 
Missing concentration values will be excluded from the calculation of concentration 
summary statistics. 
- 
For calculation of PK parameters, BLQ values will be treated as zero with the exception 
that a BLQ value between 2 quantifiable concentrations will be set as missing. If 
consecutive BLQ concentrations are followed by quantifiable concentrations in the 
terminal phase, those concentrations after BLQ concentrations will be treated as 
missing. 
- 
Missing concentrations will be treated as missing from the PK parameter calculations 
(no imputation will be performed). 
- 
For graphical presentations, all BLQs will be set to missing. 
 
8.3 Plasma Concentrations 
Serial blood samples for plasma pharmacokinetic analysis of denosumab will be collected up to 2 
hours before dosing (Predose) and at 8 and 16 hours (± 2 hours), 24, 48, and 72 hours (± 4 hours), 
and on Days 6 (120 hours, ± 1 day), 8 (168 hours, ± 1 day), 11 (240 hours, ± 1 day), 15 (336 hours, 
± 2 days), 22 (504 hours, ± 2 days), 29 (672 hours, ± 2 days), 43 (1008 hours, ± 3 days), 57 (1344 
hours, ± 3 days), 71 (1680 hours, ± 3 days), 85 (2016 hours, ± 3 days), 99 (2352 hours, ± 3 days), 
113 (2688 hours, ± 3 days), 141 (3360 hours, ± 3 days), 169 (4032 hours, ± 3 days), 197 (4704 
hours, ± 3 days), 225 (5376 hours, ± 3 days), and 253 (6048 hours, ± 3 days) after dosing. 
 
PK collections that have an actual sampling time that deviates from the predefined collection time 
windows will be assessed by the Pharmacokineticist on a case-by-case basis for the potential of 
exclusion from the calculation of concentration summary statistics. PK collections identified for 
exclusion will be flagged in the data listings and excluded from the calculation of concentration 
summary statistics. 
 
Plasma concentration and time deviation data will be presented in a data listing. Plasma 
concentration data will be summarized by scheduled time point for each treatment using the 
following descriptive statistics: number of subjects (n), arithmetic mean, SD, CV, geometric mean, 
geometric CV, median, minimum, and maximum. Geometric mean will be reported as missing 
where any concentration is zero (BLQ). Individual plasma concentration versus actual time and 
mean plasma concentration versus scheduled time profiles by treatment will be presented in figures 
on both linear and semilogarithmic scales. 
 
Plasma concentrations of denosumab will be displayed using the precision provided in the raw 
bioanalytical file received from the lab. Summary statistics for concentrations will be displayed to 
2 decimal places, with the exception of n, which will be shown as an integer. 
 


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8.4 Pharmacokinetic Parameters  
The PK parameters of denosumab will be analyzed based on the actual sampling times. In cases 
where an actual time is not recorded, the nominal time will be used. All pharmacokinetic 
parameters will be calculated using Phoenix® WinNonlin®
 
 Version 8.0 or higher or SAS®
 Version 9.4 or 
higher. 
 
The following plasma PK parameters will be calculated for denosumab:  
AUC0-last 
Area under the plasma concentration versus time curve from time zero to the 
last quantifiable concentration time point, calculated using the linear up log 
down trapezoidal rule. 
AUC0-∞ 
Area under the plasma concentration versus time curve from time 0 
extrapolated to infinity calculated per the formula: 
AUC0-∞ = AUC0-last + Clast / Kel,, where Clast is the concentration of the last 
quantifiable concentration timepoint sample and Kel is the first order rate 
constant of the terminal phase. 
Cmax 
Maximum observed plasma concentration 
Tmax 
Time to reach maximum observed plasma concentration.  
Kel 
Elimination rate constant (λz) during terminal phase 
t1/2 
Terminal phase half-life, calculated as t1/2 = ln2/Kel 
CL/F 
Apparent total body clearance following extravascular administration, 
calculated as CL/F = Dose/AUC0-∞ 
Vz/F 
Apparent volume of distribution during the terminal phase following 
extravascular administration, calculated as  
Vz/F = (CL/F)/Kel 
 
In addition to the above PK parameters, which will be listed and summarized, the following 
parameters will also be listed to document the selection of data points used to estimate t1/2 using 
non-compartmental procedures: 
 
Number points Number of data points used to estimate Kel; a minimum of 3 data points must 
be used, and Cmax must not be included. 
Kel lower 
Lower bound used for the estimation of Kel. 
Kel upper 
Upper bound used for the estimation of Kel. 
Span 
Number of elapsed half-lives over which Kel is estimated, calculated as (Kel 
upper – Kel lower) / t½. 
Rsq 
r2, the coefficient of determination (goodness of fit statistic); Kel and all 
associated parameters (AUC0-∞, t1/2, CL/F, Vz/F) will only be reported where 
r2 ≥ 0.80. 


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%AUCext 
Percentage of AUC0-∞ due to extrapolation. 
 
Additional parameters may be calculated as required. 
 
The individual PK parameters will be presented in data listings and summarized by treatment using 
the following descriptive statistics: number of subjects (n), arithmetic mean, SD, CV, median, 
minimum, and maximum. Tmax will be summarized by number of subjects, median, minimum, and 
maximum only. Geometric means will be included for Cmax, AUC0-last, and AUC0-∞.Plasma 
pharmacokinetic parameters and summary statistics will be rounded to 3 significant figures, with 
the exception of n, which will be shown as an integer, and Kel lower, Kel upper, and Tmax, which 
will be rounded to 2 decimal places. 
8.5 Statistical Analysis for Relative Bioequivalence 
An analysis of variance (ANOVA) model with treatment and stratification factors (i.e., Body 
Weight) as fixed effects will be performed on the natural log-transformed values of Cmax, AUC0-last, 
and AUC0-∞ to assess the relative bioequivalence between MB09 (test) versus EU-sourced or US-
sourced Xgeva (reference), as well as comparing EU-sourced Xgeva (test) to US-sourced Xgeva 
(reference). The geometric least squares means, ratios of the geometric least squares means, and 
corresponding 90% confidence intervals (CIs) for the ratios will be computed for Cmax, AUC0-t, 
and AUC0-∞ by taking the antilog of the least squares means from the ANOVA model on the natural 
logarithms of the corresponding PK parameters for the following comparisons: 
 
• MB09 / EU-sourced Xgeva 
• MB09 / US-sourced Xgeva 
• EU-sourced Xgeva / US-sourced Xgeva 
 
A 90% CI for the ratio will be constructed as the antilog of the confidence limits of the mean 
difference. No adjustment will be made for multiplicity. 
 
Biosimilarity will be concluded if the 90% CIs for the test to reference ratios of the geometric least 
square means for Cmax, AUC0-last, and AUC0-∞ are entirely contained within the [80.00%, 125.00%] 
interval. 
 
Forest plots will also be presented for Cmax, AUC0-last, and AUC0-∞. 
 
Nonparametric methods (Wilcoxon signed-rank test) will be performed to examine median 
differences in Tmax for MB09 vs EU-sourced Xgeva, MB09 vs US-sourced Xgeva, and EU-sourced 
Xgeva vs US-sourced Xgeva comparisons. The Hodges-Lehmann estimate, and its 90% CI will be 
calculated for the median difference between treatments, and a p-value will be generated by the 
Wilcoxon signed-rank test. 
 
Additional sensitivity analyses may also be performed excluding body weight from the model 
and/or including additional covariates that may affect the PK e.g., subject demographic, protein 
concentration of the vials, batch of test material etc. Results by site may also be presented 
separately. 


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8.6 Assessment of Impact of Immunogenicity on Pharmacokinetics 
Each subject’s overall ADA status will be included in all PK data listings: subjects will be assigned 
an overall ADA negative status where all ADA assessments are negative throughout the duration 
of the study or were only positive at baseline and negative after; if a subject has at least one 
treatment-induced (i.e., formation of ADA any time after the initial drug administration in a subject 
without pre-existing ADA) their overall ADA status will be assigned as positive. All PK tables 
(concentration summaries, parameter summaries, and statistical analyses) and summary plots 
(mean concentrations and Forest plots) will include 3 separate populations: 
 
• 
Overall (all subjects in the PK population, irrespective of ADA status) 
• 
ADA Negative (all ADA assessments are negative throughout the duration of the study 
and subjects which were only positive at baseline and negative after) 
• 
ADA Positive (at least one treatment-induced ADA positive assessment observed) 
 
In case of Treatment-boosted ADA: Pre-existing ADA that were boosted to a higher level 
following biologic drug administration (i.e., any time after the initial drug administration the ADA 
titer is greater than the baseline titer by a scientifically reasonable margin such as fourfold, similar 
analysis would be run.  
 
If there are an insufficient number of ADA positive subjects, statistical analyses will not be 
performed, and a descriptive analysis will be generated on this population.. 
 
9. Pharmacodynamics 
9.1 Data Handling 
The following procedures will be used for sCTX concentrations below the limit of quantification 
(BLQ) and missing values: 
• 
Concentration values that are BLQ will be reported as provided by the bioanalytical data 
in the PD data listings. 
• 
Concentration values that are BLQ will be treated as missing at individual time points for 
the calculation of summary statistics (e.g., mean, standard deviation [SD], etc.).  
• 
Mean concentrations will be reported as BLQ if all concentration values are BLQ, and SD 
and CV will be reported as not applicable (NA). 
• 
Missing concentration values will be excluded from the calculation of concentration 
summary statistics. 
• 
For calculation of PD parameters, BLQ values will be treated as ½ lower limit of 
quantification (LLOQ). 
• 
Missing concentration values will be treated as missing (no imputations will be performed). 
 
Serum PD concentrations will be displayed using the precision provided in the raw bioanalytical 
file received from the lab. Summary statistics for PD concentrations will be rounded to 3 
significant figures, with the exception of n, which will be shown as an integer. 


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9.2 PD Biomarker Concentrations 
Serial blood samples for serum PD analysis will be collected before up to 2 hours before dosing 
(Predose) and at 8 and 16 hours (± 2 hours), 24, 48, and 72 hours (± 4 hours), and on Days 6 (120 
hours, ± 1 day), 8 (168 hours, ± 1 day), 11 (240 hours, ± 1 day), 15 (336 hours, ± 2 days), 22 (504 
hours, ± 2 days), 29 (672 hours, ± 2 days), 43 (1008 hours, ± 3 days), 57 (1344 hours, ± 3 days), 
71 (1680 hours, ± 3 days), 85 (2016 hours, ± 3 days), 99 (2352 hours, ± 3 days), 113 (2688 hours, 
± 3 days), 141 (3360 hours, ± 3 days), 169 (4032 hours, ± 3 days), 197 (4704 hours, ± 3 days), 225 
(5376 hours, ± 3 days), and 253 (6048 hours, ± 3 days) after dosing. 
 
PD collections that have an actual sampling time that deviates from the predefined collection time 
windows will be assessed by the Pharmacokineticist on a case-by-case basis for the potential of 
exclusion from the calculation of concentration summary statistics. PK collections identified for 
exclusion will be flagged in the data listings and excluded from the calculation of concentration 
summary statistics. 
 
Serum PD concentration and time deviation data will be presented in a data listing along with 
change from baseline (CFB) and percentage change from baseline (%CFB). Serum PD 
concentration data (absolute and %CFB) will be summarized by scheduled time point for each 
treatment using the following descriptive statistics: number of subjects, arithmetic mean, SD, CV, 
geometric mean, geometric CV, median, minimum, and maximum. Individual absolute and %CFB 
serum concentration versus actual time and mean absolute and %CFB serum concentration versus 
scheduled time profiles by treatment will be presented in figures on both linear and 
semilogarithmic scales. 
9.3 Pharmacodynamic Parameters  
The PD parameters will be analyzed based on the actual sampling times. In cases where an actual 
time is not recorded, the nominal time will be used. All PD parameters will be calculated using 
Phoenix® WinNonlin® 
 Version 8.0 or higher or SAS® 
) Version 9.4 or higher. 
 
The following PD parameters will be estimated for sCTX using absolute (without baseline-
adjustment) sCTX concentrations: 
 
Cmin 
The minimum concentration (which represents the maximum PD effect) 
Tmin 
The time of occurrence of the minimum concentration 
AUEC0-last 
Area under the effect-time curve from time zero to the last quantifiable 
sCTX 
concentration 
time 
point 
using 
absolute 
data 
(without 
baseline-adjustment) and the linear trapezoidal rule. 


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AUEC0-253 
Area under the effect-time curve from time zero to Day 253 (ie, the last 
planned sampling time) using absolute data (without baseline-adjustment), 
and the linear trapezoidal rule. Where the last observation is observed 
before Day 253, the AUEC until Day 253 will be extrapolated from 
AUEC0-last, where possible. If extrapolation is not possible, AUEC0-253 will 
be set to missing. Where the last observation is observed after Day 253, the 
AUEC until Day 253 will be interpolated. 
The following PD parameters will be estimated for sCTX using %CFB sCTX values: 
Imax 
The maximum % inhibition 
TImax 
The time of occurrence of the maximum % inhibition 
AUIC0-last 
Area under the % inhibition curve from time zero to the last quantifiable 
sCTX concentration time point using percent change from baseline data 
and the linear trapezoidal rule. 
AUIC0-253 
Area under the effect-time curve from time zero to Day 253 (ie, the last 
planned sampling time) using percent change from baseline data and the 
linear trapezoidal rule. Where the last observation is observed before 
Day 253, the AUIC until Day 253 will be extrapolated from AUIC0-last, 
where possible. If extrapolation is not possible, AUIC0-253 will be set to 
missing. Where the last observation is observed after Day 253, the AUIC 
until Day 253 will be interpolated. 
 
Additional PD parameters, such as truncated AUECs or AUICs over a common time period across 
all subjects, may be calculated as required. 
 
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, and maximum. Geometric means will be included for Cmin, Imax, AUEC0-last, AUIC0-last, 
AUEC0-253, and AUIC0-253. Tmin and TImax will be summarized by number of subjects, median, 
minimum, and maximum only. 
 
PD parameters and summary statistics will be rounded to 3 significant figures, with the exception 
of n, which will be shown as an integer, and Tmin and TImax, which will be rounded to 2 decimal 
places. 
9.4 Statistical Analysis for Relative Bioequivalence 
An analysis of covariance (ANCOVA) model with treatment and stratification factors (i.e. body 
weight) as fixed effects and logged pre-dose sCTX concentrations (baseline) fitted as a covariate 
will be performed on the natural log-transformed values of AUEC0-253 and AUIC0-253 to assess the 
relative bioequivalence between MB09 (test) versus EU-sourced or US-sourced Xgeva (reference), 
as well as comparing EU-sourced Xgeva (test) to US-sourced Xgeva (reference). The geometric 
least squares means, ratios of the geometric least squares means, and corresponding 90% 
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means from the ANCOVA model on the natural logarithms of the corresponding PD parameters 
for the following comparisons: 
 
• 
MB09 / EU-sourced Xgeva 
• 
MB09 / US-sourced Xgeva 
• 
EU-sourced Xgeva / US-sourced Xgeva 
 
A 90% CI for the ratio will be constructed as the antilog of the confidence limits of the mean 
difference. No adjustment will be made for multiplicity. Biosimilarity in PD biomarker will be 
reported as the test to reference ratio of geometric means and its corresponding 90% CI for AUEC0-
253 and AUIC0-253 PD parameters. 
 
Forest plots will also be presented for AUEC0-253 and AUIC0-253. 
9.5 Assessment of Impact of Immunogenicity on Pharmacodynamics 
Select analyses may be performed for subsets with or without ADA as appropriate. 
 
10. Safety Analysis 
All safety summaries and analyses will be based upon the safety population. 
10.1 Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  
A treatment-emergent AE (TEAE) is defined as any event not present before exposure to study 
drug or any event already present that worsens in intensity or frequency after exposure. 
A serious AE (SAE) is defined as any AE that results in any of the following outcomes: death, a 
life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal 
activities of daily living, or a congenital anomaly or birth defect. Important medical events that 
may not result in death, be life threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the Subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.  
The AE’s relationship to study treatment will be evaluated by the investigator. The following 
relationships will be collected on eCRF: related, or not related.  
All AEs will be graded for intensity according to the CTCAE, Version 5.0 – November 2017 
(DHHS 2017). All other laboratory and clinical AEs not outlined in the CTCAE that occur in a 


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subject will be assessed (graded) for intensity and then classified into 1 of 5 clearly defined 
categories as follows: 
- 
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; limits age-
appropriate instrumental activities of daily living (eg, preparing meals, shopping for 
groceries or clothes, using the telephone, managing money). 
- 
Grade 3 (Severe): Medically significant but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; limits self-care 
activities of daily living (eg, bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden). 
- 
Grade 4 (Life-threatening): Urgent intervention indicated. 
- 
Grade 5 (Death). 
 
An overall AE summary will be generated presenting the frequency and percentage of subjects 
and the number of AEs by treatment for the following: 
- 
Any AE 
- 
Any TEAE 
- 
Any treatment-related TEAE  
- 
Any moderate TEAE 
- 
Any treatment-related moderate TEAE 
- 
Any treatment-related severe TEAE 
- 
Any SAE 
- 
Any treatment-related SAE 
- 
Any TEAE leading to early discontinuation 
- 
Any death  
 
All AEs will be coded using MedDRA (version 24.0). The TEAEs will be summarized by 
treatment, severity, and relationship to the study drug. The frequency of TEAEs (the number of 
TEAEs, the number of subjects experiencing a TEAE, and the percentage of subjects experiencing 
a TEAE) will be summarised by treatment, severity grade, and by Medical Dictionary for 
Regulatory Activities system organ class and preferred term. 
The proportion of subjects experiencing at least one TEAE will be compared among the treatments 
using Fisher's exact test at 0.05 significance level. As adverse events from the same body system 
may be correlated and there may also be correlations between adverse events from different body 


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systems, to control the family-wise error rate, Bonferroni correction will be applied to resulting p-
values from Fisher´s test. 
Any severe or serious AEs will be tabulated. For any AEs that change severity ratings the AE will 
be included only once under the maximum severity rating in the summaries. 
The TEAE summary tables will be sorted by SOC and PT. System organ class will be displayed in 
descending order of overall frequency then alphabetically. Preferred term will be displayed in 
descending order of overall frequency and then alphabetically within SOC. A Subject with 2 or 
more events within the same level of summarization will be counted only once in that level using 
the most severe incident or most related incident. Percentages will be based on the number of 
subjects in each treatment in the safety population. 
All AEs will be presented in a data listing. Separate data listings will be generated for 
treatment-related AEs, SAEs, and AEs leading to study discontinuation.  
10.2 Clinical Laboratory Evaluations 
The following laboratory tests will be performed: 
Hematology 
 
Leukocyte count and percentage and absolute differentials (basophils, 
eosinophils, lymphocytes, monocytes, neutrophils), hematocrit, 
hemoglobin, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, mean corpuscular volume, platelet count, 
red blood cell count, and red blood cell distribution width 
Coagulation 
INR, prothrombin time, aPTT 
Serum Chemistry 
 
ALT, albumin, ALP, AST, bilirubin (total, direct, indirect), BUN, 
calcium, chloride, cholesterol (total, high-density lipoprotein, and 
calculated low-density lipoprotein), CK, gamma-glutamyltransferase, 
globulin, glucose, lactate dehydrogenase, phosphorus, potassium, 
sodium, total protein, triglycerides, uric acid, creatinine, and GFR. 
GFR will be calculated by the MDRD equation: 175 × (standardized 
serum creatinine/88.4)-1.154 × (age)-0.203 × (1.212 if black) 
Urinalysis 
 
Appearance, bilirubin, color, glucose, ketones, leukocyte esterase, 
reflex microscopy (performed if dipstick is positive for protein or the 
blood value is 1+ or greater; and includes bacteria, casts, crystals, 
epithelial cells, red blood cells, and white blood cells), nitrites, occult 
blood, pH, protein, specific gravity, turbidity, and urobilinogen 
Serology 
Hepatitis B surface antigen, anti-hepatitis B core antigen, anti-hepatitis 
B surface antigen, hepatitis B DNA test (optional), HCV antibody, and 
HIV antibody types 1 and 2 (screening only) 


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Other tests 
 
All subjects: COVID-19 test, alcohol test (breath/urine), urine drug 
screen (amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine 
metabolites, 
cotinine, 
methamphetamines, 
tricyclic 
antidepressants, and opiates) 
 
The hematology, coagulation, serum chemistry, and urinalysis tests will be performed at the 
timepoints indicated in the schedule of assessments (schedules of assessments can be found in 
Section 14). 
All clinical laboratory test results will be presented in the data listings. Laboratory values that are 
outside of the normal reference range will be flagged in the data listings. 
Actual results and change from baseline for hematology, coagulation, serum chemistry and 
urinalysis at each time point will be summarized for the safety population. Shift from baseline in 
terms of low/normal/high for hematology and serum chemistry tests, and in terms of 
normal/abnormal for urinalysis tests will be summarized for the safety population.  
10.3 Vital Sign Measurements 
Vital signs will include systolic and diastolic blood pressure, respiratory rate, and tympanic 
temperature, and will be measured at the timepoints indicated in the schedule of assessments after 
the subject has been in the supine position for at least 5 minutes (schedules of assessments can be 
found in Section 14). 
All vital sign, body weight, and height measurements will be presented in a data listing. The actual 
values and change from baseline values at each time point will be summarized for the safety 
population. 
10.4 Physical Examination 
A full physical examination will be performed at screening (at minimum, assessment of skin, head, 
oral cavity, ears, eyes, nose, throat, neck, thyroid, lungs, heart, cardiovascular, abdomen, lymph 
nodes, and musculoskeletal system/extremities). A brief physical examination will be performed 
at check-in, Day 225, and EOS (at minimum, assessment of oral cavity, skin, lungs, cardiovascular 
system, and abdomen [liver and spleen]). Interim physical examinations may be performed at the 
discretion of the investigator, if necessary, to evaluate AEs or clinical laboratory abnormalities.  
All physical examination results will be presented in a data listing. Dental and otolaryngological 
examinations will be done at screening and will be presented in a separate data listing. 




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11. Changes in the Planned Analysis 
Any changes from this statistical analysis plan will be documented in the CSR for this study. 


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12. References 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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13. Schedule of Assessments 
 
Abbreviations: AEs, adverse events; BMI, body mass index; COVID-19, coronavirus disease 2019; ECG, electrocardiogram; EOS, end of study; H, hour; ICF, informed consent form; M, 
month,  PD, pharmacodynamic; PK, pharmacokinetic; QTcF, QT interval corrected for heart rate using Fridericia’s formula; SC, subcutaneous. 
Notes: 
(a) When procedures overlap or occur at the same time point, all blood draws should follow vital signs or ECGs, and PK sampling should be timed to occur last and as close to the 
scheduled time point as possible. 
(b) Discharge following 24-hour PK/PD sample collection. 
(c) Follow-up visits will occur from Day 3 through EOS visit on Day 253. 
(d) Serology testing will include hepatitis B surface antigen, anti-hepatitis B core antigen, anti-hepatitis B surface antigen, hepatitis C virus antibodies, and human immunodeficiency virus 
types 1 and 2 antibodies. Hepatitis B DNA test can be done as a confirmatory test in exceptional cases, if needed. 
(e) Urine drug screen/alcohol test (urine/breath) will occur at screening and check-in per the clinic’s standard procedures. 


 
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(f) The BMI (kg/m2) will be calculated at check-in using the following formula: weight (kg)/height (m2). Height will be measured at screening only. Only weight will be measured at EOS 
visit. 
(g) A full physical examination will be performed at screening (at minimum, assessment of skin, head, oral cavity, ears, eyes, nose, throat, neck, thyroid, lungs, heart, cardiovascular, 
abdomen, lymph nodes, and musculoskeletal system/extremities). A brief physical examination will be performed at check-in, Day 225, and EOS (at minimum, assessment of oral cavity, 
skin, lungs, cardiovascular system, and abdomen [liver and spleen]). Interim physical examinations may be performed at the discretion of the investigator, if necessary, to evaluate AEs or 
clinical laboratory abnormalities. 
(h) To be performed by dentist and otolaryngologist, respectively at screening only. 
(i) Vital signs will include systolic and diastolic blood pressure, respiratory rate, pulse rate, and tympanic temperature and will be measured after the subject has been in the supine position 
for at least 5 minutes. Tympanic temperature will be measured at screening, Days 2, 22, 225, and EOS. Vital signs will be measured within 15 minutes prior to study drug dosing on Day 1. 
(j) Single 12-lead ECG recordings will be made after the subject has been in the supine position for at least 5 minutes. A single repeat measurement is permitted at screening for eligibility 
determination. Measurements of the following intervals will be reported: RR interval, PR interval, QRS width, QT interval, and QTcF. Assessments should include comments on whether 
the tracings are normal or abnormal; rhythm; presence of arrhythmia or conduction defects; morphology; any evidence of myocardial infarction; or ST-segment, T-wave, and U-wave 
abnormalities. 
(k) A complete list of assessments is provided in Section 6.4.2. Blood and urine samples will be collected after overnight fasting for 10 hours and prepared per the clinic’s standard 
procedures. The same visit windows will apply for safety laboratory sample collection as for PK (refer to footnote (o)). 
(l) The clinic will follow standard procedures and/or local guidelines with respect to COVID-19 testing at screening and any other timepoints during the study, if deemed necessary by the 
investigator. 
(m) Randomisation should be done on Day -1 or Day 1 prior to initiating any study procedures. 
(n) The time of study drug dosing will be called “0” hour and is denoted with grey shading. A single SC dose of 35 mg of the study drug will be administered in the upper arm to each 
subject. Subjects will remain semi-supine for the first 4 hours after administration unless moving is medically necessary, requires procedures, or means going to the washroom. 
(o) Blood samples for PK analysis of the study drug (MB09 or Xgeva) in plasma and PD analysis of area under the effect curve will be collected up to 2 hours prior to study drug dosing 
and after dosing at 8 and 16 hours (± 2 hours), 24, 48, and 72 hours (± 4 hours), Days 6, 8, and 11 (± 1 day), Days 15, 22, and 29 (± 2 days), Days 43, 57, 71, 85, 99, 113, 141, 169, 197, 
225, and 253 (± 3 days). At each time point, blood samples will be collected after overnight fasting of at least 10 hours. 
(p) Samples for immunogenicity analysis will be obtained prior to study drug dosing and at the timepoints indicated in the schedule of events. If hypersensitivity occurs after the study drug 
dosing, additional samples for immunogenicity testing may be obtained at the discretion of the investigator to determine serum sickness. 
(q) Adverse events and SAEs will be assessed from the time of signing the ICF until EOS and should be followed until they are resolved, stable, or judged by the investigator to be not 
clinically significant.