A Randomized, Double-Blind, Parallel Design, Repeat Dose, 2-arm, Multicenter Study Comparing the Efficacy, Safety, Immunogenicity, and Pharmacokinetic Profiles of AVT03 and US-Prolia® in Postmenopausal Women With Osteoporosis, ALVOBOND
Phase: PHASE3
Conditions: Osteoporosis, Postmenopausal
Sponsor: Alvotech Swiss AG

 
CLINICAL STUDY PROTOCOL 
PROTOCOL TITLE: 
A Randomized, Double-Blind, Parallel Design, 
Repeat Dose, 2-arm, Multicenter Study Comparing 
the Efficacy, Safety, Immunogenicity, and 
Pharmacokinetic Profiles of AVT03 and US-Prolia® 
in Postmenopausal Women with Osteoporosis, 
ALVOBOND 
STUDY NUMBER: 
AVT03-GL-C01 
EUDRACT NUMBER: 
2021-005071-40 
 
SPONSOR: 
Alvotech Swiss AG 
 
ORIGINAL PROTOCOL 
VERSION AND DATE: 
Version 1.0, 15 Feb 2022 
AMENDED PROTOCOL 
VERSION AND DATE: 
Version 2.0, 03 Mar 2022 
AMENDED PROTOCOL 
VERSION AND DATE: 
Version 3.0, 03 Aug 2022 
AMENDED PROTOCOL 
VERSION AND DATE: 
Version 4.0 Final, 10 Mar 2023 
 
CONFIDENTIAL 
This document and its contents are the property of and confidential to Alvotech Swiss AG.  Any 
unauthorized copying or use of this document is prohibited. 
 
 
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Protocol AVT03-GL-C01
AVT03 
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SPONSOR APPROVAL FORM 
Protocol Title: A Randomized, Double-Blind, Parallel Design, Repeat Dose, 2-arm, 
Multicenter Study Comparing the Efficacy, Safety, Immunogenicity, and 
Pharmacokinetic Profiles of AVT03 and US-Prolia® in Postmenopausal Women with 
Osteoporosis, ALVOBOND 
Study No: AVT03-GL-C01 
Original Protocol Version and Date: Version 1.0, 15 Feb 2022 
Amended Protocol Version and Date: Version 2.0, 03 Mar 2022 
Amended Protocol Version and Date: Version 3.0, 03 Aug 2022 
Amended Protocol Version and Date: Version 4.0 Final, 10 Mar 2023 
This study will be conducted in compliance with the clinical study protocol, International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, 
Good Clinical Practice, and applicable local regulatory requirements. 
This study protocol was subject to critical review and has been approved by the relevant 
members of the Sponsor. 
The undersigned have reviewed the content of this protocol and have approved the clinical study 
protocol.  The Investigator will be supplied with details of any significant or new findings, 
including adverse events, relating to treatment with the study drug.  Any modifications of the 
clinical study protocol must be agreed upon by the Sponsor and the Investigator and must be 
documented in writing. 
 
 
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Head of Clinical and Medical Affairs 
Alvotech Swiss AG 
 
Date 
Head of Clinical Development and Patient Safety 
Alvotech Swiss AG 
 
Date  
 
 
 
 
 
 
Biostatistics Lead 
Alvotech Swiss AG 
 
Date 
Chief Principal Investigator 
MediclubGeorgia Tbilisi 
 
 
 
 
 
 
 
 
 
Date 
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13 March 2023
14 March 2023
13. März 2023
14 March 2023

Alvotech Swiss AG 
Protocol AVT03-GL-C01
AVT03 
Version 4.0 Final, 10 Mar 2023
 
Confidential 
Page 4 of 81 
 
 
President, National Osteoporosis Foundation of South 
Africa 
 
Date 
Medical & Scientific Consultant  
 
 
Date 
 
 
DocuSign Envelope ID: 5A29786D-9A46-486F-9876-7755F9A1E0FC
13 March 2023
13 March 2023

Alvotech Swiss AG 
Protocol AVT03-GL-C01
AVT03 
Version 4.0 Final, 10 Mar 2023
 
Confidential 
Page 5 of 81 
 
AVT03-GL-C01 
A RANDOMIZED, DOUBLE-BLIND, PARALLEL DESIGN, REPEAT 
DOSE, 2-ARM, MULTICENTER STUDY COMPARING THE EFFICACY, 
SAFETY, IMMUNOGENICITY, AND PHARMACOKINETIC PROFILES 
OF AVT03 AND US-PROLIA® IN POSTMENOPAUSAL WOMEN WITH 
OSTEOPOROSIS, ALVOBOND 
 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
The information contained in this protocol and all other information relevant to AVT03 are the 
confidential and proprietary information of Alvotech Swiss AG, and except as may be required 
by federal, state, or local laws or regulation, may not be disclosed to others without prior written 
permission of Alvotech Swiss AG. 
I have read the protocol, including all appendices, and I agree that it contains all of the necessary 
information for me and my staff to conduct this study as described.  I will conduct this study as 
outlined herein, in accordance with International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use, Good Clinical Practice, and applicable 
national, state, and local regulations and will make a reasonable effort to complete the study 
within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Alvotech Swiss AG or specified 
designees.  I will discuss the material with them to ensure that they are fully informed about 
AVT03 and the study. 
 
 
 
Signature 
 Date 
Investigator Name (printed) 
 Site Number 
 
 
 
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STUDY SYNOPSIS 
Protocol Title: 
A Randomized, Double-Blind, Parallel Design, Repeat Dose, 2-arm, 
Multicenter Study Comparing the Efficacy, Safety, Immunogenicity, 
and Pharmacokinetic Profiles of AVT03 and US-Prolia® in 
Postmenopausal Women with Osteoporosis, ALVOBOND 
Study Number: 
AVT03-GL-C01 
Clinical Phase: 
3 
Investigator(s)/Study 
Center(s): 
This study is planned to be conducted at study centers located in 
Bulgaria, Czech Republic, Georgia, Poland, and South Africa. 
Objectives: 
Primary Objectives: 
 To demonstrate clinical similarity of AVT03 and 
United States-licensed Prolia® (US-Prolia, generic name: 
denosumab, hereafter referred to as Prolia) in terms of percent 
change from Baseline in bone mineral density (BMD) at 12 
months. 
 To demonstrate clinical similarity of AVT03 and Prolia in terms 
of area under the percent change from Baseline in serum 
C-telopeptide of type 1 collagen up to 6 months (AUEC0-6months of 
%Cfb sCTX-1).  Note: This objective will be considered as 
primary for European Medicines Agency (EMA) submission 
only; for all other agencies, this objective will be considered as 
secondary.  
Secondary Objectives: 
 To further compare clinical similarity of AVT03 and Prolia 
 To assess and compare the safety of AVT03 with Prolia 
 To assess and compare immunogenicity of AVT03 with Prolia 
 To compare pharmacokinetic (PK) biosimilarity between AVT03 
and Prolia 
 To compare pharmacodynamic (PD) parameters between AVT03 
and Prolia 
Study Design: 
This is a randomized, double-blind, parallel design, repeat dose, 
2-arm, multicenter study comparing the efficacy, safety, 
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immunogenicity, and PK profiles of AVT03 and Prolia in 
postmenopausal women with osteoporosis. 
After successful completion of the screening activities, eligible 
subjects will be randomized in a 1:1 ratio to receive either AVT03 
60 mg or Prolia 60 mg, administered as a subcutaneous (s.c.) 
injection on Day 1 and Day 180 (Month 6).  At Month 12, subjects in 
the AVT03 treatment group will receive a third dose of AVT03 
60 mg administered s.c. while subjects in the Prolia treatment group 
will be re-randomized in a 1:1 ratio to receive either Prolia 60 mg or 
AVT03 60 mg on Day 365 (Month 12), administered s.c.  Subject 
randomization will be stratified by number of years since menopause 
(≤5 years or >5 years) and prior biologic therapy for osteoporosis 
(Yes or No).  Two weeks after the Month 12 administration, there 
will be a safety follow-up visit.  Afterwards, subjects will be 
followed until the end of study (EoS) visit at Month 18 (ie, 6 months 
after the last dose at Month 12). 
Duration of 
Treatment: 
Subjects will participate in the study for up to 19 months: 
 Screening: Day -28 to -1 
 Active Period: Day 1 to Month 18 
o Treatment on Day 1, Day 180 (Month 6), and Day 365 
(Month 12) 
o Safety Follow-up 
 Safety Follow-up visit 2 weeks after Month 12 
administration (Month 12 [+ 2 weeks]) 
 Safety Follow-up visit 3 months after Month 12 
administration (Month 15) 
 Safety Follow-up/EoS visit 6 months after Month 12 
administration (Month 18) 
Planned Sample Size 
and Treatment 
Group(s): 
Approximately 476 subjects will be randomly assigned in a 1:1 ratio 
to AVT03 and Prolia treatment arms. 
Target Population: 
Postmenopausal women with osteoporosis 
Eligibility Criteria: 
Inclusion Criteria: 
To be enrolled in the study, subjects must meet the following criteria: 
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1. Postmenopausal women with osteoporosis willing to sign an 
informed consent form and able to undergo protocol related 
procedures. 
2. Age: ≥50 years.  
3. Female subject is postmenopausal according to 1 of the following 
criteria: 
a. Spontaneous amenorrhea for ≥12 consecutive months 
b. Biochemical criteria of menopause, follicle-stimulating 
hormone, >40 IU/L except surgically sterile  
c. Having had bilateral oophorectomy ≥6 weeks prior to 
Screening 
4. Body Mass Index: 18.5-32.0 kg/m2 
5. A baseline dual-energy x-ray absorptiometry scan with a T score 
≤ -2.5 and ≥ -4.0 at the lumbar spine (LS) (L1 to L4) and/or total 
hip and/or femoral neck. 
A subject must have a T score within the stated range of ≤ -2.5 
and ≥ -4.0 in at least 1 of the 3 areas: - lumbar spine (L1 to L4) - 
total hip - femoral neck. On the contrary, subjects will be 
excluded from the trial if the T score is less than -4.0 in at least 1 
of the 3 areas (ie, at the LS [L1 to L4], or total hip, or femoral 
neck).  
Note: The left hip should be scanned for the calculation of total 
hip T score.  If the left hip cannot be scanned (eg, due to left hip 
replacement, etc), the right hip can be scanned instead.  The same 
hip should be used for all dual-energy x-ray absorptiometry 
scans. 
6. At least 2 consecutive evaluable lumbar vertebrae and at least 1 
evaluable hip. 
7. Willing to receive calcium plus vitamin D supplements. 
8. No history or evidence of a clinically significant disorder, 
condition, or disease that, in the opinion of the Investigator, 
would pose a risk to subject safety. 
9. Resting supine systolic blood pressure of ≤150 mmHg and 
diastolic blood pressure of ≤90 mmHg.  Other vital signs showing 
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no clinically relevant deviations according to the Investigator’s 
judgment. 
10. 12-lead electrocardiogram (ECG) recording without signs of 
clinically relevant pathology or showing no clinically relevant 
deviations as judged by the Investigator.  
11. Subject smokes <10 cigarettes per day within 3 months of 
Screening.  Note: It is strongly recommended that subjects do not 
smoke during their participation in the study. 
12. Recommended to abstain from alcohol from 48 hours prior to 
study drug administration, and 24 hours prior to study visits. 
Exclusion Criteria: 
Subjects will be ineligible for the study if any of the following 
criteria apply: 
1. Evidence of clinically relevant pathology, especially prior 
diagnosis of bone disease, or any uncontrolled condition that will 
affect bone metabolism such as, but not limited to: osteogenesis 
imperfecta, hyperparathyroidism, non-controlled hyperthyroidism 
(thyroid stimulating hormone (TSH) <0.5 mIU/L), non-controlled 
hypothyroidism (TSH ≥5.0 mIU/L), osteomalacia, rheumatoid 
arthritis, psoriatic arthritis, ankylosing spondylitis, current 
flare-up of osteoarthritis and/or gout, active malignancy, renal 
disease (defined as creatinine clearance <50 mL/min as calculated 
by Cockcroft-Gault formula ), Paget's disease of the bone, recent 
bone fracture (within 6 months), and malabsorption syndrome.   
2. History and/or presence of 1 severe or more than 1 moderate 
vertebral fractures confirmed by x-ray (according to 
Genant semiquantitative method). 
3. History of hip fracture. 
4. Presence of active healing fractures. 
5. Previous treatment with denosumab and previous use of the 
following medications: 
a. Intravenous bisphosphonates, fluoride, or strontium ranelate 
at any dose within 5 years prior to Screening 
b. Oral bisphosphonates used for >3 years cumulative use, and 
any dose within 12 months of Screening  
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c. Parathyroid hormone (PTH) or PTH derivatives (eg, 
teriparatide, abaloparatide), and selective estrogen receptor 
modulators (eg, raloxifene), within 1 year of Screening 
d. Romozosumab within 30 days prior to Screening 
e. Calcitonin within 6 months of Screening 
f. Other bone metabolism drugs: administration of any of the 
following treatments within the last 3 months, 
i. anabolic steroids or testosterone 
ii. glucocorticoids (>5 mg/day prednisone or equivalent for 
>10 days) 
iii. systemic hormone replacement therapy 
iv. tibolone 
v. calcitriol  
vi. anticonvulsants (except benzodiazepines and pregabalin) 
vii. heparin 
viii. 
systemic use of ketoconazole, androgens, 
adrenocorticotropic hormone (ACTH), cinacalcet or any 
cathepsin K inhibitor (eg, odanacatib), aluminium, 
lithium, protease inhibitors, methotrexate, 
gonadotropin-releasing hormone agonists 
6. Osteonecrosis of the jaw (ONJ) or risk factors for ONJ such as 
invasive dental procedures (eg, tooth extraction, dental implants, 
oral surgery in the past 6 months), periodontal, and/or pre-
existing dental disease requiring therapy. 
7. Evidence of hypo/hypercalcemia at Screening defined as <8.6 or 
>10.5 mg/dL.  
Note:  If hypocalcaemia can be excluded based on calcium, 
corrected calcium, albumin, PTH, vitamin D3 values but ionized 
calcium is pending, the subject may be randomized, as per 
Investigator assessment and confirmation that exclusion criterion 
7 has not been met. This needs to be recorded on source 
documents. 
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8. Known vitamin D deficiency (25-hydroxy vitamin D level 
<20 ng/mL [50 nmol/L]) after supplementation at Screening. 
9. Known intolerance to calcium or vitamin D supplement. 
10. Any current active infections, including localized infections, or 
any recent history (within 1 week prior to study drug 
administration) of active infections or a history of recurrent or 
chronic infections. 
11. Presence of known current infection with hepatitis B or presence 
of positive serology – ie, hepatitis B surface antigen (HBsAg) 
and/or hepatitis B core antibody (anti HBc), hepatitis C virus 
(HCV) antibody or human immunodeficiency virus (HIV) at 
Screening. 
Note:  Any subject with positive anti-HBc at Screening should be 
reviewed and evaluated by the Investigator to exclude active 
infection. It is at the Investigator’s discretion whether to extend 
diagnostics to exclude current infection of hepatitis B. A local 
HBV quantitative DNA by PCR test may be performed within the 
screening window visit. 
12. Hematology and chemistry laboratory results outside the 
reference ranges, which are clinically significant, and, in the 
opinion of the Investigator or designee, could cause this study to 
be detrimental to the subject. 
13. Donation of more than 500 mL of blood within the 8 weeks prior 
to study drug administration. 
14. Hypersensitivity to denosumab or its constituents. 
15. A recent history of major surgery including spine surgery due to 
disc herniation, spinal stenosis, or similar condition within 
3 months prior to randomization. 
16. History or presence of malignancy within 5 years (with the 
exception of successfully treated basal cell carcinoma). 
17. Inability to communicate or cooperate with the Investigator 
because of language difficulties or poor mental development or 
incapacitation. 
18. A history (within the previous 3 years) or evidence of alcohol or 
drug abuse (including soft drugs like cannabis products). 
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19. Vaccination with a live vaccine with the exception of flu vaccine 
within the previous month.  Coronavirus disease 2019 
vaccination is not considered an exclusion criterion. 
20. Any other condition which in the view of the Investigator is 
likely to interfere with the study or put the subject at risk. 
21. Current participation or history of participation in an 
investigational trial in the last 30 days or period less than 5 half-
lives of the medicinal product under investigation - whichever is 
longer.  For investigational products or drugs for which PD effect 
lasts longer than 5 half-lives, the wash-out period may be 
extended. 
22. A compromised immune system or treatment with 
immunosuppressants. 
 
Study Drug(s): 
Investigational Product: AVT03 60 mg given as a s.c. injection on 
Day 1, Day 180 (Month 6), and Day 365 (Month 12) 
Reference Product: Prolia 60 mg given as a s.c. injection on Day 1, 
Day 180 (Month 6), and Day 365 (Month 12) 
Primary 
Endpoint(s): 
Percent change from Baseline in LS BMD at 12 months 
Area under the percent change from Baseline in serum C-telopeptide 
of type 1 collagen up to 6 months (AUEC0-6months of %Cfb sCTX-1).  
Note: This endpoint will be considered as primary for EMA 
submission only; for all other agencies, this endpoint will be 
considered as secondary. 
Secondary 
Endpoint(s): 
Efficacy endpoint 
 Percent change from Baseline in LS BMD at 6 and 18 months 
 Percent change from Baseline in hip and femoral neck BMD at 6, 
12, and 18 months 
 Incidence of new morphometric vertebral fractures at 12 and 
18 months 
Pharmacodynamic endpoints 
 Percent change from Baseline in sCTX-1 at 3, 6, 9, 12, and 
18 months 
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Safety endpoints 
 Incidence, nature, and severity of adverse events including 
adverse drug reactions  
 Frequency and severity of injection site reactions  
 Frequency and severity of findings in routine safety parameters, 
including clinical laboratory assessments (hematology, clinical 
biochemistry, coagulation, urinalysis, and urine microscopy), 
vital signs, ECG, and physical examination  
Immunogenicity endpoint 
 Frequency and titer of anti-drug antibodies and frequency of 
neutralizing antibodies against AVT03 and Prolia at predose and 
Day 1, Day 2, Day 12, Day 30, Day 60, Day 90, Day 180, 
Day 270, Day 365 (Month 12), Day 365 (Month 12) +2 weeks, 
Month 15, and Month 18 (EoS) after treatment. 
Pharmacokinetic endpoint 
 Serum trough concentration of AVT03 and Prolia 
Statistical 
Procedures: 
The percent change from Baseline in LS BMD at 6 and 12 months 
will be analyzed using mixed model for repeated measures including 
treatment, visit, treatment-by-visit interaction, and prior biologic 
therapy for osteoporosis (Yes/No) as categorical variables and the 
baseline BMD and number of years since menopause as continuous 
covariates.  The least square mean estimates will be provided for 
each treatment group at each visit with their standard errors (SE).  
The difference of least square means between the treatment groups 
and associated SE, 2-sided 95% confidence interval (CI) (as required 
by EMA) and 2-sided 90% CI (as required by Food and Drug 
Administration) will be provided for 12 months.  At 12 months, if the 
95%/90% CIs are completely contained within the pre-specified 
equivalence margin of [-1.45%, 1.45%], a clinical similarity will be 
demonstrated respectively. 
The primary efficacy endpoint analysis will be based on the 
Full Analysis Set (FAS) which includes all randomized subjects who 
received at least 1 dose of randomized study treatment.  Subjects will 
be analyzed according to the study treatment arm they were 
randomized to.  For the primary endpoint analysis, in order to provide 
the most sensitive analysis set to detect potential differences between 
AVT03 and Prolia, the intercurrent events (ICEs) that can lead to 
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attenuation of treatment differences are defined, the subjects with any 
of those ICEs will be excluded from the analysis of primary endpoint.  
As a sensitivity analysis, the primary endpoint analysis will be 
repeated based on the FAS without exclusion of any subjects due to 
the ICEs specified for the main estimator. 
For the primary efficacy analysis and sensitivity analysis of the 
primary efficacy endpoint, the missing values of percent change from 
Baseline in LS BMD at 12 months may be handled using multiple 
imputation as needed, details will be provided in the statistical 
analysis plan.  PD endpoints will also be analyzed descriptively.  If 
the normality assumption is not met, then other methods may be 
utilized, such as log-transformation or use of geometric means. 
In addition, for the submission to EMA, the area under the percent 
change from Baseline in serum C-telopeptide of type 1 collagen up to 
6 months (AUEC0-6months of %Cfb sCTX-1) will be analyzed as 
primary PD endpoint.  The log transformed PD data (AUEC0-6months 
of %Cfb sCTX-1) will then be analyzed using an analysis of 
covariance (ANCOVA) model including the treatment as factor and 
the baseline sCTX-1 as continuous covariate.  The 95% CI for the 
geometric mean ratio (GMR) between treatment groups will be 
calculated.  The PD similarity will be demonstrated if the 95% CIs of 
GMR lie entirely within the pre-specified margin of (0.80, 1.25).  The 
analysis of the PD endpoint will be based on the PD Analysis Set.  
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ...............................................................................................1 
SPONSOR APPROVAL FORM ..................................................................................................2 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT ...............................................5 
STUDY SYNOPSIS .......................................................................................................................5 
Inclusion Criteria: ..........................................................................................................................6 
Exclusion Criteria: .........................................................................................................................8 
TABLE OF CONTENTS ............................................................................................................14 
LIST OF TABLES .......................................................................................................................16 
LIST OF FIGURES .....................................................................................................................17 
LIST OF ABBREVIATIONS .....................................................................................................18 
1 
INTRODUCTION AND RATIONALE .............................................................................21 
1.1 
Background ......................................................................................................................21 
1.1.1 
Background Disease Review .....................................................................................21 
1.1.2 
Compound Review .....................................................................................................21 
1.2 
Study Rationale ................................................................................................................22 
1.3 
Dose Rationale ..................................................................................................................22 
1.4 
Study Endpoint Rationale ...............................................................................................22 
1.5 
Risks and Benefits for Subjects ......................................................................................22 
2 
STUDY OBJECTIVES ........................................................................................................23 
2.1 
Primary Objectives ..........................................................................................................23 
2.2 
Secondary Objectives.......................................................................................................23 
3 
STUDY ENDPOINTS ..........................................................................................................24 
3.1 
Primary Endpoints...........................................................................................................24 
3.2 
Secondary Endpoints .......................................................................................................24 
3.2.1 
Efficacy Endpoint.......................................................................................................24 
3.2.2 
Pharmacodynamic Endpoints ...................................................................................24 
3.2.3 
Safety Endpoints ........................................................................................................24 
3.2.4 
Immunogenicity Endpoint ........................................................................................24 
3.2.5 
Pharmacokinetic Endpoint .......................................................................................25 
4 
STUDY PLAN .......................................................................................................................26 
4.1 
Study Design .....................................................................................................................26 
4.2 
Study Duration .................................................................................................................27 
5 
STUDY POPULATION .......................................................................................................28 
5.1 
Inclusion Criteria .............................................................................................................28 
5.2 
Exclusion Criteria ............................................................................................................29 
5.3 
Subject Withdrawal/Discontinuation Criteria ..............................................................31 
6 
STUDY TREATMENT AND MANAGEMENT ...............................................................33 
6.1 
Description ........................................................................................................................33 
6.1.1 
Formulation and Preparation ...................................................................................33 
6.1.2 
Labeling ......................................................................................................................33 
6.1.3 
Storage ........................................................................................................................33 
6.2 
Shipment and Blinding ....................................................................................................33 
6.3 
Treatment Assignment ....................................................................................................34 
6.4 
Dose and Administration .................................................................................................35 
6.5 
Dose Reduction and/or Discontinuation Rules ..............................................................35 
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6.6 
Accountability ..................................................................................................................36 
6.7 
Treatment Compliance ....................................................................................................36 
6.8 
Prior and Concomitant Medications and Conditions ...................................................36 
6.8.1 
Allowed Medications ..................................................................................................37 
6.8.2 
Prohibited Medications .............................................................................................37 
7 
STUDY CONDUCT..............................................................................................................38 
7.1 
Schedule of Assessments ..................................................................................................38 
7.2 
Study Procedures by Time Point ....................................................................................42 
7.2.1 
Screening .....................................................................................................................42 
7.2.2 
Active Period ..............................................................................................................42 
7.2.3 
End of Study ...............................................................................................................43 
7.2.4 
Unscheduled Visits .....................................................................................................43 
7.3 
Study Procedures for Early Termination ......................................................................43 
8 
DESCRIPTION OF ASSESSMENTS ................................................................................44 
8.1 
Efficacy Assessments .......................................................................................................44 
8.2 
Pharmacodynamic Assessments .....................................................................................44 
8.3 
Safety Assessments ...........................................................................................................44 
8.3.1 
Physical Examinations ...............................................................................................44 
8.3.2 
Vital Signs ...................................................................................................................45 
8.3.3 
Electrocardiogram .....................................................................................................45 
8.3.4 
Clinical Laboratory Tests..........................................................................................45 
8.3.5 
Adverse Events ...........................................................................................................47 
8.3.6 
Injection Site Reactions .............................................................................................47 
8.4 
Immunogenicity Assessments .........................................................................................48 
8.5 
Pharmacokinetic Assessments ........................................................................................48 
9 
ADVERSE EVENT REPORTING .....................................................................................49 
9.1 
Definitions and Criteria ...................................................................................................49 
9.1.1 
Adverse Events ...........................................................................................................49 
9.1.2 
Serious Adverse Events .............................................................................................49 
9.1.3 
Unexpected Adverse Drug Reactions .......................................................................50 
9.1.4 
Clinical Laboratory Changes ....................................................................................50 
9.1.5 
Adverse Events of Special Interest ...........................................................................51 
9.1.6 
Assessment of Severity ...............................................................................................53 
9.1.7 
Assessment of Relationship .......................................................................................54 
9.1.8 
Action Taken Regarding Study Drug(s) ..................................................................54 
9.1.9 
Other Action Taken for Event ..................................................................................54 
9.1.10 
Adverse Event Outcome ............................................................................................55 
9.2 
Reporting Procedures and Requirements .....................................................................55 
9.2.1 
Adverse Events ...........................................................................................................55 
9.2.2 
Serious Adverse Events .............................................................................................57 
9.2.3 
Adverse Events of Special Interest ...........................................................................58 
10 STATISTICS .........................................................................................................................59 
10.1 
General Procedures .........................................................................................................59 
10.2 
Sample Size .......................................................................................................................59 
10.3 
Analysis Populations ........................................................................................................60 
10.3.1 
Enrolled Set ................................................................................................................60 
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10.3.2 
Full Analysis Set .........................................................................................................60 
10.3.3 
Pharmacodynamic Analysis Set................................................................................60 
10.3.4 
Safety Analysis Set .....................................................................................................60 
10.4 
Statistical Methods ...........................................................................................................60 
10.4.1 
Protocol Deviations ....................................................................................................60 
10.4.2 
Subject Disposition.....................................................................................................61 
10.4.3 
Demographic and Baseline Characteristics .............................................................61 
10.4.4 
Analysis of Efficacy ....................................................................................................61 
10.4.5 
Pharmacodynamics ....................................................................................................64 
10.4.6 
Analysis of Safety .......................................................................................................64 
10.4.7 
Immunogenicity..........................................................................................................66 
10.4.8 
Pharmacokinetics .......................................................................................................66 
10.4.9 
Interim Analysis .........................................................................................................66 
11 STUDY MANAGEMENT AND RESPONSIBILITIES ...................................................67 
11.1 
Ethics .................................................................................................................................67 
11.1.1 
Good Clinical Practice ...............................................................................................67 
11.1.2 
Independent Ethics Committee ................................................................................67 
11.1.3 
Informed Consent ......................................................................................................67 
11.1.4 
Confidentiality ............................................................................................................67 
11.2 
Auditing and Monitoring ................................................................................................67 
11.3 
Data and Safety Monitoring Board ................................................................................68 
11.4 
Data Handling, Documentation, and Record Keeping .................................................68 
11.4.1 
Source Documentation...............................................................................................68 
11.4.2 
Direct Access to Source Data and Documents .........................................................68 
11.4.3 
Record Retention .......................................................................................................69 
11.4.4 
Study Documentation ................................................................................................69 
11.4.5 
Data Management Considerations ...........................................................................69 
11.5 
Indemnification ................................................................................................................70 
11.6 
Amendments .....................................................................................................................70 
11.7 
Study Termination ...........................................................................................................70 
11.8 
Clinical Study Report ......................................................................................................71 
12 PUBLICATION POLICY ....................................................................................................72 
13 REFERENCES .....................................................................................................................73 
14 APPENDICES .......................................................................................................................76 
14.1 
Contact Information ........................................................................................................76 
14.2 
Causes of Secondary Osteoporosis .................................................................................77 
14.3 
Injection Site Reaction Grading Scheme .......................................................................80 
 
LIST OF TABLES 
Table 6.1: 
Details of Study Drugs .........................................................................................34 
Table 7.1: 
Schedule of Assessments ......................................................................................39 
Table 10.1: 
Historical Data for Percent Change from Baseline in Lumbar Spine Bone 
Mineral Density at 12 Months and Meta-Analysis Results ..............................59 
 
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LIST OF FIGURES 
Figure 4.1: 
Study Schematic ...................................................................................................28 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation Definition 
ACTH 
adrenocorticotropic hormone 
ADA 
anti-drug antibodies 
ADR 
adverse drug reaction 
AE 
adverse event 
AESIs 
adverse events of special interest 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
anti-HBc 
Hepatitis B core antibody 
AST 
aspartate aminotransferase 
AUEC0-6months area under the effect curve 
BMD 
bone mineral density 
BMI 
body mass index 
BUN 
blood urea nitrogen 
Cfb 
change from Baseline 
COVID-19 
coronavirus disease 2019 
CI 
confidence interval 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CSR 
clinical study report 
DXA 
dual-energy x-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
EoS 
end of study 
EoT 
End of Treatment 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
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Abbreviation Definition 
FSH 
follicle-stimulating hormone 
GMR 
geometric mean ratio 
H 
heavy 
HBsAg 
hepatitis B surface antigen 
HCO3 
bicarbonate 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICEs 
intercurrent events 
IEC 
Independent Ethics Committee 
ICF 
informed consent form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
ID 
identification number 
IRT 
Interactive Response Technology 
ISRs 
injection site reactions 
LDH 
lactate dehydrogenase 
LS 
lumbar spine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures  
MVF 
multiple vertebral fractures 
ONJ 
osteonecrosis of the jaw 
PD 
pharmacodynamic 
PTH 
Parathyroid hormone 
PK 
pharmacokinetic 
RANKL 
receptor activator of nuclear factor kappa B ligand 
SAE 
serious adverse event 
SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 
SAP 
statistical analysis plan 
SAS 
Safety Analysis Set 
sCTX-1 
serum C-terminal telopeptide of type 1 collagen 
s.c. 
subcutaneous 
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Abbreviation Definition 
SD 
standard deviation 
SE 
standard error 
SERMs 
selective estrogen receptor modulators 
SoA 
Schedule of Assessments 
SOP 
standard operating procedure 
TEAE 
treatment-emergence adverse event 
TSH 
thyroid stimulating hormone 
US 
United States 
WHO 
World Health Organization 
 
 
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1 INTRODUCTION AND RATIONALE 
1.1 
Background 
1.1.1 
Background Disease Review 
Osteoporosis is a systemic skeletal disease characterized by microarchitectural deterioration and 
high fragility of bone tissue, resulting in low bone mineral density (BMD) and poor bone quality, 
generally ascribable to estrogen deficiency or ageing.1  One in 2 postmenopausal women will 
have an osteoporotic fracture in her lifetime.2  Those who have had a fracture are at high risk of 
subsequent fractures.3  It is estimated that the prevalence of osteoporosis rises from 1in 3 people 
aged 50 to 60 years old to more than 50% of people aged over 80 years.  By 2050, the global 
number of osteoporosis sufferers will reach 6 million (including both males and females), 3/4 of 
whom will reside in developing countries.4,5 
Bone remodeling occurs over several weeks and is performed by clusters of bone-resorbing 
osteoclasts and bone-forming osteoblasts arranged within temporary anatomical structures 
known as “basic multicellular units”.6  Receptor activator of nuclear factor kappa B ligand 
(RANKL), a member of the tumor necrosis factor family of proteins, has been well-documented 
as an essential factor in the formation, activation, and survival of osteoclasts.7,8,9  RANKL 
production is increased when estrogen is decreased (in menopause and with hormone ablation 
therapy) which leads to an increase in bone resorption, and excessive RANKL has been 
implicated in bone diseases associated with increased bone resorption.10,11  Studies on mice 
revealed that the administration of soluble RANKL results in an increase in the formation and 
activation of osteoclasts that lead to osteoporosis.8 
1.1.2 
Compound Review 
AVT03 (denosumab) is a recombinant fully human IgG2 monoclonal antibody to RANKL that 
contains 2 kappa light (L) chains, each comprised of 215 amino acids and 2 heavy (H) chains, 
each comprised of 448 amino acids (excluding the COOH terminal lysine), which are disulfide-
bonded to form a 4-chain molecule (H2L2).  It contains a single N-linked glycosylation site at 
Asn298 amino acid residue of each H chain.  The N-linked structures consist of biantennal, core-
fucosylated species with galactose and sialic acid heterogeneity with the major N-glycan 
structures being FA2 and FA2G1.  It has a total molecular weight of approximately 147 kDa.12 
The non-clinical development program for AVT03 has been designed in accordance with the 
current regulatory requirements for the non-clinical development of biosimilar monoclonal 
antibodies, as published by the European Medicines Agency (EMA) and Food and Drug 
Administration (FDA).13,14  For justification of the plan not to conduct further in vivo studies 
prior to initiating the clinical program and further details regarding non-clinical studies, refer to 
Section 1.4 of the Investigator Brochure. 
 To date, AVT03 has not been tested in humans.  As a proposed biosimilar, the safety profile 
of AVT03 is expected to be similar to the safety profile of Prolia. 
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This study aims to compare efficacy, safety, immunogenicity, and pharmacokinetics (PK), 
between the test product AVT03 and reference medicinal product, United States-licensed Prolia® 
(US-Prolia, generic name: denosumab, hereafter referred as Prolia), as part of a global biosimilar 
development program. 
1.2 
Study Rationale 
The purpose of the comparative efficacy and safety study in postmenopausal women with 
osteoporosis is to demonstrate clinical similarity without evidence of meaningful differences 
between AVT03 and the reference product Prolia after administration of 2 subcutaneous (s.c.) 
doses of the test or reference drug. 
In addition, in order to evaluate safety and immunogenicity after repeated dosing, subjects will 
receive a third dose in 180 days (6 months) after the second dose. 
1.3 
Dose Rationale 
AVT03 or Prolia (60 mg) will be administered to subjects, per the approved dosing regimen for 
postmenopausal osteoporosis.15,16 
1.4 
Study Endpoint Rationale 
The efficacy and safety endpoints for this study are considered standard endpoints for the 
indication of postmenopausal osteoporosis as outlined in the EMA/Committee for Medicinal 
Products for Human Use Guideline on the Evaluation of Medicinal Products in the Treatment of 
Primary Osteoporosis (EMEA/CPMP/EWP/552/95).17  Furthermore, in accordance with the 
above guidelines, the selected endpoints should allow assessment of clinically meaningful 
differences between AVT03 and Prolia in a comparative equivalence clinical study. 
1.5 
Risks and Benefits for Subjects 
The totality of evidence available to date from an ongoing analytical program suggests that 
AVT03 is similar to Prolia (US- and European Union [EU]-sourced) with respect to 
physiochemical and biological activity.  The risks and benefits for subjects receiving AVT03 are 
the same as those established for Prolia.  Refer to the Prolia Prescribing Information for further 
details.15  Adverse events of special interest (AESIs) encompass all relevant warnings and 
precautions from the Prolia label (Section 9.1.5). 
 
 
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2 STUDY OBJECTIVES 
2.1 
Primary Objectives 
The primary objectives of this study are: 
 To demonstrate clinical similarity of AVT03 and US-licensed Prolia® (US-Prolia, generic 
name: denosumab, hereafter referred to as Prolia) in terms of percent change from Baseline 
in BMD at 12 months. 
 To demonstrate clinical similarity of AVT03 and Prolia in terms of area under the percent 
change from Baseline in serum C-telopeptide of type 1 collagen up to 6 months 
(AUEC0-6months of %Cfb sCTX 1).  Note: This objective will be considered as primary for 
EMA submission only; for all other agencies, this objective will be considered as secondary. 
2.2 
Secondary Objectives 
The secondary objectives of this study are: 
 To further compare clinical similarity of AVT03 and Prolia 
 To assess and compare the safety of AVT03 with Prolia 
 To assess and compare immunogenicity of AVT03 with Prolia 
 To compare PK biosimilarity between AVT03 and Prolia 
 To compare pharmacodynamic (PD) parameters between AVT03 and Prolia 
 
 
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3 STUDY ENDPOINTS 
Similarity of AVT03 (test treatment) compared to Prolia (reference treatment) will be evaluated 
with regards to efficacy, PD, safety, immunogenicity, and PK using the following endpoints: 
3.1 
Primary Endpoints 
 Percent change from Baseline in lumbar spine (LS) BMD at 12 months 
 Area under the percent change from Baseline in serum C-telopeptide of type 1 collagen up to 
6 months (AUEC06months of %Cfb sCTX1).  Note: This endpoint will be considered as 
primary for EMA submission only; for all other agencies, this endpoint will be considered as 
secondary. 
3.2 
Secondary Endpoints 
3.2.1 
Efficacy Endpoint 
 Percent change from Baseline in LS BMD at 6 and 18 months 
 Percent change from Baseline in hip and femoral neck BMD at 6, 12, and 18 months 
 Incidence of new morphometric vertebral fractures at 12 and 18 months 
3.2.2 
Pharmacodynamic Endpoints 
 Percent change from Baseline in sCTX-1 at 3, 6, 9, 12, and 18 months 
3.2.3 
Safety Endpoints 
 Incidence, nature, and severity of adverse events (AE) including adverse drug reactions 
(ADRs) 
 Frequency and severity of injection site reactions (ISRs) 
 Frequency and severity of findings in routine safety parameters, including clinical laboratory 
assessments (hematology, clinical biochemistry, coagulation, urinalysis, and urine 
microscopy), vital signs, electrocardiograms (ECG), and physical examination  
3.2.4 
Immunogenicity Endpoint 
 Frequency and titer of anti-drug antibodies (ADA) and frequency of neutralizing antibodies 
against AVT03 and Prolia at predose and Day 1, Day 2, Day 12, Day 30, Day 60, Day 90, 
Day 180, Day 270, Day 365 (Month 12), Day 365 (Month 12) + 2 weeks, Month 15, and 
Month 18 (End of Study [EoS]) after treatment. 
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3.2.5 
Pharmacokinetic Endpoint 
 Serum trough concentration of AVT03 and Prolia 
 
 
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4 STUDY PLAN 
4.1 
Study Design 
This is a randomized, double-blind, parallel design, repeat dose, 2-arm, multicenter study 
comparing the efficacy, safety, immunogenicity, and PK profiles of AVT03 and Prolia in 
postmenopausal women with osteoporosis. 
On Day 1, after successfully completing screening activities, eligible subjects will be randomized 
into Groups 1 and 2, in a 1:1 ratio (AVT03: Prolia).  Subject randomization will be stratified by 
number of years since menopause (≤5 years or >5 years) and prior biologic therapy (for 
osteoporosis Yes or No). 
 Group 1: Subjects will receive AVT03 60 mg administered s.c. on Days 1 and 180 
(Month 6). 
 Group 2: Subjects will receive Prolia 60 mg administered s.c. on Days 1 and 180 (Month 6). 
At Month 12, subjects in the Group 1 (AVT03) will receive a third dose of AVT03 60 mg 
administered s.c. while subjects in the Group 2 (Prolia) will be re-randomized in a 1:1 ratio to 
receive either:  
 Group 2a: Subjects will receive AVT03 60 mg administered s.c. on Day 365 (Month 12). 
 Group 2b: Subjects will receive Prolia 60 mg administered s.c. on Day 365 (Month 12). 
Two weeks after the Month 12 administration, there will be a safety follow-up visit.  Thereafter, 
subjects will be followed until the EoS visit at Month 18 (ie, 6 months after the last dose at 
Month 12). 
Note: Post trial treatment will be provided to the subject.  The Investigator must ensure adequate 
osteoporosis treatment according to local guidelines is provided for all subjects who have been 
enrolled into the active period of the study. 
The study is summarized graphically in Figure 4.1. 
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Figure 4.1: 
Study Schematic 
 
Abbreviations: EoS = End of Study; s.c. = subcutaneous. 
4.2 
Study Duration 
Subjects will participate in the study for up to 19 months: 
 Screening: Day -28 to -1 
 Active Period: Day 1 to Month 18 
o Treatment on Day 1, Day 180 (Month 6), and Day 365 (Month 12) 
o Safety Follow-up 
 Safety Follow-up visit 2 weeks after Month 12 administration (Month 12 
[+ 2 weeks]) 
 Safety Follow-up visit 3 months after Month 12 administration (Month 15) 
 Safety Follow-up/EoS visit 6 months after Month 12 administration (Month 18) 
 
 
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5 STUDY POPULATION 
Subjects must meet all inclusion criteria and none of the exclusion criteria during the Screening 
Phase to be enrolled in the study.  No deviations will be permitted from the inclusion or 
exclusion criteria.  The Medical Monitor will perform eligibility review for any given subject, 
before randomization. 
Specific entry criteria are detailed in Section 5.1 and Section 5.2.  
Any subject designated as a screen failure may be rescreened once after consultation with the 
Sponsor, or designated representative (see Section 7.2.1). 
5.1 
Inclusion Criteria 
To be enrolled in the study, subjects must meet the following criteria: 
1. Postmenopausal women with osteoporosis willing to sign an informed consent form (ICF) 
and able to undergo protocol related procedures. 
2. Age: ≥50 years. 
3. Female subject is postmenopausal according to 1 of the following criteria: 
a. Spontaneous amenorrhea for ≥12 consecutive months 
b. Biochemical criteria of menopause follicle-stimulating hormone (FSH) >40 IU/L except 
surgically sterile 
c. Having had bilateral oophorectomy ≥6 weeks prior to Screening 
4. Body Mass Index (BMI): 18.5.0-32.0 kg/m2 
5. A baseline dual-energy x-ray absorptiometry (DXA) scan with a T score ≤ -2.5 and ≥ -4.0 at 
the LS (L1 to L4) and/or total hip and/or femoral neck. 
A subject must have a T score within the stated range of ≤-2.5 and ≥-4.0 in at least 1 of the 3 
areas: - Lumbar spine (L1 to L4) - Total hip - Femoral neck. On the contrary, subjects will be 
excluded from the trial if the T score is less than -4.0 in at least 1 of the 3 areas (ie, at the LS 
[L1 to L4], or total hip, or femoral neck). 
Note: The left hip should be scanned for the calculation of total hip T score.  If the left hip 
cannot be scanned (eg, due to left hip replacement, etc), the right hip can be scanned instead.  
The same hip should be used for all DXA scans.  
6. At least 2 consecutive evaluable lumbar vertebrae and at least 1 evaluable hip. 
7. Willing to receive calcium plus vitamin D supplements. 
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8. No history or evidence of a clinically significant disorder, condition, or disease that, in the 
opinion of the Investigator, would pose a risk to subject safety. 
9. Resting supine systolic blood pressure of ≤150 mmHg and diastolic blood pressure of 
≤90 mmHg.  Other vital signs showing no clinically relevant deviations according to the 
Investigator’s judgment. 
10. 12-lead ECG recording without signs of clinically relevant pathology or showing no 
clinically relevant deviations as judged by the Investigator. 
11. Subject smokes <10 cigarettes per day within 3 months of Screening. 
Note: It is strongly recommended that subjects do not smoke during their participation in the 
study. 
12. Recommended to abstain from alcohol from 48 hours prior to drug administration, and 
24 hours prior to study visits. 
5.2 
Exclusion Criteria 
Subjects will be ineligible for the study if any of the following criteria apply: 
1. Evidence of clinically relevant pathology, especially prior diagnosis of bone disease, or 
any uncontrolled condition that will affect bone metabolism such as, but not limited to: 
osteogenesis imperfecta, hyperparathyroidism, non-controlled hyperthyroidism (thyroid 
stimulating hormone (TSH) <0.5 mIU/L), non-controlled hypothyroidism 
(TSH ≥5.0 mIU/L), osteomalacia, rheumatoid arthritis, psoriatic arthritis, ankylosing 
spondylitis, current flare-up of osteoarthritis and/or gout, active malignancy, renal disease 
(defined as creatinine clearance <50 mL/min as calculated by Cockcroft-Gault formula ), 
Paget's disease of the bone, recent bone fracture (within 6 months), and malabsorption 
syndrome.  For potential causes of secondary osteoporosis, please see Appendix 14.2.  
Note: Appendix 14.2 is a guideline for the Investigators. 
2. History and/or presence of 1 severe or more than 1 moderate vertebral fractures confirmed 
by x-ray (according to Genant semiquantitative method). 
3. History of hip fracture 
4. Presence of active healing fractures 
5. Previous treatment with denosumab and previous use of the following medications: 
a. Intravenous bisphosphonates, fluoride, or strontium ranelate at any dose within 5 years 
prior to Screening 
b. Oral bisphosphonates used >3 years cumulative use, and any dose within 12 months of 
Screening  
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c. Parathyroid hormone (PTH) or PTH derivatives (eg, teriparatide, abaloparatide), and 
selective estrogen receptor modulators (SERMs) (eg, raloxifene), within 1 year of 
Screening 
d. Romozosumab within 30 days prior to Screening 
e. Calcitonin within 6 months of Screening 
f. Other bone metabolism drugs: administration of any of the following treatments within 
the last 3 months, 
i. anabolic steroids or testosterone 
ii. glucocorticoids (>5 mg/day prednisone or equivalent for >10 days) 
iii. systemic hormone replacement therapy 
iv. tibolone 
v. calcitriol 
vi. anticonvulsants (except benzodiazepines and pregabalin) 
vii. heparin 
viii. 
systemic use of ketoconazole, androgens, adrenocorticotropic hormone 
(ACTH), cinacalcet or any cathepsin K inhibitor (eg, odanacatib), aluminium, 
lithium, protease inhibitors, methotrexate, gonadotropin-releasing hormone 
agonists 
6. Osteonecrosis of the jaw (ONJ) or risk factors for ONJ such as invasive dental procedures 
(eg, tooth extraction, dental implants, oral surgery in the past 6 months), periodontal, 
and/or pre-existing dental disease requiring therapy. 
7. Evidence of hypo/hypercalcemia at Screening defined as <8.6 or >10.5 mg/dL. 
Note:  If hypocalcaemia can be excluded based on calcium, corrected calcium, albumin, 
PTH, vitamin D3 values but ionized calcium is pending, the subject may be randomized, as 
per Investigator assessment and confirmation that exclusion criterion 7 has not been met. 
This needs to be recorded on source documents. 
8. Known vitamin D deficiency (25-hydroxy vitamin D level <20 ng/mL [50 nmol/L]) after 
supplementation at Screening. 
9. Known intolerance to calcium or vitamin D supplement. 
10. Any current active infections, including localized infections, or any recent history (within 
1 week prior to study drug administration) of active infections or a history of recurrent or 
chronic infections. 
11. Presence of known current infection with hepatitis B or presence of positive serology – ie, 
hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (anti-HBc), 
hepatitis C virus (HCV) antibody or human immunodeficiency virus (HIV) at Screening. 
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5.3 
Subject Withdrawal/Discontinuation Criteria 
A subject will be considered to have completed the study when she completes the Month 18 
(EoS) Visit.  Subjects are considered to have completed the treatment period per protocol if they 
receive study treatment on Day 1, Day 180, and Day 365 (Month 12).  For subjects who 
complete the treatment period or prematurely discontinue the study treatment for any reason, the 
end of treatment (EoT) visit must be completed.  For these subjects, if the discontinuation 
Note:  Any subject with positive anti-HBc at Screening should be reviewed and evaluated 
by the Investigator to exclude active infection. It is at the Investigator’s discretion whether 
to extend diagnostics to exclude current infection of hepatitis B. A local HBV quantitative 
DNA by PCR test may be performed within the screening window visit. 
12. Hematology and chemistry laboratory results outside the reference ranges, which are 
clinically significant, and, in the opinion of the Investigator or designee, could cause this 
study to be detrimental to the subject. 
13. Donation of more than 500 mL of blood within the 8 weeks prior to study drug 
administration. 
14. Hypersensitivity to denosumab or its constituents. 
15. A recent history of major surgery including spine surgery due to disc herniation, spinal 
stenosis, or similar condition within 3 months prior to randomization. 
16. History or presence of malignancy within 5 years (with the exception of successfully 
treated basal cell carcinoma). 
17. Inability to communicate or cooperate with the Investigator because of language 
difficulties or poor mental development or incapacitation. 
18. A history (within the previous 3 years) or evidence of alcohol or drug abuse (including soft 
drugs like cannabis products). 
19. Vaccination with a live vaccine with the exception of flu vaccine within the previous 
month.  Coronavirus disease 2019 (COVID-19) vaccination is not considered an exclusion 
criterion. 
20. Any other condition which in the view of the Investigator is likely to interfere with the 
study or put the subject at risk. 
21. Current participation or history of participation in an investigational trial in the last 30 days 
or period less than 5 half-lives of the medicinal product under investigation - whichever is 
longer.  For investigational products or drugs for which PD effect lasts longer than 
5 half-lives, the wash-out period may be extended. 
22. A compromised immune system or treatment with immunosuppressants. 
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occurred within (or less than) 6 weeks after the last dose of study drug, EoT visit should be 
conducted as soon as possible.  In addition to EoT visit, EoS visit should be conducted at least 6 
weeks after the last dose of the study drug.  For subjects who discontinue the study treatment 
prematurely, if the discontinuation occurred in at least 6 weeks after the last dose of the study 
drug, only EoS visit will be needed as the last study visit.  The early EoS Visit will include an 
evaluation of safety and immunogenicity (formation of ADA). 
A termination electronic case report form (eCRF) page should be completed for every subject 
who receives study drug, whether or not the subject completes the study.  The reason for any 
early discontinuation should be indicated on this form.  The primary reason for a subject 
discontinuing early should be selected from the following standard categories: 
 Adverse Event: Clinical or laboratory events occurred that, in the medical judgment of the 
Investigator for the best interest of the subject, are grounds for discontinuation.  These events 
include serious adverse events (SAEs) and nonserious AEs regardless of relation to the study 
drug. 
 Death: The subject died.  Death report case report form (CRF) to collect Date of Death, 
Reason (SAE, Other, Unknown). 
 Withdrawal of Consent: The subject desired to withdraw from further participation in the 
study in the absence of an investigator-determined medical need to withdraw.  If the subject 
gave a reason for withdrawing, it should be recorded in the eCRF. 
 Withdrawal by Subject: An indication that the subject has removed herself from the study or 
from one or more segments of the study. 
 Protocol Deviation: The subject’s findings or conduct failed to meet the protocol entry 
criteria or failed to adhere to the protocol requirements (eg, drug noncompliance, failure to 
return for defined number of visits). 
 Lost to Follow-up: The subject stopped coming for visits and study personnel were unable to 
contact the subject.  If the subject fails to attend a scheduled visit, there will be 2 attempts to 
contact the subject via telephone and 2 written communications.  If these receive no reply, 
the subject will be considered lost to follow-up. 
 Investigator Decision in the Subject’s Best Interest. 
 Other: The subject was discontinued for a reason other than those listed above, such as theft, 
loss of study drug, or termination of study by Sponsor. 
Subjects who discontinue early will not be replaced.  
 
 
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6 STUDY TREATMENT AND MANAGEMENT 
6.1 
Description 
Information about the study drugs is provided in Table 6.1.  
Table 6.1: 
Details of Study Drugs 
 
Preparations to Be Administered 
Trade (generic) Name 
AVT03 
Prolia 
(Denosumab) 
Strength(s) 
60 mg/mL 
60 mg/mL 
Route 
Subcutaneous 
Subcutaneous 
Formulation 
Solution for injection 
Solution for injection 
Dose(s) 
60 mg 
60 mg 
6.1.1 
Formulation and Preparation 
AVT03 and Prolia are provided in pre-filled syringes and contain excipients according to the 
pharmacopeial standards for parenteral drugs. 
AVT03 will be formulated at the same concentrations approved for Prolia, using the same 
excipients qualitatively and quantitatively. 
6.1.2 
Labeling 
Each carton box and syringe will be labeled according to country-specific requirements. 
6.1.3 
Storage 
Study drug must be refrigerated between 2°C and 8°C (36°F and 46°F) in the carton box 
provided to protect it from exposure to light. 
Site storage conditions should be monitored by the site personnel and reviewed by the clinical 
research associate (CRA) during site visits.  Deviations from the storage requirements must be 
documented and reported to the Sponsor. 
Complete instructions for proper study drug storage and handling will be provided in the 
Study Drug Manual. 
6.2 
Shipment and Blinding 
Both study drugs will be supplied by the Sponsor.  No study drug will be shipped to a site until 
written Independent Ethics Committee (IEC) authorization and regulatory authority approval has 
been received by the Sponsor or its representative. 
Blinding of the study will be achieved by the following measures: 
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 Prolia and AVT03 pre-filled syringes will be blinded using an appropriate masking method 
to maintain the study blinding.  Additional information on the masking method will be 
provided in the pharmacy manual. 
 Subjects and investigators will remain unaware of the treatment allocation until study 
completion. 
 Dedicated blinded and unblinded teams will be implemented within the Sponsor and contract 
research organization (CRO) before the Month 12 (+ 2 weeks) Data Unblinding.  After the 
Month 12 (+ 2 weeks) Data Unblinding, only the unblinded team will become aware of the 
subject treatment allocation.  Further details, including details of the assigned Sponsor and 
CRO blinded and unblinded teams, will be provided in the study’s Blinded-Unblinded Plan. 
 A subject’s treatment assignment should only be unblinded when knowledge of the treatment 
is essential for the further management of the subject in this study.  If knowledge of the study 
drug is necessary for optimal emergency treatment, the blind may be broken by an 
Investigator through access of the Interactive Response Technology (IRT).  Individual 
subject treatment assignments may be unblinded only in the case of an SAE or AE that 
requires knowledge of the study drug received by the subject in order to provide appropriate 
treatment or management of the SAE or AE or if required for regulatory reporting.  
Whenever possible, the Sponsor or its designee (ie, Sponsor Medical Lead or designee) will 
be consulted in the decision to unblind a subject; otherwise, the Sponsor or its designee will 
be notified as soon as possible in the event that unblinding of an individual subject’s 
treatment assignment has occurred prior to study completion.  Every effort is to be made to 
limit study site personnel unblinding to only those individuals providing direct care to that 
subject. 
 Any intentional or unintentional breaking of the blind is to be reported immediately to the 
Sponsor. 
6.3 
Treatment Assignment 
Once the subject has signed the ICF at Screening, site personnel will connect to the IRT system 
through an Internet browser to assign a subject identification number (ID).  The subject ID will 
include the site number (4 digits), and 3-digit subject number, assigned sequentially starting with 
001.  This number will be utilized to identify the subject throughout the study period.  Dropouts 
(subjects who discontinue study drug early and subjects who are randomized but did not receive 
at least 1 dose of study drug) will not be replaced.  See Section 7.2.1 regarding rescreening.  
Rescreened subjects should be assigned a new subject ID.  No individual is allowed to re-enter 
the study if previously randomized and/or dosed. 
Eligible subjects will be assigned to study drug in accordance with the randomization schedule 
generated by an independent unblinded statistician using the interactive web response system. 
On Day 1, approximately 476 subjects will be randomly assigned in a 1:1 ratio to receive 1 of the 
following treatments: 
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 Group 1: Subjects will be assigned to receive AVT03 60 mg s.c. on Day 1 and Day 180 
(Month 6). 
 Group 2: Subjects will be assigned to receive Prolia 60 mg s.c. on Day 1 and Day 180 
(Month 6). 
At Month 12, subjects in AVT03 treatment group will receive a third dose of AVT03 60 mg 
administered s.c. while subjects in Prolia treatment group will be re-randomized in a 1:1 ratio to 
receive either: 
 Group 2a: Subjects will receive AVT03 60 mg administered s.c. on Day 365 (Month 12). 
 Group 2b: Subjects will receive Prolia 60 mg administered s.c. on Day 365 (Month 12). 
On Day 1, subject randomization will be stratified by number of years since menopause 
(≤5 years or >5 years) and prior biologic therapy for osteoporosis (Yes or No).  The 
randomization list will be issued by 
 Biostatistical Operations. 
6.4 
Dose and Administration 
The recommended dose of Prolia for subjects with postmenopausal osteoporosis is 60 mg 
administered as a single s.c injection once every 6 months.15,16  In this study, AVT03 or Prolia 
will be administered per the approved dosing regimen for postmenopausal osteoporosis.  
Subjects will receive study drug on Day 1, Day 180 (Month 6), and Day 365 (Month 12). 
The s.c. injection will be administered in the upper arm, the upper thigh, or the abdomen.  
Injection should never be given into areas where the skin is tender, bruised, red, or hard.  The 
skin of the site of injection will be disinfected, gently pinched, and the injection needle will be 
inserted into the pinched skin at an angle of 45 degrees.  Immediately after dosing, a cotton ball 
or gauze pad will be pressed over the injection site and held for 10 seconds.  Subjects will be 
instructed not to rub the area after injection.  Additional dosing instructions are provided in the 
pharmacy manual.  The maximum delay allowed in drug administration is 4 weeks.  The 
Month 12 visit should NOT be shifted if Month 6 study drug administrations is delayed by a 
month.  In any case, all efforts should be made to ensure the subject is dosed within 4 weeks of 
the originally planned dosing points. 
Study drug will be administered at the study center by study staff. 
6.5 
Dose Reduction and/or Discontinuation Rules 
There will be no dose modifications in this study.  Dose interruptions could occur for safety 
reasons (eg, AEs, urgent surgery, etc) at the discretion of the Investigator.  If this occurs, subject 
should be dosed as soon as possible after Investigator’s consultation with the Medical Monitor. 
In the judgment of the Investigator, if the subject experiences intolerable AEs that appear to be 
related to the study drug, they should be permanently discontinued from study drug but will be 
encouraged to continue in the study (refer to Section 5.3). 
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6.6 
Accountability 
The study site will be supplied with a sufficient quantity of study drug to treat randomized 
subjects.  Blinded study drug will be shipped under appropriate storage conditions to site 
personnel according to the regulations of the study country.  Each delivery must be 
acknowledged by the addressee by confirming receipt of the study drug shipment in IRT.  Study 
drug cannot be assigned to a subject until the site confirms receipt in the IRT. 
A dispensing log will be kept by site personnel who will record the dates and quantity of the 
study drug administered to each subject.  Used study drug syringes, after injections have been 
performed at sites, will be disposed of at sites per each Institution’s standard operating procedure 
(SOP) or policy; empty carton kit boxes are to be stored until the CRA visit.  All empty carton 
kit boxes and unused study drug kits are to be held at the site until the CRA has completed 
reconciliation.  Once the site’s CRA has reviewed and confirmed study drug accountability, 
empty carton kit boxes may be destroyed on site.  The Sponsor may also request that the site 
return any unused syringes to the Sponsor or its designee once the site’s CRA has reviewed and 
confirmed accountability. 
At all times the syringes must remain in the masked package (as appropriate, see Section 6.2). 
6.7 
Treatment Compliance 
Subjects will receive the study drug from a trained staff member.  The date and time of each dose 
administered will be recorded in the source documents and in the eCRF. 
6.8 
Prior and Concomitant Medications and Conditions 
Concomitant medications, both prescription and nonprescription (including over-the-counter 
medicine, vitamins, supplements, and herbal supplements), taken within 6 months before the 
Screening Visit and up to EoS visit will be recorded in the source documents and entered into the 
“Prior and Concomitant Medication” eCRF.  Additionally, all medications received for 
osteoporosis, irrespective of when they were received, will be recorded.  Doses of concomitant 
medications should remain stable, if possible, during the study.  All concomitant medications 
taken throughout the course of the study, including any medications required to treat AEs or 
concomitant medical conditions and any changes in concomitant medications, will also be 
recorded in study files and entered into the “Prior and Concomitant Medication” eCRF. 
Medical history findings (ie, significant medical conditions, diseases, or surgeries) that the 
subject has experienced within 6 months of Screening and started before signing of the ICF will 
be documented.  Additional medical conditions present at the time informed consent is given will 
be regarded as concomitant medical conditions. 
All recorded prior and concomitant medications will be coded according to the latest version of 
the World Health Organization Drug Dictionary (WHO Drug Global B3 2021 March 1 or later). 
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6.8.1 
Allowed Medications 
Throughout the study, the Investigator may prescribe any concomitant medication or treatment 
deemed necessary to provide supportive care except for those listed under Section 6.8.2. 
6.8.2 
Prohibited Medications 
The following concomitant medications are prohibited during the study (and/or during the 
indicated time periods before the study) (see also Exclusion Criteria, Section 5.2): 
1. Intravenous bisphosphonates, fluoride or strontium ranelate within 5 years prior to Screening 
2. Oral bisphosphonates used >3 years cumulative use, and any dose within 12 months of 
Screening  
3. PTH or PTH derivatives, eg, teriparatide, abaloparatide, and SERMs, eg, raloxifene within 1 
year of Screening 
4. Romozosumab within 30 days prior to Screening 
5. Calcitonin within 6 months of Screening 
6. Other bone metabolism drugs: administration of any of the following treatments within the 
last 3 months 
a. anabolic steroids or testosterone 
b. glucocorticoids (>5 mg/day prednisone or equivalent for >10 days) 
c. systemic hormone replacement therapy 
d. tibolone 
e. calcitriol 
f. anticonvulsants (except benzodiazepines and pregabalin) 
g. heparin 
h. systemic use of ketoconazole, androgens, ACTH, cinacalcet or any cathepsin K inhibitor 
(eg, odanacatib), aluminium, lithium, protease inhibitors, methotrexate, gonadotropin-
releasing hormone agonists 
 
 
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7 STUDY CONDUCT 
Unless otherwise indicated, all assessments will be performed by the Investigator or designated 
study personnel. 
After signing the ICF, each subject will be screened to ensure eligibility for the study. 
A pandemic public health emergency, like COVID‑ 19, may impact the conduct of this clinical 
trial.  In the case of unforeseen circumstances, a decision for each individual subject to remain 
and/or start in the study has to be made.  This should be done on a case-by-case basis by the 
Investigator on his/her best medical judgment.  All applicable local laws and IEC regulations 
regarding study visits should be followed, including the use of personal protective equipment. 
Attempts should be made to perform all assessments in accordance with the protocol where 
possible.  Investigators should closely monitor and document all deviations to the study protocol 
and share with the Sponsor, or designated representative, in a timely manner. 
In case it is not possible to perform all assessments due to an emergency, focus should be given 
to assessments necessary to ensure the safety of subjects and those of most scientific value to the 
study.  Procedures to be considered in the event of a regional or national emergency declared by 
a governmental agency may include: 
 If onsite visits are not possible, remote visits may be planned. 
 If onsite visits are not possible, visit windows may be extended for efficacy or safety 
assessments that cannot be obtained remotely, following consultation with the 
Medical Monitor. 
 If feasible, a phone call with the subject for assessments may be allowed. 
 Use of local clinics/laboratories may be allowed for urinalysis, chemistry, coagulation, and 
hematology. 
7.1 
Schedule of Assessments 
The procedures to be performed throughout the study are outlined in the Schedule of 
Assessments (SoA) (Table 7.1). 
 
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Table 7.1: 
Schedule of Assessments 
PERIOD 
 
 
 
ACTIVE PERIOD 
 
TREATMENT PERIOD 
FOLLOW-UP PERIOD/EOS 
DAY[a] 
 
SCREENING 
PREDO
SE 
DAY 1 
DAY 
1 
DAY 
2 
DAY 
12 
DAY 
30 
DAY 
60 
DAY 
90 
DAY 
180 
(Month 
6) 
DAY 
210 
DAY 
270 
DAY 365 
(Month 
12)  
EoT[n] 
Day 365 
(Month 12 
[+ 2] 
weeks) 
Month 
15 
Mo
nth 
18 
EoS
[b] 
WINDOW(DAY) 
DAY -28 
TO -1 
± 0 
day 
± 0 
day 
± 0 
day 
± 0 
day 
± 5 
day 
± 5 
day 
± 5 
day 
± 5 
day 
± 5 
day 
± 5 
day 
± 5 
day 
+ 2 day 
± 5 
day 
± 5 
day 
Informed consent[c] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs[d]  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight, Height and BMI[e] 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (except surgically 
sterile or with spontaneous 
amenorrhea for ≥ 12 
consecutive months) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology and 
coagulation[f] 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry[f] 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis[f] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serology (HBsAg, 
anti-HBc, HCV, and HIV 
tests) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 tests 
X[g] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
X[h] 
 
 
 
Study drug administration[i] 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
DXA scan of LS (L1 to 
L4), total hip and/or 
femoral neck for BMD 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Lateral thoraco-lumbar 
spine x-ray 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
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PERIOD 
 
 
 
ACTIVE PERIOD 
 
TREATMENT PERIOD 
FOLLOW-UP PERIOD/EOS 
DAY[a] 
 
SCREENING 
PREDO
SE 
DAY 1 
DAY 
1 
DAY 
2 
DAY 
12 
DAY 
30 
DAY 
60 
DAY 
90 
DAY 
180 
(Month 
6) 
DAY 
210 
DAY 
270 
DAY 365 
(Month 
12)  
EoT[n] 
Day 365 
(Month 12 
[+ 2] 
weeks) 
Month 
15 
Mo
nth 
18 
EoS
[b] 
WINDOW(DAY) 
DAY -28 
TO -1 
± 0 
day 
± 0 
day 
± 0 
day 
± 0 
day 
± 5 
day 
± 5 
day 
± 5 
day 
± 5 
day 
± 5 
day 
± 5 
day 
± 5 
day 
+ 2 day 
± 5 
day 
± 5 
day 
Blood sampling for PK[j] 
 
X 
X[k] 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Blood sampling for sCTX-
1[j] 
 
X 
X[k] 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
X 
Blood sampling for 
immunogenicity (ADA)[j] 
 
X 
X[k] 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Prior and concomitant 
medications and conditions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection site assessment[l] 
 
X 
X 
X 
X 
 
 
 
X 
X 
 
X 
X 
 
 
ISR diaries distribution 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
Calcium and vitamin D 
supplements distribution[o] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety telephone call 
 
 
 
 
 
 
 
X[m] 
a. 
Calculated using the first day of assigned treatment as Day 1 and unless otherwise specified in other footnotes for a specific activity. 
b. 
Subjects who discontinue the study treatment prematurely for any reason will be encouraged to attend an early EoT visit.  For these subjects, a safety follow-up visit 
should be performed at least 6 weeks after last dose of study drug.  If the last study visit is at least 6 weeks after the last dose of study drug, this may be considered as 
early EoS and a separate safety follow-up visit is not required.   
c. 
Should be obtained before any study-related procedures are performed.   
d. 
Vital signs on Day 1 will be measured predose (within 60 min prior to dosing), and 1 h (±10 min), 4 h (±30 min) postdose.  For details, refer Section 8.3.2. 
e. 
Height and BMI will be measured at Screening only. 
f. 
Laboratory assessments include hematology (CBC including hemoglobin, hematocrit, white blood cell count with 5-part differential, red blood cell and platelet count).  
Coagulation: prothrombin time, international normalized ratio, and partial thromboplastin time.  Blood chemistry: HCO3, calcium, phosphorus, magnesium, albumin, 
glucose, serum creatinine, total protein, and BUN.  Liver function tests: AST, ALT, LDH, alkaline phosphatase, total and direct bilirubin.  Routine urinalysis: dipstick 
and microscopy including protein, specific gravity, glucose, and blood.  Dipstick urinalysis is sufficient as long as the result is <2+ (urinalysis is also acceptable).  If 
urine dipstick is ≥2+, 24-hour urine must demonstrate ≤1 g of protein in 24 hours.  Other laboratory tests to be performed are described in Section 8.3.4.5. 
g. 
Local or central polymerase chain reaction test will be done during Screening as per Investigator’s discretion based upon subjects’ signs and symptoms.  Additional 
tests may be performed as per Investigator’s discretion. 
h. 
At Month 12, subjects in Prolia treatment group will be re-randomized. 
i. 
Dose interruptions could occur for safety reasons (eg, AEs, urgent surgery, etc) at the discretion of the Investigator.  If this occurs, subject should be dosed as soon as 
possible after Investigator’s consultation with the Medical Monitor. 
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j. 
With the exception of Day 1, samples for all required timepoints (PREDOSE Day 1, D2, D12, D30, D60, D90, D180, D210, D270, D365, D365+2w, Month 15 and 
Month 18), will be collected following an overnight fast of at least 8 hours and should be drawn during morning hours between 07.30 and 10.00 AM.  On Day180 
(Month 6), and Day 365 (Month 12) sampling should be performed PRIOR to dosing. 
k. 
On Day 1 samples should be drawn during morning hours between 07.30 and 10.00 AM and at least 6 ± 2 hours after dosing and the subjects can have light meal 
after dosing.   
l. 
Day 1, Day 180, and Day 365 (Month 12) injection site assessments will be performed predose (within 60 min prior to dosing) and at 15 min (±2 min), 30 min (±5 
min), 1 h (±5 min), and 2 h (±5 min) postdose.  Further details are provided in Section 8.3.6. 
m. Subjects will receive monthly phone calls between visits, from Day 90 to Month 18 to collect safety information (AE and concomitant medication review).  
Additionally, subjects will receive a phone call 7 (+ 2) days after administration of study drug on Day 180 and Day 365 to collect information on ISR.  However, if the 
monthly phone call overlaps with the ISR call, then only 1 call is required. 
n. 
Post trial treatment will be provided to the subject.  The Investigator must ensure adequate osteoporosis treatment according to local guidelines is provided for all 
subjects who have been enrolled into the active period of the study. 
o. 
Calcium and vitamin D supplements will be provided by the Sponsor.  Dose adjustment can be done at the discretion of the Investigator.  More details are provided in 
Section 9.1.5.2. 
Abbreviations: ADA = anti- drug antibodies; ALT = alanine aminotransferase; AST = aspartate aminotransferase; anti-HBc = hepatitis B core antibody; BMD = bone mineral 
density; BMI = body mass index; BUN = blood urea nitrogen; CBC = complete blood count; DXA = dual-energy x-ray absorptiometry; EoS = End of Study; EoT = End of 
Treatment; FSH = follicle-stimulating hormone; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HCO3 = bicarbonate; HIV = human immunodeficiency virus; 
ICF = informed consent form; ISR = injection site reaction; LDH = lactate dehydrogenase; LS = lumbar spine; PK = pharmacokinetic; SARS-CoV-2 = severe acute respiratory 
syndrome coronavirus 2; sCTX-1 = serum C-terminal telopeptide of type 1 collagen;  
 
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7.2 
Study Procedures by Time Point 
7.2.1 
Screening 
The assessments during the Screening phase will determine the subjects’ eligibility for the study 
and their ability to comply with protocol requirements by completing all screening assessments.  
Randomization cannot be done before Medical Monitor’s approval, ie, eligibility review. 
The Screening Visit is to occur within 28 calendar days prior to the start of study drug 
administration.  After the subject has signed the ICF, screening assessments will be performed as 
indicated in the SoA (Table 7.1) and recorded in the subject’s source documentation/medical 
record.  Information from the medical records (progress notes) and other source documents will 
be promptly transcribed to the appropriate section of the eCRF. 
Any subject designated as a screen failure may be rescreened once after consultation with the 
Medical Monitor or designated representative and will be required to recomplete the applicable 
screening activities.  Rescreened subjects should be assigned a new subject ID (Section 6.3). 
Data from subjects who fail screening will be recorded in source data.  At a minimum, the 
following data should be recorded in the eCRF: 
 Demographic information (subject number; year of birth, age, gender, race, ethnicity [if 
applicable]) 
 Version and date of informed consent 
 Reason for screen failure 
 Screening/Rescreening Visit date 
For screen failures who experience an SAE, the following data should be collected in the eCRF 
in addition to the data specified above: 
 SAE page 
All information related to the SAE not limited to but including concomitant medication, medical 
history, and any other information are needed for an SAE complementary page. 
7.2.2 
Active Period 
The active period will include 14 in-clinic study visits (with study drug administered at study site 
at 3 of these 14 visits) from Day 1 through Month 18 in which safety, PD, PK, and efficacy 
assessments will be performed.  Subjects will receive monthly phone calls between visits, from 
Day 90 to Month 18 to collect safety information.  Subjects will receive a phone call 7 (+ 2) days 
after administration of study drug on Day 180 and Day 365 (Month 12) to collect information on 
ISR and will have a follow-up visit 2 weeks after the Month 12 administration to collect safety 
information as indicated in the SoA (Table 7.1), which will be recorded in the subject′s source 
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documentation/medical record.  Information from the medical records (progress notes) and other 
source documents will be promptly transcribed to the appropriate section of the eCRF. 
7.2.3 
End of Study 
At this visit, safety, PK, and efficacy assessments will be performed, as indicated in the SoA 
(Table 7.1) and recorded in the subject′s source documentation/medical record.  Information 
from the medical records (progress notes) and other source documents will be promptly 
transcribed to the appropriate section of the eCRF. 
Note: Post trial treatment will be provided to the subjects.  The Investigator must ensure 
adequate osteoporosis treatment according to local guidelines is provided for all subjects who 
have been enrolled into active period of the study. 
7.2.4 
Unscheduled Visits 
Subjects may be asked to return to the study center for additional visits if considered necessary 
by the Investigator.  Unscheduled visits will include hematology, chemistry, PK, ADA samples 
and may include any other procedures listed in the SoA (Table 7.1), with the exception of 
dosing.  
7.3 
Study Procedures for Early Termination 
Please refer to Section 5.3 with regard to subject early withdrawal/discontinuation criteria. 
 
 
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8 DESCRIPTION OF ASSESSMENTS 
All assessments will be performed throughout the study as noted in the SoA (Table 7.1). 
8.1 
Efficacy Assessments 
All subjects will undergo DXA scans of LS (L1 to L4), total hip and/or femoral neck and lateral 
thoraco-lumbar spine x-rays as indicated in the SoA (Table 7.1).  If left hip cannot be scanned 
(eg, due to left hip replacement, etc), right hip can be scanned instead.  However, it is required to 
always scan the same hip.  The DXA technician should always refer back to the baseline scans to 
be able to get the correct positioning. 
Detailed instruction on scanning and x-ray procedure will be provided in a procedural manual.  It 
is recommended that the same DXA machine should be used for a subject throughout the study.  
It is further recommended that the same technician performs the DXA scan for the subject 
throughout the study.  Additionally, DXA scan images should be read centrally. 
To minimize missing data in the statistical analysis of efficacy endpoints, efforts should be made 
to collect efficacy data for all subjects.  Even for those subjects who discontinued study 
treatment but did not withdraw their consent, efforts should be made to collect efficacy data 
whenever possible. 
8.2 
Pharmacodynamic Assessments 
A biomarker of bone resorption and formation (sCTX-1) will be collected in all subjects as 
indicated in the SoA (Table 7.1).  Samples will be stored for up to 5 years and destroyed 
thereafter. 
Details of the procedures to be followed for sample collection, storage, and shipment will be 
documented in a separate Laboratory Manual. 
8.3 
Safety Assessments 
8.3.1 
Physical Examinations  
A physical examination consists of general, head, eyes, ears, nose, throat, respiratory, 
gastrointestinal, extremity, musculoskeletal, cardiovascular, central nervous system, lymph node, 
and skin evaluations and height and any other physical conditions of note. 
Body weight without shoes will be recorded in kilograms.  BMI will be calculated using the 
subject’s body weight and height in cm at Screening.  
A physical examination will be performed as indicated in the SoA (Table 7.1). 
An AE is to be reported for all changes identified as clinically significant (or noteworthy) by the 
Investigator. 
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8.3.2 
Vital Signs  
Vital signs will include body temperature (C), respiratory rate, supine and sitting radial heart 
rate, and supine and sitting systolic and diastolic blood pressures.  Sitting recordings are to be 
made after the subject has been sitting for at least 1 minute.  Supine recordings will be made 
after the subject has been in the supine position for at least 3 minutes.  
An AE is to be reported for all changes identified as clinically significant (or noteworthy) by the 
Investigator. 
8.3.3 
Electrocardiogram 
A 12-lead ECG will be performed, as indicated in the SoA (Table 7.1), after the subject has been 
in the supine position for at least 10 minutes, will include all 12 standard leads, and will be 
recorded at a paper speed of 25 mm/second.  Standard ECG parameters will be measured.  
Fridericia formula will be used to calculate QTc.  A qualified physician (ie, Investigator) must 
evaluate all ECGs for the presence of abnormalities and clinical significance.  A consulting 
cardiologist, per the Investigator’s decision, may read any abnormalities of clinical concern to 
the qualified physician. 
8.3.4 
Clinical Laboratory Tests 
Clinical laboratory tests are to be performed as indicated in the SoA (Table 7.1) and listed below.  
Tests can be repeated under certain circumstances as required by the Investigator after 
consultation with the Medical Monitor. 
Laboratory samples will be analyzed by a central laboratory to ensure consistent interpretation of 
results.  Details of procedures to be followed for sample collection, storage, and shipment will be 
documented in a separate Laboratory Manual. 
In the exceptional case that shipment to the central laboratory is impossible due to COVID-19 
related restrictions or other unexpected problems with central laboratory, the safety samples may 
be analyzed by the local laboratory upon approval by the Medical Monitor and Sponsor.  Local 
laboratory test results and normal ranges should be recorded in the eCRF in international units.   
In the event of an unexplained clinically noteworthy abnormal laboratory test value, the test 
should be repeated immediately and followed up until it has returned to the normal range and/or 
an adequate explanation of the abnormality is found. 
8.3.4.1 
Chemistry 
Subjects will have the following tests: bicarbonate (HCO3), calcium, phosphorus, magnesium, 
albumin, glucose, serum creatinine, total protein, and BUN, and liver function tests: AST, ALT, 
LDH, alkaline phosphatase, total and direct bilirubin. 
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8.3.4.2 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count (with differential), and 
platelet count will be assessed. 
8.3.4.3 
Coagulation 
Prothrombin time, international normalized ratio, and partial thromboplastin time will be 
assessed. 
8.3.4.4 
Urinalysis 
Dipstick and microscopy including protein, specific gravity, glucose, and blood will be assessed.  
Dipstick urinalysis is sufficient as long as the result is <2+ (urinalysis is also acceptable).  If 
urine dipstick is ≥2+, 24-hour urine must demonstrate ≤1 g of protein in 24 hours. 
8.3.4.5 
Other Laboratory Tests 
Human Immunodeficiency Virus and Hepatitis Screening 
All subjects will be tested for HBsAg and anti-HBc, HCV antibodies, and HIV at Screening.   
In accordance with local regulations, an additional consent will be obtained for HIV testing.  
Notification of state and federal/national authorities, as required by law, will be the responsibility 
of the Investigator. 
Follicle-Stimulating Hormone Test 
FSH testing will be performed at Screening.  Subjects should have FSH >40 IU/L in order to be 
eligible for this study if not surgically sterile or with spontaneous amenorrhea for ≥12 
consecutive months. 
Thyroid Stimulating Hormone and Parathyroid Hormone 
TSH and PTH testing will be performed at Screening.  Subjects should have TSH between ≥0.5 
and <5.0 mIU/L in order to be eligible for this study. 
25-Hydroxy Vitamin D Test 
25-hydroxy vitamin D testing will be performed at Screening.  Subjects should have 
25-hydroxy vitamin D level ≥20 ng/mL (50 nmol/L) after supplementation at Screening in order 
to be eligible for this study.  At the discretion of the Investigator and based on standard of care, 
additional 25-hydroxy vitamin D testing can be performed during the study if vitamin D 
deficiency is suspected or if calcium levels are low. 
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Severe Acute Respiratory Syndrome Coronavirus 2 Tests 
Local or central polymerase chain reaction test will be done during Screening as per 
Investigator’s discretion based upon subject’s signs and symptoms.  Additional tests may be 
performed as per Investigator’s discretion. 
8.3.5 
Adverse Events 
All AEs occurring after signing the ICF up to the EoS Visit will be recorded. 
See Section 9 for additional information. 
8.3.6 
Injection Site Reactions 
The Investigator will assess study drug injection sites as per the SoA (Table 7.1).  Subjects will 
need to be present on site during 2 hours after the injection.  Any findings (eg, pain/tenderness, 
erythema/redness, swelling/induration, pruritus/itching, hematoma/ecchymosis/bruising) will be 
recorded by the Investigator in the source documents (progress notes) and assessed if they meet 
the AE criteria.   
Subjects will be issued with a paper ISR diary at each of the 3 visits when study drug is 
administered (ie, Day 1, Day 180, and Day 365).  This paper diary is to be used as a “memory 
aid” so that, if necessary, subjects can record information relating to ISRs.  Subjects will also be 
provided with a ruler on the Day 1 visit to measure the size of ISRs.  Subjects will be trained on 
collecting ISR symptoms on the Day 1 visit and will be re-trained on Day 180 and Day 365 
visits.  Procedures related to ISR diary are outlined below: 
1. Subjects will be issued with a paper ISR diary on Day 1 for them to fill in at home.  Subjects 
will attend study visits 1 day and 11 days (Day 2 and Day 12) post first study drug 
administration and should bring the paper ISR diary with them to these visits.  Study staff 
should record the data contained within them. 
2. The second study drug administration occurs on Day 180.  At this visit subjects will be 
issued with a paper ISR diary to be filled in at home.  Subjects will receive a follow-up safety 
call 7 (+2) days later, and data from the paper ISR diary should be collected over the phone.  
The subject should be instructed to continue to fill in the paper ISR diary and to bring it with 
them to their next study visit. 
3. The third and final study drug administration occurs on Day 365.  At this visit subjects will 
be issued with a paper ISR diary to be filled in at home.  Subjects will receive a follow-up 
safety call 7 (+2) days later, and the data from the paper ISR diary should be collected over 
the phone.  The subject should be instructed to continue to fill in the paper ISR diary and to 
bring it with them to their next study visit. 
Subjects will return this diary at the EoS visit. 
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Only ISRs which are at least Grade 1 should be recorded as AEs (Refer to Appendix 14.3 for the 
injection site reaction grading scheme).  Not all ISRs classified as AEs should be recorded as 
AESIs. 
8.4 
Immunogenicity Assessments 
The formation of ADAs will be assessed in serum samples collected as indicated in the SoA 
(Table 7.1). 
Subjects who test positive for anti-denosumab antibody will be characterized for titer and 
neutralizing capacity.  
Details of the procedures to be followed for sample collection, storage, and shipment will be 
documented in a separate Laboratory Manual. 
8.5 
Pharmacokinetic Assessments 
Serum samples for PK assessments will be collected as indicated in the SoA (Table 7.1).  
Details of the procedures to be followed for sample collection, storage, and shipment will be 
documented in a separate Laboratory Manual. 
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9 ADVERSE EVENT REPORTING 
9.1 
Definitions and Criteria 
9.1.1 
Adverse Events 
Per International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) E2A,18 an AE is “any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product.” 
Medical interventions such as surgeries, diagnostic procedures, and therapeutic procedures are 
not AEs, but the actions taken to treat the medical condition.  They should be recorded as 
treatment(s) of the AEs. 
Medical History versus Adverse Event 
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal physical examination findings, symptoms, diseases, laboratory findings, ECG 
findings, or other abnormal findings. 
 Conditions that started up to 6 months, and up to 5 years for medically significant conditions, 
eg, carcinoma before signing of informed consent and for which no symptoms or treatment 
are present until signing of informed consent are recorded as medical history (eg, seasonal 
allergy without acute complaints). 
 Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are recorded 
as medical history (eg, allergic pollinosis). 
 Conditions or laboratory abnormalities diagnosed as part of screening assessments are 
recorded as medical history (eg, newly detected hypertension, diabetes mellitus, elevated 
liver enzymes). 
 Conditions that started or deteriorated after the administration of study drug will be 
documented as AEs (see also Section 10.4.6.2).  This includes intercurrent illnesses. 
9.1.2 
Serious Adverse Events 
An SAE or a serious adverse drug reaction is any untoward event that at any dose meets any of 
the following criteria: 
 Results in death 
 Is life-threatening 
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 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity 
 Is a congenital anomaly or birth defect 
 Is an important medical event (eg, intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias, or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse; malignancy tumors [histologically 
different from primary tumor]). 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed in the definition above.  These 
should also usually be considered serious. 
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.  An 
SAE is not necessarily severe; eg, an overnight hospitalization for a diagnostic procedure, or 
therapeutic procedure for an AE, must be reported as an SAE even though the occurrence is not 
medically serious.  By the same token, a severe AE is not necessarily serious: nausea of several 
hours’ duration may be rated as severe but may not be considered serious. 
9.1.3 
Unexpected Adverse Drug Reactions 
An unexpected ADR is a reaction for which the nature or severity is not consistent with the 
applicable product information (see US Package Insert15 and EU summary of product 
characteristics for Prolia16).  Until product information is amended, expedited reporting is 
required for additional occurrences of the reaction.  Reports that add significant information on 
specificity or severity of a known, already documented SAE constitute unexpected events.  For 
example, an event more specific or more severe than described in the Investigator′s Brochure 
would be considered “unexpected.”  Specific examples would be (a) acute renal failure as a 
labeled ADR with a subsequent new report of interstitial nephritis, and (b) hepatitis with a first 
report of fulminant hepatitis. 
Guidance on reporting AEs and SAEs is described in Section 9.2. 
9.1.4 
Clinical Laboratory Changes 
Any abnormality in a laboratory value that is new in onset or which has worsened in severity or 
frequency from the baseline condition and meets one of the following criteria will be recorded on 
the AE pages of the eCRF: 
 Is judged by the Investigator as clinically significant and/or including, but limited to: 
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a. Requires therapeutic intervention or diagnostic tests 
b. Leads to discontinuation of study drug 
c. Has accompanying or inducing symptoms or signs 
d. Meets at least the Common Terminology Criteria for Adverse Events v5 Grade 3 
criteria.18 
9.1.5 
Adverse Events of Special Interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to study 
drug, for which ongoing monitoring and immediate notification by the Investigator to the 
Sponsor is required.  Such AESIs may require further investigation to characterize and 
understand them.  The AESIs for this study encompass all relevant warnings and precautions 
from the Prolia label15,16 and AESIs include: 
 Hypersensitivity 
 Hypocalcemia (based on corrected calcium) 
 ONJ 
 Osteonecrosis of the external auditory canal 
 Atypical subtrochanteric and diaphyseal femoral fractures 
 Multiple vertebral fractures (MVF) following discontinuation of study treatment 
 Musculoskeletal Pain 
 Diverticulitis 
 Lichenoid Drug Eruptions 
 Cellulitis 
See Section 9.2.3 for reporting requirements. 
9.1.5.1 
Hypersensitivity 
If an anaphylactic or other clinically significant allergic reaction occurs, appropriate therapy 
should be initiated, and further use of the study drug should be discontinued. 
9.1.5.2 
Hypocalcemia 
Hypocalcemia may be exacerbated by the use of study drug.  Known pre-existing hypocalcemia 
(Grade 1 hypocalcemia as per Common Terminology Criteria for Adverse Events v519: corrected 
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serum calcium of <LLN - 8.0 mg/dL; <LLN - 2.0 mmol/L; ionized calcium <LLN - 1.0 mmol/L) 
must be corrected prior to initiating therapy with study drug.  Clinical monitoring of calcium 
levels is recommended before each dose and, in subjects predisposed to hypocalcemia within 2 
weeks after the initial dose.  If any subject presents with suspected symptoms of hypocalcemia 
during treatment, calcium levels should be measured.  Concomitant glucocorticoid treatment is 
an additional risk factor for hypocalcemia. 
All subjects should receive adequate supplements of calcium and vitamin D throughout the 
study.  Calcium and vitamin D supplements will be provided by the Sponsor.  Investigators will 
be instructed to ensure that all subjects receive at least 1000 mg/day of calcium supplement and 
800 IU/day of vitamin D supplement, however the doses can be adjusted at the discretion of the 
Investigator. 
9.1.5.3 
Osteonecrosis of the Jaw 
Good oral hygiene practices include daily brushing, flossing, and use of antibacterial oral rinses, 
and attending recommended dental check-ups, denture fittings, and routine cleanings, to decrease 
rates of periodontal disease and oral infection should be maintained during treatment with study 
drug.  Subjects who are suspected of having or who develop ONJ while on study drug should 
receive care by a dentist or an oral surgeon.  In these subjects, extensive dental surgery to treat 
ONJ may exacerbate the condition.  Discontinuation of study drug should be considered based 
on individual benefit-risk assessment. 
9.1.5.4 
Osteonecrosis of the External Auditory Canal 
Osteonecrosis of the external auditory canal has been reported with denosumab.  Possible risk 
factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy 
and/or local risk factors such as infection or trauma.  The possibility of osteonecrosis of the 
external auditory canal should be considered in subjects receiving denosumab who present with 
ear symptoms including chronic ear infections. 
9.1.5.5 
Atypical Subtrochanteric and Diaphyseal Femoral Fractures 
During the treatment with study drug, subjects should be advised to report new or unusual thigh, 
hip, or groin pain.  Any subject who presents with thigh or groin pain should be suspected of 
having an atypical fracture and should be evaluated to rule out an incomplete femur fracture.  
Subject presenting with an atypical femur fracture should also be assessed for symptoms and 
signs of fracture in the contralateral limb.  Interruption of study drug should be considered, 
pending a benefit-risk assessment, on an individual basis. 
9.1.5.6 
Multiple Vertebral Fractures Following Discontinuation of Study Treatment 
Following discontinuation of study treatment, fracture risk increases, including the risk of MVF.  
Treatment with study drug results in significant suppression of bone turnover and cessation of 
study drug results in increased bone turnover above pretreatment values 9 months after the last 
dose of study drug.  Subjects will be followed for at least 6 months after the last dose of the 
study drug in order to capture this AE. 
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If study treatment is discontinued, subjects should be transitioned to an alternative antiresorptive 
therapy.  
9.1.5.7 
Musculoskeletal Pain 
In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle 
pain has been reported in subjects taking Prolia.  The time to onset of symptoms varied from one 
day to several months after starting Prolia.  Consider discontinuing use of study drug if severe 
symptoms develop. 
9.1.5.8 
Diverticulitis 
In a single phase 3 placebo-controlled clinical trial in subjects with prostate cancer receiving 
androgen deprivation therapy an imbalance in diverticulitis AEs was observed 
(1.2% denosumab, 0% placebo).  The incidence of diverticulitis was comparable between 
treatment groups in postmenopausal women or men with osteoporosis and in women undergoing 
aromatase inhibitor therapy for non-metastatic breast cancer. 
9.1.5.9 
Lichenoid Drug Eruptions 
Lichenoid drug eruptions (eg, lichen planus-like reactions) have been reported in subjects in the 
post-marketing setting. 
9.1.5.10 
Cellulitis 
Subjects receiving denosumab may develop skin infections, predominantly cellulitis, leading to 
hospitalization.  Subjects should be advised to seek prompt medical attention if they develop 
signs or symptoms of cellulitis. 
9.1.6 
Assessment of Severity 
Each AE will be classified according to the following criteria: 
Mild: 
The AE does not interfere in a significant manner with the subject’s 
normal level of functioning. 
Moderate: 
The AE produces some impairment of functioning, but is not 
hazardous to the subject’s health. 
Severe: 
The AE produces significant impairment of functioning or 
incapacitation and is a definite hazard to the subject’s health. 
Severity versus Seriousness: Severity is used to describe the intensity of a specific event while 
the event itself may be of relatively minor medical significance (such as severe headache).  
Severity is not the same as “seriousness,” which is based on subject/event outcome at the time of 
the event. 
When changes in the severity of an AE occur more frequently than once a day, the maximum 
severity for the experience should be noted.  If the severity category changes over several days, 
those changes should be recorded as separate AEs (with distinct onset dates). 
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9.1.7 
Assessment of Relationship 
Each AE will be assessed as to its relationship to the study drug, based on the following criteria.  
Although the attribution by the Investigator will be collected for reported events, for analytic 
purposes a temporal association with the use of the study drug will be assumed sufficient for at 
least plausible association. 
Not related: 
No causal relationship exists between the study drug and the AE, but 
an obvious alternative cause exists, eg, the subject’s underlying 
medical condition or concomitant therapy. 
Related: 
There is a reasonable/plausible possibility that the AE may have been 
caused by the study drug. 
When assessing the relationship to the study drug, the following criteria will be considered: 
 Positive rechallenge 
 Positive dechallenge (resolution upon stopping the suspect study drug, in absence of other 
intervention or treatment) 
 Known class effect 
 Biological plausibility 
 Lack of alternative explanation (eg, a concomitant drug or disease) 
9.1.8 
Action Taken Regarding Study Drug(s) 
The action taken regarding the study drug as a result of an AE should be selected from one of the 
categories listed below and recorded on the eCRF:  
 Dose Not Changed: No change in study drug dose was made. 
 Drug Withdrawn: The study drug was permanently stopped. 
 Drug Interrupted: The study drug was temporarily stopped. 
 Not Applicable: Subject died, study treatment had been completed prior to reaction/event, or 
reaction/event occurred prior to the start of treatment. 
 Unknown. 
9.1.9 
Other Action Taken for Event 
Other action(s) taken as a result of the AE should be selected from 1 of the categories listed 
below and recorded on the eCRF: 
 None (ie, no treatment was required) 
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 Therapy(ies) required (ie, prescription and/or OTC medication was required to treat the AE) 
 Hospitalization or prolongation of hospitalization required (ie, hospitalization was required 
or prolonged because of the AE, whether medication was required) 
 Other 
9.1.10 
Adverse Event Outcome 
The outcome of the AE should be selected from one of the categories listed below and recorded 
on the eCRF: 
 Recovered/Resolved (ie, the subject fully recovered from the AE with no residual effect 
observed) 
 Recovering/Resolving (ie, the AE improved but has not fully resolved) 
 Not Recovered/Not Resolved (ie, the AE is still present and observable) 
 Recovered/Resolved with Sequelae (ie, the residual effects of the AE are still present and 
observable, including sequelae/residual effects) 
 Fatal (ie, “fatal” should be used when death is a direct outcome of the AE) 
 Unknown 
9.2 
Reporting Procedures and Requirements 
9.2.1 
Adverse Events 
Each time the subject is seen or contacted by the Investigator or the study staff, be it at the study 
clinic, hospital, or over the telephone, the Investigator will determine whether any AE has 
occurred by evaluating the subject.  AEs may be directly observed, reported spontaneously by 
the subject, or by questioning the subject at each contact.  Subjects should be questioned in a 
general way, without asking about the occurrence of any specific symptoms.  If AEs occur, the 
first concern will be the safety of the study subjects.  All AEs will be followed until resolved or 
stable and the outcome documented in the subject’s source documentation/medical record, and 
on the eCRF. 
Any AE that occurs after signing the ICF up to the EoS Visit will be recorded in the subject’s 
source documentation/medical record and on the AE page of the eCRF.  In case of early EoS, if 
the Investigator detects an AE in a subject up to 6 weeks after the last dose of the study drug and 
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considers the event possibly related or related to prior study drug, the Investigator should report 
it to the Sponsor or designated representative. 
For each reported AE, the following are to be reported: 
 Description of the AE: 
a. Whenever possible, an AE or SAE will be reported using a diagnostic term, 
(eg, “common cold” or “upper respiratory infection” rather than “runny nose, cough, mild 
fever”). 
b. When a diagnosis is unavailable, report the primary sign or symptom as the AE or SAE 
term with additional details included in the narrative until the diagnosis becomes 
available. 
c. If the signs and symptoms are distinct and do not suggest a common diagnosis, report 
them as individual entries of AEs or SAEs. 
 Start and end date of the AE 
 Whether the AE is an SAE, AESI, or unexpected ADR 
 Severity (Section 9.1.6) 
 Relationship to the study drug (Section 9.1.7) 
 Action taken regarding the study drug (Section 9.1.8) 
 Other action taken for the AE (Section 9.1.9) 
 Outcome (Section 9.1.10) 
Illnesses that are present at the time informed consent is given are to be regarded as concomitant 
illnesses and recorded in the medical history.  Investigators should document all significant 
illnesses that the subject has experienced within 6 months of Screening as a prior illness and all 
previous significant ones which are important for interpretation of subject overall medical 
condition.  Illnesses first occurring or detected during the study and/or worsening of a 
concomitant illness during the study are to be documented as AEs. 
All clinical laboratory results, vital signs, and ECG results or findings should be evaluated by the 
Investigator to determine their clinical significance.  Isolated abnormal clinical laboratory test 
results, vital sign findings, or ECG findings (ie, not part of a reported diagnosis) should be 
reported as AEs if they are symptomatic, lead to study drug discontinuation, require corrective 
treatment, or constitute an AE in the Investigator’s clinical judgment. 
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9.2.2 
Serious Adverse Events 
Each AE will be assessed to determine whether it meets seriousness criteria (Section 9.1.2).  If 
the AE is considered serious, the Investigator should report this event to the Pharmacovigilance 
CRO as outlined below and to the IEC/regulatory authorities according to its SOPs. 
Any SAE that occurs after signing the ICF up to the EoS Visit will be recorded in the subject’s 
source documentation/medical record and on the AE page of the eCRF.  In case of early EoS, if 
the Investigator detects an SAE in a study subject up to 6 weeks after the last dose of the study 
drug, and considers the SAE related or possibly related to this study’s study drug administration, 
the Investigator should report it to the Pharmacovigilance CRO. 
All information about SAEs will be collected and reported via the SAE Form within electronic 
data capture (EDC) and sent by email message or facsimile (contact information will be 
contained in the investigator site file).  If the EDC system is not available or if the site 
experiences a temporary disruption of the EDC system, the site staff will complete the back-up 
paper SAE Form and sent it by email message or facsimile.  If notification is made via email or 
fax, site staff must enter the SAE information into the EDC system as soon as the system 
becomes available.  The Investigator should send the initial report within 24 hours of becoming 
aware of the SAE regardless of relationship to study drug. 
At minimum, the initial report of the SAE should include the following information: 
 AE description 
 Study code/protocol number 
 Subject number and year of birth 
 Study drug 
 Reporter name and contact information 
In the case of a “minimum report” (one that solely comprises the information bulleted above), a 
more detailed follow-up report should be sent as soon as more information becomes available but 
no later than 7 calendar days after the date of the initial report.  Each SAE should be followed up 
until resolution or stabilization, and for reported deaths the Investigator should supply 
Pharmacovigilance CRO and the IEC with any additional requested information (eg, autopsy 
reports and terminal medical reports). 
The original paper SAE Form submitted should be kept at the study site with the subject’s source 
documentation/medical record or in the site’s study files.  The Sponsor or its representative will 
be responsible for determining and in turn, reporting SAEs to regulatory authorities according to 
the applicable regulatory requirements. 
SAEs that are ongoing should be followed until resolved or stabilized. 
Any suspected unexpected serious adverse reaction must be reported according to applicable 
regulatory requirements. 
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9.2.3 
Adverse Events of Special Interest 
Adverse events of special interest, encompassing all relevant warnings and precautions from the 
Prolia label, will be defined for safety analysis.  Further details will be given in the Safety 
Management Plan and the statistical analysis plan (SAP).  AESIs are listed in Section 9.1.5. 
While these are noted to be of special interest, these AEs will be reported and assessed in the 
same manner as standard AEs. 
 
 
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10 STATISTICS 
10.1 
General Procedures 
The statistical analysis will be undertaken by
in 
collaboration with Alvotech. 
A detailed SAP will be finalized and signed before database lock and unblinding.  Additional 
details will be provided in the SAP.  Any deviations from the analyses described below will be 
included in the SAP, which will be included in the clinical study report (CSR). 
All data summaries and statistical analyses will be performed using Safety Analysis Set (SAS) 
version 9.4 or higher.0 
10.2 
Sample Size 
Approximately 476 subjects will be randomized to demonstrate the clinical similarity of AVT03 
and Prolia in terms of the percent change from Baseline in LS BMD at 12 months.  Assuming a 
0.05% true difference between treatment groups, 18% non-evaluable subjects, a common 
standard deviation (SD) of 4.06%, using an equivalence margin of (-1.45%, 1.45%), 476 subjects 
will provide power of 93.7% and 87.8% at a significance level of 5% (corresponding to 90% 
confidence interval (CI) as required by FDA) and 2.5% (corresponding to 95% CI as required by 
EMA), respectively. 
From a clinical practice point of view, a percent change of less than 2 to 3% in LS BMD is 
considered as not a clinically meaningful change.21  Therefore, an equivalence margin of 
(-1.45%, 1.45%) is considered as a clinically relevant threshold to detect potential difference 
between the proposed biosimilar and reference product in terms of mean percent change from 
Baseline in BMD at Month 12. 
The equivalence margin and the common SD are derived based on the data from the historical 
clinical trials with denosumab 60 mg and placebo; details are provided in the table below. 
Table 10.1: 
Historical Data for Percent Change from Baseline in Lumbar Spine Bone 
Mineral Density at 12 Months and Meta-Analysis Results 
Publications 
Sample size 
(Denosumab 60 mg vs. 
Placebo) 
Mean difference between 
group 
Pooled SD 
Cummings et al. 200922  
220 vs. 221 
5.47% 
3.55% 
Bone et al. 200823  
164 vs. 165 
4.98% 
4.06%* 
McClung et al. 200624  
46 vs. 46 
5.54% 
3.49% 
Meta-analysis (mean difference and 
95% CI) 
 
5.32% 
(4.83%, 5.82%) 
 
Equivalence margin based on 70% 
retention 
 
[-1.45%, 1.45%] 
 
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*To be conservative, the largest SD of 4.06% among historical trials is used for the sample size calculation in Study 
AVT03-GL-C01. 
Abbreviations: CI = confidence interval; SD = standard deviation. 
In addition, for the submission to EMA, the AUEC0-6months of %Cfb sCTX-1 will be analyzed as 
the primary PD endpoint.  The coefficient of variation (CV%) of AUEC0-6months of %Cfb sCTX-1 
is estimated from simulation using a published denosumab PD model25,26 which was developed 
based on Prolia data.  Assuming a true geometric mean ratio (GMR) of 0.95, using the standard 
equivalence margin of (0.80, 1.25), 476 randomized subjects (considering 18% of non-evaluable 
rate) will provide a power of 99.9% for the PD similarity analysis of AUEC0-6months of %Cfb 
sCTX-1. 
10.3 
Analysis Populations 
10.3.1 
Enrolled Set 
The Enrolled Set includes all subjects who have given informed consent to participate in the 
study.   
10.3.2 
Full Analysis Set 
The Full Analysis Set (FAS) is defined as all randomized subjects who received at least 1 dose of 
randomized study treatment.  Subjects will be analyzed according to the study treatment arm 
they were randomized to. 
10.3.3 
Pharmacodynamic Analysis Set 
The PD Analysis Set is defined as all randomized subjects who received at least 1 dose of 
randomized study treatment and have at least 1 evaluable PD endpoint collected without any 
protocol deviation that thought to significantly affect the PD.  Subjects will be analyzed 
according to the actual study treatment received. 
10.3.4 
Safety Analysis Set 
The SAS includes all randomized subjects who received at least 1 dose of study treatment.  
Subjects will be analyzed according to the actual study treatment received. 
10.4 
Statistical Methods 
10.4.1 
Protocol Deviations 
Any deviations from the protocol should be collected and documented as described in Protocol 
Deviation Handling Plan.  All protocol deviations will be reviewed and classified as minor or 
major on a case-by-case basis by the Sponsor or its representative.  The protocol deviations 
leading to exclusion of subjects from the primary endpoint analysis will be determined prior to 
database freeze. 
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Protocol deviations related to study inclusion or exclusion criteria, conduct of the trial, subject 
management, or subject assessment should be described in the study report.  These might 
include, but are not limited to, the following: 
 Those who entered the study even though they did not satisfy the entry criteria. 
 Those who developed withdrawal criteria during the study but were not withdrawn. 
 Those who received the wrong treatment or incorrect dose. 
 Those who received an excluded concomitant treatment. 
All protocol deviations including those related to COVID-19 will be captured and presented in 
tables and listings. 
10.4.2 
Subject Disposition 
Details for the reasons and number of the screening failures will be tabulated. 
Subject disposition at EoT and EoS including reasons for premature discontinuation of treatment 
and study will be presented separately. 
10.4.3 
Demographic and Baseline Characteristics 
Treatment arms will be compared with respect to subject demographics and baseline subject and 
disease characteristics and will be summarized using descriptive statistics, but no formal 
statistical analysis tests will be performed.  The following demographics and baseline 
characteristics will be summarized: age (in years, at time of signing informed consent), gender, 
race, and ethnicity. 
10.4.4 
Analysis of Efficacy 
10.4.4.1 
Primary Efficacy Endpoint(s) 
The following estimand attributes are defined with regards to the primary efficacy endpoint 
analysis:  
Endpoint: Percent change from Baseline in LS BMD at12 months. 
Treatment: Randomized treatment groups, AVT03 and Prolia. 
Population:  
The primary endpoint analysis will be based on the FAS which includes all randomized subjects 
who received at least 1 dose of randomized study treatment.  Subjects will be analyzed according 
to the study treatment arm they were randomized to.  In order to provide the most sensitive 
analysis set to detect potential differences between AVT03 and Prolia, the following intercurrent 
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events (ICEs) that can lead to attenuation of treatment differences are defined.27  Subjects with 
any of the following ICEs will be excluded from the analysis of primary endpoint: 
 Discontinuation from study treatment prior to 12 months. 
 Took prohibited concomitant medications prior to 12 months that impact the primary 
endpoint. 
 Received incorrect study treatment instead of the randomized treatment. 
 Additional protocol deviations that impact the assessment of primary endpoint, which will be 
determined in a blinded data review meeting prior to database lock. 
As a sensitivity analysis, the primary endpoint analysis will be repeated based on the FAS 
without exclusion of any subjects due to the ICEs specified for the main estimator. 
Population Level Summary: 
The following statistical hypotheses will be tested to demonstrate the clinical similarity of 
AVT03 and Prolia in terms of percent change from Baseline in LS BMD at 12 months. 
The null hypothesis, 
𝐻0:  𝜇𝐴𝑉𝑇03 −𝜇Prolia ≤ −1.45%  𝑜𝑟 𝜇𝐴𝑉𝑇03 −𝜇Prolia ≥ −1.45%, 
the alternative hypothesis  
𝐻𝐴: | 𝜇𝐴𝑉𝑇03 −𝜇Prolia | < 1.45% 
where 𝜇𝐴𝑉𝑇03 and 𝜇Prolia  are the mean percent change from Baseline in LS BMD at 12 months 
in AVT06 and Prolia group respectively. 
The percent change from Baseline in LS BMD at 6 and 12 months will be analyzed using a 
mixed model for repeated measures (MMRM) including treatment, visit, treatment-by-visit 
interaction, and prior biologic therapy for osteoporosis (Yes/No) as categorical variables, and the 
baseline BMD and number of years since menopause as continuous covariates.  An unstructured 
covariance structure will be used to model the within-subject error and an adjustment to the 
degrees of freedom will be made using the Kenward-Roger’s approximation. 
The least square mean estimates will be provided for each treatment group at each visit with their 
standard errors (SE).  The difference of least square means between the treatment groups and 
associated SE, 2‑ sided 95% CI (as required by EMA) and 2-sided 90% CI (as required by FDA) 
will be provided for 12 months.  At 12 months, if the 95%/90% CIs are completely contained 
within the pre-specified equivalence margin of [-1.45%, 1.45%], a clinical similarity will be 
demonstrated respectively. 
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For the primary analysis and sensitivity analysis of the primary endpoint, the missing values of 
percent change from Baseline in LS BMD at 12 months may be handled using multiple 
imputation as needed, details of which will be provided in the SAP. 
In addition, for the submission to EMA, the area under the percentage change from baseline in 
serum C-telopeptide of type 1 collagen up to 6 months (AUEC0-6months of %Cfb sCTX-1) will be 
analyzed as primary PD endpoint.  The following statistical hypotheses will be tested to 
demonstrate the PD similarity of AVT03 and Prolia in terms of AUEC0-6months of %Cfb sCTX-1. 
The null hypothesis, 
H0: GMAVT03 ⁄GMProlia ≤80% or GMAVT03 ⁄GMProlia ≥125%  
The alternative hypothesis is:  
H1: 80% < GMAVT03 ⁄GMProlia <125%  
where GMAVT03 and GMProlia denote the geometric means of AUEC0-6months of %Cfb sCTX-1 in 
the AVT03 and Prolia groups, respectively. 
The analysis of the PD endpoint will be based on the PD Analysis Set.  The similar ICE strategy 
as for the primary endpoint (percent change from Baseline in LS BMD at 12 months) will be 
implemented for the analysis of PD endpoint AUEC0-6months of %Cfb sCTX-1, ie, the subjects 
with the ICEs that can lead to attenuation of treatment differences will be excluded from the 
analysis of AUEC0-6months of %Cfb sCTX-1.  The log transformed PD data (AUEC0-6months of 
%Cfb sCTX-1) will then be analyzed using an analysis of covariance (ANCOVA) model 
including the treatment as factor and the baseline sCTX-1 as continuous covariate.  The 95% CI 
for the GMR between treatment groups will be calculated.  The PD similarity will be 
demonstrated if the 95% CIs of GMR lie entirely within the pre-specified margin of (0.80, 1.25). 
Subgroup Analysis 
The subgroup analyzes of the primary efficacy endpoint will be performed by key baseline 
characteristics based on the FAS.  Within each subgroup, the primary endpoint will be analyzed 
using the same method as for the primary endpoint.  The results of subgroup analysis will be 
interpreted descriptively.  Subgroups of interest for the primary efficacy endpoint include: 
 Number of years since menopause (≤5 years, >5 years) 
 Prior biologic therapy for osteoporosis (Yes/No) 
Other subgroup analysis will be defined in the SAP as needed.  
10.4.4.2 
Secondary Efficacy Endpoint(s) 
The secondary efficacy endpoints for this study are the percent change from Baseline in the LS 
BMD at 6 and 18 months, percent change from Baseline in hip and femoral neck BMD at 6, 12, 
and 18 months, and incidence of new morphometric vertebral fractures at 12 and 18 months.  
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The same analysis methods used for the primary will also be used for the secondary continuous 
efficacy endpoints.  The number and percentage of subjects who had new morphometric 
vertebral fractures will be provided by visit. 
The analysis results of secondary efficacy endpoints will be interpreted descriptively. 
10.4.4.3 
Handling of Dropouts and Missing Observations  
The multiple imputation method (to handle the missing primary endpoint data) may be 
undertaken and detailed in the SAP prior to unblinding the study. 
10.4.4.4 
Multiplicity 
The secondary efficacy endpoint analysis results will be interpreted descriptively only.  No alpha 
adjustments are planned for this study. 
As mentioned in Section 10.4.4.1, for the submission to EMA, the AUEC0-6months of %Cfb 
sCTX-1 will be analyzed as primary PD endpoint.  For EMA, the primary efficacy endpoint (ie, 
Percent change from Baseline in LS BMD at 12 months) and primary PD endpoint will share the 
familywise type 1 error rate of 5%, no alpha adjustment is needed for the additional PD primary 
endpoint analysis.28   
10.4.5 
Pharmacodynamics 
For the submission to EMA, the AUEC0-6months of %Cfb sCTX-1 will be analyzed as primary PD 
endpoint (see details in Section 10.4.4.1). 
For the submission to other agencies, the AUEC0-6months of %Cfb sCTX-1 will be analyzed as 
secondary PD endpoint, and the analysis result will be interpreted descriptively. 
The descriptive statistics of CTX-1 level between treatment groups over all time points will be 
provided and will be presented graphically including individual and mean (per treatment) 
concentration-time profiles. 
Details will be provided in the SAP.  
10.4.6 
Analysis of Safety 
Safety analyzes will be presented by the treatment received for all subjects in the SAS.  Safety 
summaries will be presented by treatment and overall. 
10.4.6.1 
Extent of Exposure 
For the study drug (AVT03 or Prolia), study drug exposure will be summarized. 
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10.4.6.2 
Adverse Events 
All AEs occurring after signing the ICF up to the EoS Visit or 6 weeks after the last scheduled 
study visit will be recorded.  All AEs will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) Version 24.0 or higher. 
A treatment-emergence adverse event (TEAE) is defined as any AE that has an onset on or after 
the dose of study drug, or any pre-existing condition that has worsened on or after the first dose 
of study drug. 
The incidence of TEAEs (number and percent of subjects reporting the AE at least once during 
the study), SAEs, AEs related to study drug, SAEs related to treatment, and AEs leading to study 
discontinuation will be summarized by treatment. 
The incidence of TEAEs and treatment-related AEs will also be summarized by maximum 
severity by MedDRA primary system organ class and preferred term.  The summary will include 
the total number and percentage of subjects reporting a particular event. 
In counting the number of events reported, a continuous event, ie, reported more than once and 
which did not cease, will be counted only once; non-continuous AEs reported several times by 
the same subject will be counted as multiple events. 
AESIs will be listed and may be summarized separately.  
10.4.6.3 
Electrocardiogram 
Shift tables for change in 12-lead ECG parameters from Baseline to each post-baseline visit will 
be presented by treatment and visit. 
10.4.6.4 
Vital Signs and Body Weight 
Vital sign data and body weight (observed and change from Baseline) will be listed and 
summarized using descriptive statistics by treatment and visit. 
10.4.6.5 
Physical Examination 
Abnormal physical examination data will be summarized by treatment and visit.  Clinically 
significant findings will be listed. 
10.4.6.6 
Clinical Laboratory Tests 
Each hematology, coagulation, urinalysis, and serum chemistry parameter (observed and change 
from Baseline) will be summarized using descriptive statistics by treatment and visit.  In 
addition, each measurement will be classified as below, within, or above normal range, based on 
ranges supplied by the laboratory used.  For laboratory data, abnormal values will be flagged in 
the data listings and a list of clinically significant abnormal values will be presented.  Shift tables 
for change in laboratory parameters from Baseline to each post-baseline visit will be presented. 
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Presence of HBsAg, HCV antibodies and HIV at Screening will be summarized by treatment.  
SARS-CoV-2 antigens will be summarized by treatment and visit. 
10.4.6.7 
Concomitant Medications 
Concomitant medications include all medications and therapies during the study except for 
planned study drugs.  Concomitant medications will be coded according to the latest version of 
the WHO Drug Dictionary (WHO Drug Global B3 2021 March 1 or later) and will be 
summarized by treatment with number and percentage of subjects receiving each category of 
medication. 
10.4.7 
Immunogenicity 
Presence of ADAs and neutralizing antibodies will be compared between treatments. 
The number and percentage of subjects developing ADAs will be tabulated for each 
treatment-by-visit and the nAbs and the titers will be summarized for ADA positive subject. 
10.4.8 
Pharmacokinetics 
Serum concentrations of AVT03 and Prolia will be summarized by treatment and visit using 
descriptive statistics.  The steady-state serum trough concentrations of AVT03 and Prolia will be 
compared. 
10.4.9 
Interim Analysis 
No interim analysis is planned for this study. 
 
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11 STUDY MANAGEMENT AND RESPONSIBILITIES 
11.1 
Ethics 
11.1.1 
Good Clinical Practice 
The study will be performed in accordance with this protocol, local national laws (as applicable), 
ICH guideline for Good Clinical Practice,29 and the most recent guidelines of the Declaration of 
Helsinki.30 
11.1.2 
Independent Ethics Committee 
Conduct of the study must be approved by an appropriately constituted IEC.  Approval is 
required for the study protocol, Investigator’s Brochure, protocol amendments, ICFs, subject 
information sheets, and advertising materials.  No study drug will be shipped to a site until 
written IEC authorization has been received by the Sponsor or its representative. 
11.1.3 
Informed Consent 
For each study subject, a written ICF will be obtained before any protocol-related activities are 
performed.  As part of this procedure, the Investigator or a designated representative must 
explain orally and in writing the nature, duration, and purpose of the study, and the action of the 
study drug in such a manner that the subject and (if applicable) appointed guardian are aware of 
the potential risks, inconveniences, or adverse effects that may occur.  Subjects should be 
informed that they may withdraw from the study at any time.  They will receive all information 
that is required by local regulations and ICH guidelines.  The consenting/re-consenting process 
will be explained in detail and documented in source documents.  The Investigator or a 
designated representative will provide the Sponsor or its representative with a copy of the 
IEC-approved ICF before the start of the study. 
11.1.4 
Confidentiality 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is gained from the Sponsor.  However, authorized regulatory officials, IEC personnel, the 
Sponsor and its authorized representatives are allowed full access to the records. 
11.2 
Auditing and Monitoring 
To ensure accurate, complete, and reliable data
will provide instructional material to 
the study sites and the Sponsor at a start-up training session to instruct the investigators and 
study coordinators.  This session will give instruction on the protocol, the completion of the 
eCRFs, and study procedures. 
This study will be monitored for quality assurance at all stages of its development by the clinical 
research personnel employed by the Sponsor or its representative.  A Monitoring Plan will be 
developed and approved by the Sponsor and 
using a risk-based monitoring approach 
with the primary focus on critical data and processes that if inaccurate, not performed, or 
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performed incorrectly, would threaten the protection of human subjects or the integrity of the 
study results.  Monitoring may include remote monitoring, personal visits, and/or telephone 
communication to assure that the investigation is conducted according to the protocol, SOPs, 
Good Clinical Practice guidelines, and applicable regulatory requirements.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable and 
have been processed correctly.  As defined in the Monitoring Plan, eCRFs may be reviewed 
remotely or onsite for completeness, clarity, and consistency with source documents available for 
each subject.  At the conclusion of the study,
will conduct a quality review of the 
database. 
The study may be audited by the Sponsor,
and/or regulatory agencies at any time.  
Investigators will be given a notice before an audit occurs. 
Medical advisors and CRAs or assistants may request to witness subject evaluations occurring as 
part of this protocol.  The Investigator and appropriate personnel will be periodically requested 
to attend meetings/workshops organized by the Sponsor to assure acceptable protocol execution.  
The study may be subject to audit by the Sponsor or by regulatory authorities.  If such an audit 
occurs, the Investigator must agree to allow access to required subject records.  By signing this 
protocol, the Investigator grants permission to personnel from the Sponsor, its representatives, 
and appropriate regulatory authorities, for on-site monitoring of all appropriate study 
documentation, as well as on-site review of the procedures employed in eCRF generation, where 
clinically appropriate. 
11.3 
Data and Safety Monitoring Board 
No data safety monitoring board or committee will be used in this study. 
11.4 
Data Handling, Documentation, and Record Keeping 
11.4.1 
Source Documentation 
Note that a variety of original documents, data, and records for a given subject (eg, hospital 
records, clinical and office charts, laboratory notes, memoranda, subject’s diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, 
at the laboratories, and at medico-technical departments involved in the clinical study) will be 
considered as source documents in this study.  eCRF entries may be considered source data if the 
eCRF is the site of the original recording (ie, there is no other written or electronic record of 
data).  
11.4.2 
Direct Access to Source Data and Documents 
The Investigator/institution will provide direct access to source data and documents for 
trial-related monitoring, audits, IEC review, and regulatory inspection. 
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11.4.3 
Record Retention 
The Investigator must arrange for retention of study records at the site.  The nature of the records 
and the duration of the retention period must meet the requirements of the relevant regulatory 
authority but should not be less than 2 years after the first marketing approval.  In addition, the 
retention period must meet the requirements of the most stringent authority.  The Investigator 
should take measures to prevent accidental or premature destruction of these documents.  The 
responsible Investigator will notify the Sponsor prior to destruction of study records (eg, site 
master file) after end of required retention period or/and if the Investigator intends to move 
(relocate) or retires. 
11.4.4 
Study Documentation 
By signing a copy of the country-specific regulatory form(s), the Investigator or designated 
representative acknowledges that he/she has received a copy of the Investigator’s Brochure on 
AVT03 and assures the Sponsor that he/she will comply with the protocol and the provisions 
stated in the country-specific regulatory form(s).  No changes in this protocol can be made 
without the Sponsor’s written approval. 
11.4.5 
Data Management Considerations 
The data collection tool for this study will be a validated EDC system called 
  Subject 
data necessary for analysis and reporting will be entered/transmitted into a validated database or 
data system. 
Data required according to this protocol will be recorded by investigational site personnel via 
data entry into the internet-based EDC software system 
, which the CRO has licensed 
from 
 and the CRO have validated 
 for use in 
clinical studies and the CRO will validate the system configuration for this specific protocol.  
 allows for the application of software logic to set up data entry screens and data checks to 
ensure the completeness and accuracy of the data entered by the site personnel.  The CRO 
extensively applies the logic to ensure data are complete and reflect the clinical data 
requirements of the study.  Alvotech trained staff will perform User Acceptance Testing in 
conjunction with the CRO to ensure the application of this logic to confirm data are complete 
and reflect the clinical data requirements of the study.  The site personnel resolve data queries 
resulting from the application of the software logic.  The data are stored at a secure host facility 
maintained by 
 who own their own set of backup and disaster recovery plans 
and can be transferred to the URL owner whenever required. 
All access to th
system is through a password-protected security system that is part of 
the
 software.  All internal Alvotech and external investigator site personnel seeking 
access must go through a thorough 
 training process before they are granted access to 
 for use in Alvotech's clinical study.  Training records are maintained. 
Alvotech as the Sponsor will ensure that the Investigator has control of and continuous access to 
eCRF data. 
DocuSign Envelope ID: 5A29786D-9A46-486F-9876-7755F9A1E0FC

Alvotech Swiss AG 
Protocol AVT03-GL-C01
AVT03 
Version 3.0, Final, 03 Aug 2022
 
Confidential 
Page 71 of 81 
 
A service desk is staffed with trained personnel to answer questions and ensure access is 
maintained such that data entry can proceed in a timely manner and supports all personnel with 
access to the
system. 
The
ystem contains a system-generated audit trail that captures any changes made to a 
data field, including who made the change, why the change was made, and the date and time, it 
was made.  This information is available both at the investigator’s site and at Alvotech based on 
specific user data access permission.  Data entries made in the 
 EDC screens are supported 
by source documents maintained for all subjects enrolled in this study. 
11.5 
Indemnification 
The Sponsor’s indemnification of the Investigator and institution during the conduct of this study 
is addressed in a letter of indemnification provided as a separate document.  Other 
indemnification or insurance will be provided as necessary under local regulations. 
11.6 
Amendments 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by the Sponsor.  A protocol change intended to eliminate an apparent immediate 
hazard to subjects may be implemented immediately, provided the IEC is notified within 
5 calendar days. 
Any permanent change to the protocol must be handled as a protocol amendment.  The written 
amendment must be submitted to the IEC and the Investigator must await approval before 
implementing the changes.  The Sponsor will submit protocol amendments to the appropriate 
regulatory authorities for approval. 
If in the judgment of the IEC, the Investigator, and/or the Sponsor, the amendment to the 
protocol substantially changes the study design and/or increases the potential risk to the subject 
and/or has an impact on the subject's involvement as a study subject, the currently approved 
written ICF will require similar modification.  In such cases, informed consent will be renewed 
for subjects enrolled in the study before continued participation. 
11.7 
Study Termination 
The Sponsor reserves the right to terminate the study at any time.  Both the Sponsor and the 
Investigator or designated representative reserve the right to terminate the study at the 
Investigator′s site at any time.  Should this be necessary, the Sponsor or a specified designee will 
inform the appropriate regulatory authorities of the termination of the study and the reasons for 
its termination , and the Investigator or designated representative will inform the IEC of the same 
within the required time frame.  In terminating the study, the Sponsor and the Investigator or 
designated representative will assure that adequate consideration is given to the protection of the 
subjects’ interests.  Alvotech will not provide Prolia after termination of the study or upon 
discontinuation of the study for the subject. 
DocuSign Envelope ID: 5A29786D-9A46-486F-9876-7755F9A1E0FC

Alvotech Swiss AG 
Protocol AVT03-GL-C01
AVT03 
Version 3.0, Final, 03 Aug 2022
 
Confidential 
Page 72 of 81 
 
In addition, the trial may be terminated by the IEC or further to any regulatory inspection 
findings.  In case of suspension, the study may resume once the raised concerns are addressed, 
and satisfy the Sponsor, IEC, and/or the regulatory authorities. 
11.8 
Clinical Study Report 
A primary CSR will be prepared including data available at the Month 12 + 2 weeks database 
freeze for all subjects and Month 18 data for 10% of the subjects and a final CSR including data 
collected up to Month 18 for all subjects. 
Both CSRs will be prepared according to the ICH guideline on Structure and Contents of 
Clinical Study Reports.  A final CSR will be prepared regardless of whether the study is 
completed or prematurely terminated.  The Sponsor will provide each Investigator with a copy of 
the final report for retention. 
 
 
DocuSign Envelope ID: 5A29786D-9A46-486F-9876-7755F9A1E0FC

Alvotech Swiss AG 
Protocol AVT03-GL-C01
AVT03 
Version 3.0, Final, 03 Aug 2022
 
Confidential 
Page 73 of 81 
 
12 PUBLICATION POLICY 
Authorship of any publications resulting from this study will be determined on the basis of the 
Uniform Requirement for Manuscripts Submitted to Biomedical Journals (International 
Committee of Medical Journal Editors), which states: 
 Authorship credit is to be based on (1) substantial contributions to conception and design, 
acquisition of data, or analysis and interpretation of data; (2) drafting the article or revising it 
critically for important intellectual content; (3) final approval of the version to be published.  
Authors are to meet conditions 1, 2, and 3. 
 When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals are to fully 
meet the criteria for authorship defined above. 
 Acquisition of funding, collection of data, or general supervision of the research group, 
alone, does not justify authorship. 
 All persons designated as authors are to qualify for authorship, and all those who qualify are 
to be listed. 
 Each author is to have participated sufficiently in the work to take public responsibility for 
appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) based on this 
study must be submitted to Alvotech for review.  The Clinical Trial Agreement among the 
institution, Investigator, and Alvotech will detail the procedures for, and timing of, Alvotech’s 
review of publications. 
 
DocuSign Envelope ID: 5A29786D-9A46-486F-9876-7755F9A1E0FC

Alvotech Swiss AG 
Protocol AVT03-GL-C01
AVT03 
Version 3.0, Final, 03 Aug 2022
 
Confidential 
Page 74 of 81 
 
13 REFERENCES 
DocuSign Envelope ID: 5A29786D-9A46-486F-9876-7755F9A1E0FC

Alvotech Swiss AG 
Protocol AVT03-GL-C01
AVT03 
Version 3.0, Final, 03 Aug 2022
Confidential 
Page 75 of 81 
 
DocuSign Envelope ID: 5A29786D-9A46-486F-9876-7755F9A1E0FC

Alvotech Swiss AG 
Protocol AVT03-GL-C01
AVT03 
Version 3.0, Final, 03 Aug 2022
Confidential 
Page 76 of 81 
 
 
DocuSign Envelope ID: 5A29786D-9A46-486F-9876-7755F9A1E0FC

Alvotech Swiss AG 
Protocol AVT03-GL-C01
AVT03 
Version 3.0, Final, 03 Aug 2022
 
Confidential 
Page 77 of 81 
 
14 APPENDICES 
14.1 
Contact Information 
Role 
Name and Contact Information 
Sponsor Medical and 
Development Lead 
Sponsor  
Project Management 
Medical Monitor 
CRO  
Project Management 
EDC System Provider 
Central Laboratory 
Investigational Product 
Distribution 
DocuSign Envelope ID: 5A29786D-9A46-486F-9876-7755F9A1E0FC

Alvotech Swiss AG 
Protocol AVT03-GL-C01
AVT03 
Version 3.0, Final, 03 Aug 2022
 
Confidential 
Page 78 of 81 
 
Role 
Name and Contact Information 
Central Imaging 
Interactive Response 
Technology  
Abbreviations: CRO = contract research organization; EDC = electronic data capture 
The names of other study personnel are provided in a separate vendor management plan to the 
site. 
14.2 
Causes of Secondary Osteoporosis 
Note: This appendix is a guideline for the Investigators.  Controlled conditions that are not 
specifically mentioned in the exclusion criteria 1 are to be evaluated and subjects can be included 
as per Investigator’s criteria and/or after discussion with the medical monitor on a case-by-case 
basis (eg, well controlled diabetes type 1 or 2; history of anorexia nervosa, etc.).  Medical 
conditions or prohibited medications specified in the inclusion and exclusion criteria are 
exclusionary. 
 Anorexia nervosa 
 Gastrointestinal malabsorption (eg, celiac disease, postoperative states) 
 Vitamin D and/or calcium deficiency 
 Hyperthyroidism 
 Hyperparathyroidism 
 Cushing's syndrome 
 Hypogonadism (hypogonadotropic or hypergonadotropic) 
 Hypercalciuria 
 Rheumatoid arthritis and other inflammatory conditions 
DocuSign Envelope ID: 5A29786D-9A46-486F-9876-7755F9A1E0FC

Alvotech Swiss AG 
Protocol AVT03-GL-C01
AVT03 
Version 3.0, Final, 03 Aug 2022
 
Confidential 
Page 79 of 81 
 
 Alcoholism 
 Smoking  
 Renal disease 
 Liver disease 
 Homocystinuria  
 Hereditary hemochromatosis 
 HIV infection and/or medications 
 Diabetes (types 1 and 2) 
 Bone marrow processes 
 Systemic mastocytosis 
 Gaucher disease 
 Thalassemia major 
Medications 
 Glucocorticoids 
 Immunosuppressants (cyclosporine) 
 Antiseizure medications (particularly phenobarbital and phenytoin) 
 Gonadotropin-releasing hormone agonists (when used to suppress ovulation) 
 Heparin 
 Chemotherapy leading to amenorrhea 
 Thiazolidinediones 
 Depot medroxyprogesterone acetate 
Possible contributors 
 Excess thyroid hormone 
 Depression and/or SSRI use 
DocuSign Envelope ID: 5A29786D-9A46-486F-9876-7755F9A1E0FC

Alvotech Swiss AG 
Protocol AVT03-GL-C01
AVT03 
Version 3.0, Final, 03 Aug 2022
 
Confidential 
Page 80 of 81 
 
 Proton pump inhibitors 
 
DocuSign Envelope ID: 5A29786D-9A46-486F-9876-7755F9A1E0FC

Alvotech Swiss AG 
Protocol AVT03-GL-C01
AVT03 
Version 3.0, Final, 03 Aug 2022
 
Confidential 
Page 81 of 81 
 
14.3 
Injection Site Reaction Grading Scheme 
Injection Site Reaction Grading Scheme 
Intensity Grading 
Reaction 
Absent (0) 
or not 
clinically 
significant  
Mild (1) 
Moderate (2) 
Severe (3) 
Potentially Life-
threatening (4) 
Pain 
Absent 
Does not interfere 
with activity 
Repeated use of non-narcotic 
pain reliever >24 hours or 
interferes with activity 
Any use of narcotic 
pain reliever or 
prevents daily activity 
Hospital visit or 
hospitalization 
Tenderness 
Absent 
Mild discomfort to 
touch 
Discomfort with movement 
Significant 
discomfort at rest 
Hospital visit or 
hospitalization 
Erythema/redness 
Not 
clinically 
significant, 
<2.5 cm 
2.5 to 5.0 cm 
5.1 to 10.0 cm 
>10.0 cm 
Necrosis or exfoliative 
dermatitis 
Induration/swelling 
Not 
clinically 
significant, 
<2.5 cm 
2.5 to 5.0 cm and does 
not interfere with 
activity 
5.1 to 10.0 cm or interferes 
with activity 
>10.0 cm or prevents 
daily activity 
Necrosis 
Pruritus/Itching 
Absent  
Mild 
Moderate 
Severe 
Hospital visit or 
hospitalization 
Hematoma/Ecchymosis/Bruising 
Not 
clinically 
significant, 
<2.5 cm  
2.5 to 5.0 cm and does 
not interfere with 
activity 
5.1 to 10.0 cm or interferes 
with activity 
>10.0 cm or prevents 
daily activity 
Necrosis 
 
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