A Randomized, Double-Blind, Multinational, Multicenter Study to Compare Efficacy, Safety, and Immunogenicity of TVB-009P and Denosumab (Prolia®) in Patients With Postmenopausal Osteoporosis
Phase: PHASE3
Conditions: Osteoporosis, Postmenopausal
Sponsor: Teva Pharmaceuticals USA

Efficacy/Safety Study–Postmenopausal Osteoporosis
Clinical Study Protocol with Amendment 02
Study TVB009-IMB-30085
1
 
Clinical Study Protocol with Amendment 02 
Study Number TVB009-IMB-30085
A Randomized, Double-Blind, Multinational, Multicenter Study to Compare Efficacy, 
Safety, and Immunogenicity of TVB-009P and Denosumab (PROLIA®1) in Patients with 
Postmenopausal Osteoporosis
Short title: A Randomized, Double-Blind Study on Efficacy, Safety, and Immunogenicity of 
TVB-009P in Adults with Postmenopausal Osteoporosis
Title of the protocol for lay people: A Study to Test if TVB-009P is Effective in Relieving 
Postmenopausal Osteoporosis
Efficacy and Safety Study (Phase 3)
IND number: 137313;
EudraCT number: 2020-005548-48
EMA Decision number of Pediatric Investigation Plan: Not applicable
Article 45 or 46 of 1901/2006 does not apply
Protocol with Amendment 02 
Version Date: 29 June 2021 
Sponsor
Teva Branded Pharmaceutical
Products R&D, Inc.
145 Brandywine Parkway
West Chester, PA 19380
United States of America
Information regarding clinical laboratories and other departments and institutions is 
found in Appendix A
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as directed by the 
provisions of the International Council for Harmonisation (ICH); United States (US) Code of Federal Regulations 
(CFR), and European Union (EU) Directives and Regulations (as applicable in the region of the study); national 
country legislation; and the sponsor’s Standard Operating Procedures (SOPs).
Confidentiality Statement
This document contains confidential and proprietary information (including confidential commercial information 
pursuant to 21CFR§20.61) and is a confidential communication of Teva Branded Pharmaceutical Products R&D, 
Inc. and its affiliates The recipient agrees that no information contained herein may be published or disclosed 
without written approval from the sponsor.
© 2021 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved.
                                                
1 PROLIA is a registered trademark of Amgen, Inc.

Efficacy/Safety Study–Postmenopausal Osteoporosis
Clinical Study Protocol with Amendment 02
Study TVB009-IMB-30085
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AMENDMENT HISTORY
The protocol for study TVB009-IMB-30085 (original protocol dated 09 December 2020) has 
been revised and reissued as follows:
Amendment 01
03 February 2021
No patients enrolled to date
Local Amendment 01 for Germany
19 May 2021
No patients enrolled to date
Amendment 02
29 June 2021
14 patients enrolled to date
The Summary of Changes to the Protocol includes the corresponding reason/justification for 
each change and is provided in Section 16.

Efficacy/Safety Study–Postmenopausal Osteoporosis
Clinical Study Protocol with Amendment 02
Study TVB009-IMB-30085
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INVESTIGATOR AGREEMENT
Clinical Study Protocol with Amendment 02 
Study TVB009-IMB-30085
A Randomized, Double-Blind, Multinational, Multicenter Study to Compare Efficacy, 
Safety, and Immunogenicity of TVB-009P and Denosumab (PROLIA®) in Patients with 
Postmenopausal Osteoporosis
Version Date: 29 June 2021
Principal Investigator: 
Title:
Address of Investigational Center:
Tel:
I have read the protocol with Amendment 02 and agree that it contains all necessary details for 
carrying out this study. I am qualified by education, experience, and training to conduct this 
clinical research study. The signature below constitutes agreement with this protocol and 
attachments, and provides assurance that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according to 
national or local legal and regulatory requirements and applicable regulations and guidelines.
I will make available the protocol and all information on the investigational medicinal product 
(IMP) that were furnished to me by the sponsor to all physicians and other study personnel 
reporting to me who participate in this study and will discuss this material with them to ensure 
that they are fully informed regarding the IMP and the conduct of the study. I agree to keep 
records on all patient information, IMP shipment and return forms, and all other information 
collected during the study, in accordance with national and local GCP regulations as well as all 
other national and international laws and regulations.
Principal Investigator
Signature
Date
Executed signature pages are maintained separately within the Trial Master File

Efficacy/Safety Study–Postmenopausal Osteoporosis
Clinical Study Protocol with Amendment 02
Study TVB009-IMB-30085
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CLINICAL STUDY PROTOCOL SYNOPSIS
With Amendment 02 
Study TVB009-IMB-30085
Title of Study: A Randomized, Double-Blind, Multinational, Multicenter Study to Compare 
Efficacy, Safety, and Immunogenicity of TVB-009P and Denosumab (PROLIA®) in Patients 
with Postmenopausal Osteoporosis
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Investigational New Drug (IND) Number: 137313
New Drug Application (NDA) 
Number: na
Biologics License Application (BLA) Number: naEuropean Drug Regulatory 
Authorities Clinical Trials (EudraCT) Number: 2020-005548-48
European Medicines Agency (EMA) Decision number of Pediatric Investigation Plan: 
Article 45 or 46 of 1901/2006 does not apply
Name of Investigational Medicinal Products (IMP): Test IMP: TVB-009 (denosumab) 
solution for injection 60 mg/mL (1 mL) prefilled syringe (PFS) (TVB-009P). Reference 
IMP: PROLIA United States (US) (denosumab) solution for injection 60 mg/mL (1 mL) PFS.
EudraVigilance (EV) code for the IMP, if applicable: Not applicable
Type of Study: Efficacy and safety (Phase 3)
Indication: Postmenopausal osteoporosis (PMO)
Is this study conducted to investigate the New Use of an approved, marketed product? No
Number of Investigational Centers Planned: The study is planned to be conducted in 
approximately 75 investigational centers
Countries Planned: The study is planned to be conducted in approximately 10 countries
Number of Patients Planned (total): Approximately 326 patients (163 per arm) will be 
randomized to achieve approximately
 at the end of the main 
52-week treatment period.
Study Population: Female adult patients with PMO ≥60 and ≤90 years of age
Primary and Secondary Objectives and Endpoints: The objectives of this study are to 
demonstrate that there are no clinically meaningful differences in efficacy, safety, and 
immunogenicity between TVB-009P and PROLIA US administered subcutaneously (sc) in 
patients with PMO. The primary and secondary study objectives and endpoints are presented 
below.

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Primary and Secondary Study Objectives and Endpoints
Objectives
Endpoints
The primary objective of the study is 
to demonstrate that there are no 
clinically meaningful differences in 
efficacy between TVB-009P and 
PROLIA US administered 
subcutaneously in patients with 
postmenopausal osteoporosis.
The primary efficacy endpoint is 

the percent change from baseline in lumbar spine-bone mineral 
density (LS-BMD) at week 52 based on centrally assessed 
dual-energy X-ray absorptiometry (DXA) measurements

The co-primary efficacy endpoint for the European Union (EU) 
submission is the percent change from baseline in serum 
C-telopeptide cross-link of type 1 collagen (sCTX-1) at 
week 26. For the EU submission, this endpoint is regarded as
co-primary. For the United States (US) submission, this 
endpoint is regarded as secondary
A secondary objective is to compare 
further efficacy and pharmacodynamic 
parameters between TVB-009P and 
PROLIA US.
The secondary efficacy and pharmacodynamic endpoints are:

percent change from baseline in LS-BMD at week 26 based on 
centrally assessed DXA measurements

percent change from baseline in femoral neck bone mineral 
density (BMD) by DXA at week 26 and at week 52

percent change from baseline in total hip BMD by DXA at 
week 26 and at week 52

percent change from baseline in sCTX-1 at all time points

sCTX-1 suppression at week 4

percent change from baseline in procollagen type 1 N propeptide 
(P1NP) at week 26 and week 52

incidence of fractures up to week 52
A secondary objective of the study is 
to compare efficacy and 
pharmacodynamic parameters 
between TVB-009P and PROLIA US
after a single transition from PROLIA
US to TVB-009P.
The pharmacodynamic/efficacy endpoints in the transition period are:

percent change from week 52 in LS-BMD by DXA at week 78

difference between percent change from baseline in sCTX-1 
between week 52 and week 78

percent change from week 52 in femoral neck BMD by DXA at 
week 78

percent change from week 52 in total hip BMD by DXA at 
week 78

difference between percent change from baseline in P1NP 
between week 52 and week 78

incidence of fractures up to week 78
A secondary objective of this study is 
to compare the safety and tolerability, 
including device-related events, 
between TVB-009P and PROLIA US
throughout the study.
A secondary objective of this study is 
to compare the safety and tolerability 
between TVB-009P and PROLIA US
after a single transition from PROLIA
US to TVB-009P, including 
device-related events.
The safety and tolerability endpoints are:

adverse events (and the number of patients who withdraw from 
the study due to adverse events)

vital signs

laboratory tests (hematology, serum chemistry, and urinalysis)

electrocardiogram (ECG)

local tolerability at injection site

use of concomitant medications

device-related adverse events and malfunctions
A secondary objective of this study is 
The immunogenicity endpoint is:

Efficacy/Safety Study–Postmenopausal Osteoporosis
Clinical Study Protocol with Amendment 02
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Objectives
Endpoints
to assess the immunogenicity of 
TVB-009P in comparison with 
PROLIA US throughout the study.
A secondary objective of this study is 
to assess the immunogenicity of 
TVB-009P in comparison with 
PROLIA US after a single transition 
from PROLIA US to TVB-009P.

incidence of patients with confirmed positive anti-drug antibody 
(ADA) sample
For confirmed positive samples, the ADA titer and the neutralizing 
potential will be tested.
The effect of positive immunogenicity findings on pharmacokinetics, 
efficacy, and safety will be assessed if applicable.
Exploratory Objectives and Endpoints
Objectives
Endpoints
An exploratory objective of this 
study is to compare pharmacokinetics 
between TVB-009P and PROLIA US 
throughout the study.
The pharmacokinetic endpoints are:

serum concentration before next dose (Ctrough), before second 
and third dose, and 6 months after third dose

serum concentration at 2 weeks postdose (C2weeks)
Pharmacokinetic endpoints derived from population pharmacokinetics 
analysis are:

area under the curve over the dosing period (AUC0-tau) after first 
dose

Ctrough before second dose

maximum observed concentration (Cmax) after first dose
Primary Estimand:
The primary estimand assesses clinically meaningful differences in effectiveness in patients with 
PMO, based on surrogate measures, focusing on the causal effects attributable to the IMP.
The primary estimand is the difference in mean percent change in lumbar spine-bone mineral 
density (LS-BMD) from baseline at week 52 between TVB-009P and PROLIA US treatment 
arms, regardless of intercurrent events, in the target population of patients with PMO who 
receive at least one dose of IMP and have both a baseline and at least 1 post-baseline assessment 
of LS-BMD. For the submission in the US, this estimand is regarded as primary and for the 
submission in the European Union (EU), this estimand is regarded as co-primary.
The co-primary estimand for the EU filing is the difference in mean percent change in serum C 
telopeptide cross link of type 1 collagen (sCTX-1) from baseline at week 26, between TVB-009P 
and PROLIA US treatment arms, regardless of intercurrent events in the target population of 
patients with PMO. The same analysis set will be used for both estimands and therefore patients 
who terminate before week 26 will not be included in the sCTX-1 analysis. For the EU 
submission, this estimand is regarded as co-primary. For the US submission, this estimand is 
regarded as secondary.
General Study Design: This is a multinational, multicenter, randomized, double-blind study to 
demonstrate similar efficacy and safety of TVB-009P compared to PROLIA US over 78 weeks 
administered sc at doses of 60 mg every 26 weeks (3 injections) in patients with PMO. 

Efficacy/Safety Study–Postmenopausal Osteoporosis
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blinding of the sponsor until the main treatment period is unblinded, the re-randomization 
process will be performed for all patients, including the patients in the TVB-009P group.
Investigational Medicinal Products: Dose, Pharmaceutical Form, Route of Administration, 
and Administration Rate
IMP name
Test IMP
Reference IMP
Trade name or company-assigned 
number
TVB-009P
PROLIA US
Formulation
Active
60 mg/mL
60 mg/mL
Acetate
17 mM
17 mM
Sorbitol
4.7%
4.7%
Polysorbate 20
0.01%
0.01%
Sodium hydroxide
pH to 5.2
pH to 5.2
Water for injection
qs to 1 mL
qs to 1 mL
Unit dose strength(s)/Dosage level(s)
60 mg/mL
60 mg/dose
60 mg/mL 
60 mg/dose
Route of administration
sc injection
sc injection
Device
Automatically activated needle 
safety guard
Manually activated needle safety 
guard
Manufacturer
Teva Branded Pharmaceutical 
Products R&D, Inc., West 
Chester, Pennsylvania, USA
Amgen Inc., One Amgen Center 
Drive, Thousand Oaks, California 
91320-1799, USA
Storage conditions
2°C to 8°C (36°F to 46°F), 
protected from direct light and 
heat. Avoid vigorous shaking
2°C to 8°C (36°F to 46°F), 
protected from direct light and 
heat. Avoid vigorous shaking
IMP=investigational medicinal product; PFS=prefilled syringe; qs=quantum satis; sc=subcutaneous; US=United 
States; USA=United States of America
Duration of Patient Participation and Maximal Exposure to IMP: The total duration of 
patient participation in the study is planned to be approximately 82 weeks including up to an 
approximate 4-week screening period, approximately a 52-week double-blind main treatment 
period, and an approximately 26-week double-blind transition period. Patients will receive a 
maximum of three injections of 60 mg denosumab.
End of Study: EOS is defined as the last visit of the last patient of the transition period.
Plans for Treatment or Care after the Patient Has Ended Participation in the Study: After 
study end, no IMP will be provided as PROLIA is commercially available.
Selection of Patients/Study Population
Inclusion Criteria: Patients may be included in this study only if they meet all of the following 
criteria:
a.
The patient provides a signed and dated written informed consent.
b. The patient is a clinically stable, ambulatory, female postmenopausal adult (≥60 and 
≤90 years) with a diagnosis of osteoporosis.

Efficacy/Safety Study–Postmenopausal Osteoporosis
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c.
The patient is of postmenopausal status, defined as:

Spontaneous amenorrhea for >12 months, or

Spontaneous amenorrhea >6 months and serum follicle stimulating hormone 
(FSH) and estradiol (E2) in menopausal range, or

Surgical menopause at least 6 weeks before the start of screening.
d. The patient has a body weight ≥50 kg and ≤90 kg (≥110 lb and ≤198 lb) at screening.
e.
The patient agrees to be supplemented with 1000 mg calcium and at least 400 IU 
vitamin D daily from screening until the last visit.
f.
The patient has a bone mineral density (BMD)-measurement T-score of less than -2.5 
but not less than -4.0 by dual energy X-ray absorptiometry (DXA) at the lumbar spine 
at screening based on central reader assessment.
g. The patient has at least 3 (three) vertebrae in the L1-L4 region that are evaluable by 
DXA.
h. The patient has serum 25 (OH) vitamin D level >20 ng/mL at screening and no 
current hyper- or hypocalcemia, defined as albumin-adjusted serum calcium outside 
the normal range, as assessed by the central laboratory. Vitamin D and calcium 
supplements will be provided and patients may be rescreened once to re-evaluate 
calcium and/or vitamin D level post repletion.
i.
The patient must be willing and able to comply with study restrictions and to remain 
at the investigational center for the required duration during the study period, and 
willing to return to the investigational center for further visits, as applicable, and the 
follow-up procedures and assessments as specified in this protocol.
Exclusion Criteria: Patients will be excluded from participating in this study if they meet any of 
the following criteria:
a.
The patient has a known malabsorption of calcium or vitamin D supplements.
b. The patient has a metabolic or bone disease (except osteoporosis) such as Paget’s 
disease, Cushing’s disease, rheumatoid arthritis, sclerosteosis, osteomalacia, 
osteogenesis imperfecta, osteopetrosis, ankylosing spondylitis, hyperprolactinemia, 
malabsorption syndrome, osteomyelitis, multiple myeloma or related 
lymphoproliferative disorder, or bone metastases.
c.
The patient has a current, uncontrolled hyperthyroidism or hypothyroidism, per 
patient report or chart review.
d. The patient has hypoparathyroidism or hyperparathyroidism (irrespective of current 
controlled or uncontrolled status).
e.
The patient has a history and/or presence of risk factors of osteonecrosis of the jaw, as 
determined by the principal investigator, (eg, unhealed open soft tissue lesions in the 
mouth, poor oral hygiene, periodontal disease, poorly fitting dentures, history of 
dental disease, recent or planned invasive dental procedures such as tooth extractions 

Efficacy/Safety Study–Postmenopausal Osteoporosis
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within the next 18 months), presence of anemia or coagulopathy at screening, and/or 
inability to maintain oral hygiene during the study.
f.
The patient has a history and/or presence of 1 severe or more than 2 moderate 
vertebral fractures (as determined by central reading of lateral spine X-ray during the 
screening period).
g. The patient has a history and/or presence of hip fracture or atypical femur fracture.
h. The patient has participated in another study of an IMP (or a medical device) within 
the previous 30 days or 5 half-lives of the IMP (whichever is longer) or longer if 
required by local regulations, or is currently participating in another study of an IMP 
(or a medical device).
i.
The patient has a known hypersensitivity to any components of the IMPs stated in this 
protocol or to calcium or vitamin D.
j.
The patient has a renal impairment manifested with an estimated glomerular filtration 
rate (eGFR) <45 mL/min.
k. The patient has cardiac disease as per investigator's discretion, including 
electrocardiogram (ECG) abnormalities at screening indicating significant risk of 
safety for patients participating in the study.
l.
The patient has a malignancy or past malignancy (except for local non-melanoma 
skin cancer fully resected).
m. The patient has a current skin infection(s).
n. The patient has infectious disease:

Acute infection and/or antibiotic treatment must be resolved 28 days prior to the 
first dose of IMP.

Any relevant chronic infection.

Ongoing hepatitis B, hepatitis C, human immunodeficiency virus (HIV) Types 1 
or 2 infection.

Positive test for coronavirus disease 2019 (COVID-19) during screening or 
patient reporting a recent history of confirmed COVID-19 which had not fully 
recovered more than 14 days before screening.
o. The patient has any medical condition that (treated or untreated), in the opinion of the 
investigator, could jeopardize or would compromise the patient’s safety or ability to 
participate in this study.
p. The patient has had any prior treatment with denosumab (PROLIA or XGEVA or 
biosimilars of denosumab products).
q. The patient has used intravenous bisphosphonates within less than 5 years prior to 
screening.
r.
The patient has used oral bisphosphonates within the 12 months prior to start of 
screening and/or cumulative use >3 years before the start of screening.

Efficacy/Safety Study–Postmenopausal Osteoporosis
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For continuous variables, descriptive statistics will be provided for actual values and changes 
from baseline to each time point. For categorical variables, patient counts and percentages will 
be provided.
If any patient dies during the study, a listing of deaths will be provided and all relevant 
information will be discussed in the patient narrative included in the clinical study report (CSR).
Tolerability Analysis: If more than 10% of the patients withdraw from the study before the end 
of the main treatment period, the number of days until study discontinuation will be analyzed 
using Kaplan-Meier methodology.
Pharmacokinetic Analysis: The following exploratory pharmacokinetic parameters will be 
summarized using descriptive statistics:

serum concentration before next dose (Ctrough), before second and third dose, and 6 
months after third dose

serum concentration at 2 weeks postdose (C2weeks)
Details of the pharmacokinetic analysis of the area under the curve over the dosing period 
(AUC0-tau) after first dose derived from population pharmacokinetics analysis, Ctrough before 
second dose derived from population pharmacokinetics analysis, and maximum observed 
concentration (Cmax) after first dose derived from population pharmacokinetic analysis will be 
given in a separate TVB-009P population pharmacokinetic statistical analysis plan. The results 
of the population pharmacokinetic analysis will be provided in a separate report.
Immunogenicity Analysis: The immunogenicity analysis of TVB-009P, PROLIA US and 
PROLIA US/TVB-009P treatment groups will be performed after completion of the main 
treatment period at week 52 and after the completion of the transition period at week 78 (EOS).
Results of immunogenicity assessment will be listed. If more than 5 patients develop anti-drug 
antibody (ADA) anytime post-baseline, the incidence of ADA positive patients will be 
summarized by treatment group, and ADA status (positive/negative), titer level, and neutralizing 
ADA positive/negative will be summarized at each visit using descriptive statistics. The effect of 
positive immunogenicity findings on efficacy and safety may be investigated, if applicable.
Sequence of Final Analyses: Upon completion of the main treatment period the sponsor will 
unblind the main treatment period (up to and including week 52; not including third IMP dose 
and assessments following the third dose), while keeping the investigators (and other site staff 
involved in study assessments) and the patients blinded. A CSR that contains the results of the 
analysis of the main treatment period (up to and including week 52) will be submitted with the 
filing of the Marketing Authorisation Application (MAA) and/or the Biologics License 
Application (BLA). The results of the analysis of the transition period (up to and including 
week 78) will be included in a CSR addendum that is planned to be submitted in the BLA or 
during the 4-Month Safety Update after filing of the BLA and at the earliest opportunity during 
the MAA procedure.

Efficacy/Safety Study–Postmenopausal Osteoporosis
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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
AMENDMENT HISTORY .............................................................................................................2
INVESTIGATOR AGREEMENT...................................................................................................4
COORDINATING INVESTIGATOR AGREEMENT...................................................................5
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................6
LIST OF ABBREVIATIONS........................................................................................................24
1.
INTRODUCTION AND BACKGROUND INFORMATION ..................................28
1.1.
Introduction.................................................................................................................28
1.1.1.
TVB-009.....................................................................................................................28
1.1.2.
TVB-009 and Postmenopausal Osteoporosis .............................................................28
1.1.3.
Purpose of the Study...................................................................................................29
1.2.
Findings from Nonclinical and Clinical Studies.........................................................29
1.2.1.
Nonclinical Studies.....................................................................................................29
1.2.2.
Clinical Studies...........................................................................................................29
1.2.2.1.
Pharmacokinetics........................................................................................................30
1.2.2.2.
Pharmacodynamics.....................................................................................................30
1.2.2.3.
Safety and immunogenicity........................................................................................30
1.3.
Known and Potential Benefits and Risks to Patients..................................................31
1.3.1.
Known and Potential Benefits and Risks of the Test Investigational 
Medicinal Product(s) ..................................................................................................31
1.3.2.
Known and Potential Benefits and Risks of Reference Investigational 
Medicinal Product.......................................................................................................31
1.3.3.
Overall Benefit and Risk Assessment.........................................................................32
2.
STUDY OBJECTIVES AND ENDPOINTS..............................................................33
2.1.
Primary and Secondary Study Objectives and Endpoints ..........................................33
2.1.1.
Justification of Primary Endpoint...............................................................................35
3.
STUDY DESIGN .......................................................................................................36
3.1.
General Study Design and Study Schematic Diagram ...............................................36
3.2.
Planned Number of Patients and Countries................................................................37
3.3.
Justification for Study Design and Selection of Population.......................................37
3.4.
Stopping Rules for the Study......................................................................................38
3.5.
Schedule of Study Procedures and Assessments........................................................38

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4.
SELECTION AND WITHDRAWAL OF PATIENTS..............................................43
4.1.
Patient Inclusion Criteria ............................................................................................43
4.2.
Patient Exclusion Criteria...........................................................................................43
4.3.
Withdrawal Criteria and Procedures for the Patient...................................................46
4.4.
Replacement of Patients .............................................................................................47
4.5.
Rescreening.................................................................................................................47
4.6.
Screening Failure........................................................................................................47
5.
TREATMENTS..........................................................................................................48
5.1.
Investigational Medicinal Products Used in the Study...............................................48
5.1.1.
Test Investigational Medicinal Product......................................................................48
5.1.2.
Reference Investigational Medicinal Product.............................................................48
5.1.3.
Non-Investigational Medicinal Product Supplementation Treatment ........................49
5.1.4.
Medical Devices .........................................................................................................50
5.2.
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products ............................................................................50
5.2.1.
Storage and Security...................................................................................................50
5.2.2.
Labeling......................................................................................................................50
5.2.3.
Accountability.............................................................................................................50
5.3.
Justification for Investigational Medicinal Products..................................................51
5.3.1.
Justification for Dose of Test Investigational Medicinal Product ..............................51
5.3.2.
Justification for Use of Reference Investigational Medicinal Product.......................51
5.4.
Treatment After the End of the Study.........................................................................51
5.5.
Restrictions .................................................................................................................51
5.6.
Prior and Concomitant Medication or Therapy..........................................................51
5.7.
Procedures for Monitoring Patient Compliance .........................................................52
5.8.
Randomization and Blinding......................................................................................52
5.9.
Maintenance of Randomization and Blinding............................................................53
5.9.1.
Maintenance of Randomization..................................................................................53
5.9.2.
Blinding and Unblinding ............................................................................................53
5.9.3.
Data Monitoring Committee.......................................................................................54
5.10.
Total Blood Volume ...................................................................................................54
6.
ASSESSMENT OF EFFICACY AND PHARMACODYNAMICS..........................55
6.1.
Assessments of Efficacy.............................................................................................55

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6.1.1.
Lumbar Spine-Bone Mineral Density by Dual-Energy X-Ray 
Absorptiometry...........................................................................................................55
6.1.2.
Total Hip and Femoral Neck Bone Mineral Density by Dual-Energy X-Ray 
Absorptiometry...........................................................................................................55
6.1.3.
Lateral Spine X-Ray Vertebral Fracture Assessment.................................................56
6.1.4.
Assessment of Nonvertebral Fractures.......................................................................56
6.2.
Pharmacodynamics Assessment.................................................................................56
7.
ASSESSMENT OF SAFETY.....................................................................................57
7.1.
Adverse Events ...........................................................................................................57
7.1.1.
Definition of an Adverse Event..................................................................................57
7.1.2.
Recording and Reporting of Adverse Events .............................................................58
7.1.3.
Severity of an Adverse Event .....................................................................................58
7.1.4.
Relationship of an Adverse Event to the Investigational Medicinal Product.............59
7.1.5.
Serious Adverse Events..............................................................................................59
7.1.5.1.
Definition of a Serious Adverse Event .......................................................................59
7.1.5.2.
Expectedness...............................................................................................................60
7.1.5.3.
Reporting a Serious Adverse Event............................................................................61
7.1.6.
Protocol-Defined Adverse Events of Special Interest ................................................63
7.1.7.
Protocol Deviations Because of an Adverse Event ....................................................63
7.2.
Adverse Device Effects ..............................................................................................63
7.2.1.
Adverse Device Effect Reporting...............................................................................63
7.2.2.
Serious Adverse Device Effects .................................................................................63
7.2.2.1.
Serious Adverse Device Effect Reporting..................................................................64
7.3.
Clinical Laboratory Tests ...........................................................................................64
7.3.1.
Serum Chemistry, Hematology, and Urinalysis .........................................................65
7.3.2.
Other Clinical Laboratory Tests .................................................................................66
7.3.2.1.
Follicle Stimulating Hormone ....................................................................................66
7.3.2.2.
Estradiol......................................................................................................................66
7.3.2.3.
Urine Pregnancy Test .................................................................................................66
7.3.2.4.
Vitamin D ...................................................................................................................66
7.3.2.5.
Coronavirus Disease 2019 Testing.............................................................................66
7.4.
Physical Examinations................................................................................................66
7.5.
Vital Signs ..................................................................................................................66

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7.6.
Electrocardiography....................................................................................................67
7.7.
Assessment of Local Tolerability and Pain ................................................................67
7.8.
Pregnancy ...................................................................................................................68
7.9.
Medication Error and Special Situations Related to the Investigational 
Medicinal Products.....................................................................................................68
8.
ASSESSMENT OF PHARMACOKINETICS AND IMMUNOGENICITY............70
8.1.
Pharmacokinetic Assessment......................................................................................70
8.2.
Immunogenicity Testing.............................................................................................70
9.
STATISTICS ..............................................................................................................71
9.1.
Sample Size and Power Considerations .....................................................................71
9.2.
Analysis Sets...............................................................................................................71
9.2.1.
Intent-to-Treat Analysis Set........................................................................................71
9.2.2.
Modified Intent-to-Treat Analysis Set........................................................................71
9.2.3.
Safety Analysis Set.....................................................................................................72
9.2.4.
Per-Protocol Analysis Set...........................................................................................72
9.2.5.
Transition Intent-to-treat Analysis Set........................................................................72
9.2.6.
Transition Modified Intent-to-treat Analysis Set........................................................72
9.2.7.
Transition Safety Analysis Set....................................................................................72
9.3.
Data Handling Conventions........................................................................................73
9.3.1.
Handling Withdrawals and Missing Data...................................................................73
9.3.2.
Handling Below the Limit of Quantitation.................................................................73
9.4.
Study Population.........................................................................................................73
9.4.1.
Patient Disposition......................................................................................................73
9.4.2.
Demographic and Baseline Characteristics ................................................................74
9.5.
Efficacy and Pharmacodynamic Analysis ..................................................................74
9.5.1.
Primary Endpoint........................................................................................................74
9.5.2.
Secondary Endpoints ..................................................................................................74
9.5.3.
Efficacy and Pharmacodynamic Endpoints in the Transition Period.........................75
9.5.4.
Primary Efficacy Analysis..........................................................................................75
9.5.4.1.
Sensitivity/Supportive Analysis for the Primary Analysis .........................................76
9.5.4.2.
Supplementary Analysis for the Primary Analysis.....................................................76
9.5.4.3.
Secondary Efficacy and Pharmacodynamic Analysis ................................................77
9.5.4.4.
Efficacy and Pharmacodynamic Analysis in the Transition Period ...........................77

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9.6.
Multiple Comparisons and Multiplicity......................................................................78
9.7.
Safety Analysis ...........................................................................................................78
9.7.1.
Safety Analysis in the Main Treatment Period...........................................................79
9.7.2.
Safety Analysis in the Transition Period ....................................................................79
9.7.3.
Safety Analysis in the Overall Treatment Period .......................................................79
9.8.
Pharmacokinetic Analysis ..........................................................................................79
9.9.
Immunogenicity Analysis...........................................................................................79
9.10.
Sequence of Final Analyses........................................................................................80
9.11.
Reporting Deviations from the Statistical Plan ..........................................................80
10.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................81
11.
COMPLIANCE STATEMENT..................................................................................81
12.
DATA MANAGEMENT AND RECORD KEEPING ..............................................81
13.
FINANCING AND INSURANCE.............................................................................82
14.
PUBLICATION POLICY ..........................................................................................82
15.
REFERENCES ...........................................................................................................83
16.
SUMMARY OF CHANGES TO THE PROTOCOL ................................................85
16.1.
Protocol Amendment 02 dated 29 June 2021.............................................................85
16.2.
Local Protocol Amendment 01 for Germany dated 19 May 2021 .............................92
16.3.
Protocol Amendment 01 dated 03 February 2021......................................................92
APPENDIX A.
CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND 
INSTITUTIONS.........................................................................................................94
APPENDIX B.
STUDY PROCEDURES AND ASSESSMENTS BY VISIT...........................96
APPENDIX C.
QUALITY CONTROL AND QUALITY ASSURANCE ..............................105
APPENDIX D.
ETHICS ...........................................................................................................107
APPENDIX E.
LOST TO FOLLOW-UP .................................................................................108
APPENDIX F.
LIST OF PROHIBITED MEDICATIONS......................................................109
APPENDIX G.
CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS...................110
APPENDIX H.
PRODUCT COMPLAINTS............................................................................111
APPENDIX I.
PHARMACOKINETICS AND PHARMACODYNAMICS ...........................114
APPENDIX J.
IMMUNOGENICITY SAMPLES ...................................................................115
APPENDIX K.
DATA MANAGEMENT AND RECORD KEEPING ...................................116
APPENDIX L.
PUBLICATION POLICY................................................................................119

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APPENDIX M.
MANAGEMENT OF STUDY ACTIVITIES DURING COVID-19 
OUTBREAKS ..........................................................................................................120

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LIST OF TABLES
Table 1:
Study Procedures and Assessments............................................................................39
Table 2:
Investigational Medicinal Products Used in the Study...............................................49
Table 3:
The Relationship of an Adverse Event to the Investigational Medicinal 
Product........................................................................................................................59
Table 4:
Clinical Laboratory Tests ...........................................................................................65
Table 5:
Severity Assessment of Local Tolerability.................................................................68

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LIST OF FIGURES
Figure 1:
Overall Study Schematic Diagram .............................................................................37
Figure 2:
Decision Tree for Adverse Events and Adverse Device Effects Classification .........64
Figure 3:
Decision Tree for Device Deficiencies.....................................................................113

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LIST OF ABBREVIATIONS
Abbreviation
Term
Ab
antibodies
ADA
anti-drug antibody
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC0-tau
area under the curve over the dosing period
BLA
Biologics License Application
BLQ
below limit of quantitation
BMD
bone mineral density
BP
blood pressure
C2weeks
serum concentration at 2 weeks postdose
CDC
complement dependent cytotoxicity
CDMS
clinical data management system
CFR
Code of Federal Regulations (USA)
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximum observed concentration
COVID-19
coronavirus disease 2019
CRF
case report form (refers to any media used to collect study data [ie, paper or electronic])
CRO
Contract Research Organization
CSR
Clinical Study Report
Ctrough
serum concentration before next dose
DBL
database lock
DNA
deoxyribonucleic acid
DXA
dual-energy X-ray absorptiometry
E2
estradiol
ECG
electrocardiogram
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOM
end of main treatment period
EOS
end of study

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Abbreviation
Term
ET
early termination
EU
European Union
EudraCT
European Drug Authorities Clinical Trials
Fab
antigen-binding fragment
Fc
crystallizable fragment
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
GBT
Biologics, Assays & Technology
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GPSP
Global Patient Safety and Pharmacovigilance
GCA
Global Quality Assurance
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HEENT
head, eyes, ears, nose, and throat
IB
Investigator’s Brochure
ICF
informed consent form
ICH
The International Council on Harmonisation
IEC
Independent Ethics Committee
IgG2
immunoglobulin G2
IMP
investigational medicinal product
IND
Investigational New Drug
INN
international nonproprietary name
IRB
Institutional Review Board
ITT
intent-to-treat
iv
intravenous
LLOQ
lower limit of quantification
LS-BMD
Lumbar spine-bone mineral density
LSO
local safety officer
MAA
Marketing Authorisation Application
mAb
monoclonal antibody
MAR
missing at random
MDRD
Modification of Diet in Renal Disease

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Abbreviation
Term
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
MNAR
missing not at random
n
number
NRS-11
11-point pain intensity numerical response scale
OH
hydroxy
ONJ
osteonecrosis of the jaw
P1NP
procollagen type 1 N propeptide
PEF
peak expiratory flow
PFS
pre-filled syringe
PI
Prescribing Information
PMO
postmenopausal osteoporosis
PP
per-protocol
PT
preferred term
PTH
parathyroid hormone
qs
quantum
RANK
receptor activator of nuclear factor kappa-B
RANKL
receptor activator of nuclear factor kappa-Β ligand
RSI
reference safety information
RTSM
Randomization and Trial Supply Management
SMP
SAE Management Plan
SAP
statistical analysis plan
sc
subcutaneous/ly
sCTX-1
serum C-telopeptide cross-link of type 1 collagen
SD
standard deviation
SERM
selective estrogen receptor modulator
SOC
system organ class
SOP
standard operating procedure
SPC
Summary of Product Characteristics
SUSAR
suspected unexpected serious adverse reaction
TmITT
transition modified intent-to-treat
ULN
upper limit of normal
US
United States
USA
United States of America

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Abbreviation
Term
USPI
United States Prescribing Information
V
visit
VC
videoconference
W
week
WHO
World Health Organization
WHODrug
World Health Organization Drug Dictionary
XML
Extensible Markup Language

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1.
INTRODUCTION AND BACKGROUND INFORMATION
1.1.
Introduction
1.1.1.
TVB-009
TVB-009 is a fully human immunoglobulin G2 (IgG2)/kappa monoclonal antibody (mAb) 
directed against receptor activator of nuclear factor kappa-Β ligand (RANKL), which is being 
developed by Teva as a biosimilar candidate to PROLIA2 and XGEVA3 with the active 
substance denosumab. Denosumab is currently licensed as PROLIA and XGEVA, both being 
first approved in the US in 2010, and in the EU in 2010 (PROLIA) and 2011 (XGEVA). 
TVB-009 has been engineered by the development of deoxyribonucleic acid (DNA) vectors 
encoding a protein that is 100% identical to the amino acid sequence of denosumab heavy and 
light chains.
Biosimilarity assessment results, from functional assays of both the antigen-binding fragment 
(Fab) and crystallizable fragment (Fc) domain-related activity, demonstrate that TVB-009 values 
were generally in the range or similar to US-licensed PROLIA reference product for all critical 
product parameters related to the denosumab mechanism of action. Minor differences were 
observed in the disulfide isoform distribution, and complement dependent cytotoxicity (CDC) 
activity but these differences were not considered to be clinically meaningful. Analytical 
(structural and functional) evaluation demonstrates TVB-009 similarity to PROLIA based on 
substantial data, risk assessment and totality of evidence approach.
Several molecular signals are involved in regulating bone resorption by osteoclasts and bone 
formation by osteoblasts during the process of normal bone remodeling. In particular, RANKL is 
a key activator of osteoclasts. Binding to its receptor, receptor activator of nuclear factor 
kappa-B (RANK), on osteoclast precursors and mature osteoclasts promotes the terminal 
differentiation, activation, and survival of osteoclasts, which in turn stimulate bone resorption. 
Denosumab targets the process of bone resorption by binding with a high degree of specificity 
and affinity to RANKL, preventing the activation of RANK and thus, the stimulation of 
osteoclasts (Sohn et al 2014). Due to its key role in osteoclast activation, RANKL is instrumental 
in facilitating osteoclast-induced bone resorption across a range of bone diseases.
1.1.2.
TVB-009 and Postmenopausal Osteoporosis
Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to 
an increased risk of fracture. Osteoporosis causes more than 8.9 million fractures annually 
worldwide, of which more than 4.5 million occur in the Americas and Europe (World Health 
Organization [WHO] 2004). According to the WHO diagnostic classification, osteoporosis is 
defined by bone mineral density (BMD) at the hip or lumbar spine that is less than or equal to 
                                                
2 PROLIA is a registered trademark of Amgen, Inc.
3 XGEVA is a registered trademark of Amgen, Inc.

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2.5 standard deviations (SD)s below the mean BMD of a young-adult reference population 
(Cosman et al 2014).
Osteoporosis in postmenopausal women and elderly men has been linked to estrogen deficiency 
(Riggs 2000). Estrogen is critical for skeletal homeostasis and regulation of bone remodeling, in 
part, by modulating the expression of RANKL (Streicher et al 2017). Current Food and Drug 
Administration (FDA)-approved pharmacologic options for osteoporosis are bisphosphonates, 
calcitonin, estrogen agonist/antagonist, estrogens and/or hormone therapy, tissue-selective
estrogen complex, parathyroid hormone 1-34, and RANK ligand inhibitor (denosumab) (Cosman 
et al 2014).
TVB-009 is intended in the US for the same indications as PROLIA US and TVB-009 is 
intended in Europe for the same indications as PROLIA EU. PROLIA is currently approved for 
treatment of postmenopausal women with osteoporosis at high risk for fracture; treatment to 
increase bone mass in men with osteoporosis; treatment of glucocorticoid-induced osteoporosis; 
treatment of bone loss in men receiving androgen-deprivation therapy for prostate cancer; 
treatment of bone loss in women receiving adjuvant-aromatase-inhibitor therapy for breast 
cancer (US only) (PROLIA United States Prescribing Information [USPI] 2020; PROLIA 
Summary of Product Characteristics [SPC] 2020).
1.1.3.
Purpose of the Study
TVB-009 is a biosimilar candidate for PROLIA. The purpose of the study is to compare the 
efficacy, safety, and immunogenicity of TVB-009P and PROLIA US in patients with 
postmenopausal osteoporosis (PMO).
1.2.
Findings from Nonclinical and Clinical Studies
1.2.1.
Nonclinical Studies
Teva has addressed the nonclinical requirements in the development of TVB-009 as a biosimilar 
candidate to PROLIA in a single-dose comparative study with a 43-day follow-up period in 
cynomolgus monkeys, under Good Laboratory Practice (GLP). Results indicate similar safety 
characteristics, pharmacodynamics in terms of bone turnover biochemical markers, and exposure 
of the investigational medicinal products (IMP)s and support the safety of the planned clinical 
trials.
Further information can be found in the current version of the TVB-009 Investigator’s Brochure 
(IB).
1.2.2.
Clinical Studies
Clinical data for TVB-009P are available from a single study (Study TVB009-BE-10157). This 
first-in-human study was a randomized, double-blind, single-dose, parallel-group, 3-arm study to 
investigate the pharmacokinetic, pharmacodynamic, and safety similarity of 60 mg TVB-009P 
versus 60 mg denosumab (PROLIA US and PROLIA EU) in healthy subjects.
A total of 345 healthy subjects were enrolled into the study and randomly assigned to receive a 
single subcutaneous (sc) injection of

60 mg TVB-009P (115 subjects), or

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A total of 106 subjects (31%) reported at least 1 treatment-emergent adverse event. The 
percentage of subjects who reported at least 1 adverse event was slightly lower in the TVB-009P 
group (27%) than in the PROLIA US (33%) and PROLIA EU (32%) groups.
There were no clinically meaningful differences observed between the treatment groups for 
adverse events, laboratory tests, vital signs, electrocardiograms, and physical examination 
findings. 
Most subjects (>95%) did not report any injection site findings. The only finding reported for 
more than 1 subject was mild erythema (surface diameter of 5 mm to ≤50 mm) at 20 minutes 
post-dose (12 subjects [3%], 3-5 subjects at each treatment group) and 1 hour post-dose (3 
subjects [<1%]). No induration, warmth, swelling, or injection site pain was reported. 
A total of 3 subjects (<1%) had detectable antidrug antibodies (ADA) against denosumab. Two 
of these subjects (one in the PROLIA EU group, the other in the PROLIA US group) were ADA 
positive before and after study drug administration. Their ADA titers were low and did not 
increase after study drug administration. One subject in the PROLIA US group had an ADA 
response after study drug administration with a very low ADA titer at 2 time points (log10 titers 
of 1.6 and 1.5 for Day 15 and Day 29, respectively; the subject discontinued from the study after 
day 29).
Overall, the safety profile of TVB-009P was similar to the safety profiles of PROLIA US and 
PROLIA EU in the study. The safety profile after administration of a single dose of TVB-009P 
in healthy subjects was as expected based on the known safety profile of PROLIA.
Further information can be found in the current version of the TVB-009 IB.
1.3.
Known and Potential Benefits and Risks to Patients
1.3.1.
Known and Potential Benefits and Risks of the Test Investigational Medicinal 
Product(s)
TVB-009 is being developed as a biosimilar candidate to PROLIA and XGEVA. The safety 
profile of TVB-009 is expected to be similar to that of PROLIA (see Section 1.3.2).
To date, no new identified or potential risks were observed in TVB-009 nonclinical and clinical 
studies. Additional information is available in the IB.
1.3.2.
Known and Potential Benefits and Risks of Reference Investigational Medicinal 
Product
The identified and potential risks of PROLIA include: hypocalcemia, osteonecrosis of the jaw, 
hypersensitivity reactions, atypical subtrochanteric and diaphyseal femoral fractures, fracture 
healing complications, serious infections, dermatologic adverse reactions, musculoskeletal pain, 
multiple vertebral fractures following discontinuation of treatment, suppression of bone turnover 
and reproductive toxicity (PROLIA USPI 2020).
Additional information regarding benefits and risks to patients may be found in the PROLIA EU 
SPC (2020).

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1.3.3.
Overall Benefit and Risk Assessment 
TVB-009P is an intended biosimilar to PROLIA and physiochemical and functional 
characterization have shown similarity between the products.
In Study TVB009-BE-10157, TVB-009P 
 
 showed similar pharmacokinetics and similar pharmacodynamic effects on bone 
metabolism compared to both PROLIA sourced from the US and PROLIA sourced from the EU 
(see Section 1.2.2 for details). Comparison of the safety and immunogenicity between 
TVB-009P and PROLIA (US and EU) did not show any clinically relevant differences.
In patients with PMO the risk of fracture is high, and the patients are likely to derive significant 
benefit from a bone forming agent in clinical practice.
All patients in the study will receive active osteoporosis treatment for 18 months, either PROLIA 
US or TVB-009P or both, which is expected to show no relevant clinical difference in efficacy 
and safety compared to PROLIA.
The TVB-009P and PROLIA dosing schedule, ie, 60 mg administered as a single sc injection 
once every 6 months, reflects the recommendation for PROLIA to treat postmenopausal women 
with osteoporosis at high risk for fracture. Patients will be adequately supplemented with 
calcium and vitamin D.
The risks of treatment with TVB-009P are expected to be similar to the known risks of treatment 
with denosumab. Patients will be undergo safety monitoring and evaluation throughout the study 
as detailed in Section 7.

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2.
STUDY OBJECTIVES AND ENDPOINTS
2.1.
Primary and Secondary Study Objectives and Endpoints
The primary and secondary study objectives and endpoints are:
Objectives
Endpoints
The primary objective of the study is 
to demonstrate that there are no 
clinically meaningful differences in 
efficacy between TVB-009P and 
PROLIA US administered 
subcutaneously in patients with 
postmenopausal osteoporosis.
The primary efficacy endpoint is 

the percent change from baseline in lumbar spine-bone mineral 
density (LS-BMD) at week 52 based on centrally assessed 
dual-energy X-ray absorptiometry (DXA) measurements

The co-primary efficacy endpoint for the European Union (EU) 
submission is the percent change from baseline in serum 
C-telopeptide cross-link of type 1 collagen (sCTX-1) at 
week 26. For the EU submission, this endpoint is regarded as 
co-primary. For the United States (US) submission, this 
endpoint is regarded as secondary
A secondary objective is to compare 
further efficacy and pharmacodynamic 
parameters between TVB-009P and 
PROLIA US.
The secondary efficacy and pharmacodynamic endpoints are:

percent change from baseline in LS-BMD at week 26 based on 
centrally assessed DXA measurements

percent change from baseline in femoral neck bone mineral 
density (BMD) by DXA at week 26 and at week 52

percent change from baseline in total hip BMD by DXA at 
week 26 and at week 52

percent change from baseline in sCTX-1 at all time points

sCTX-1 suppression at week 4

percent change from baseline in procollagen type 1 N propeptide 
(P1NP) at week 26 and week 52

incidence of fractures up to week 52
A secondary objective of the study is 
to compare efficacy and 
pharmacodynamic parameters 
between TVB-009P and PROLIA US
after a single transition from PROLIA
US to TVB-009P.
The pharmacodynamic/efficacy endpoints in the transition period are:

percent change from week 52 in LS-BMD by DXA at week 78

difference between percent change from baseline in sCTX-1 
between week 52 and week 78

percent change from week 52 in femoral neck BMD by DXA at 
week 78

percent change from week 52 in total hip BMD by DXA at 
week 78

difference between percent change from baseline in P1NP 
between week 52 and week 78

incidence of fractures up to week 78
A secondary objective of this study is 
to compare the safety and tolerability, 
including device-related events, 
between TVB-009P and PROLIA US
throughout the study.
A secondary objective of this study is 
to compare the safety and tolerability 
The safety and tolerability endpoints are:

adverse events (and the number of patients who withdraw from 
the study due to adverse events)

vital signs

laboratory tests (hematology, serum chemistry, and urinalysis)

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Objectives
Endpoints
between TVB-009P and PROLIA US
after a single transition from PROLIA
US to TVB-009P, including 
device-related events.

electrocardiogram (ECG)

local tolerability at injection site

use of concomitant medications

device-related adverse events and malfunctions
A secondary objective of this study is 
to assess the immunogenicity of 
TVB-009P in comparison with 
PROLIA US throughout the study.
A secondary objective of this study is 
to assess the immunogenicity of 
TVB-009P in comparison with 
PROLIA US after a single transition 
from PROLIA US to TVB-009P.
The immunogenicity endpoint is:

incidence of patients with confirmed positive anti-drug antibody 
(ADA) sample
For confirmed positive samples, the ADA titer and the neutralizing 
potential will be tested.
The effect of positive immunogenicity findings on pharmacokinetics, 
efficacy, and safety will be assessed if applicable.
Exploratory Objectives and Endpoints
Objectives
Endpoints
An exploratory objective of this 
study is to compare pharmacokinetics 
between TVB-009P and PROLIA US 
throughout the study.
The pharmacokinetic endpoints are:

serum concentration before next dose (Ctrough), before second 
and third dose, and 6 months after third dose

serum concentration at 2 weeks postdose (C2weeks)
Pharmacokinetic endpoints derived from population pharmacokinetics 
analysis are:

area under the curve over the dosing period (AUC0-tau) after first 
dose

Ctrough before second dose

maximum observed concentration (Cmax) after first dose
Primary Estimand: The primary estimand assesses clinically meaningful differences in 
effectiveness in patients with PMO, based on surrogate measures, focusing on the causal effects 
attributable to the IMP.
The primary estimand is the difference in mean percent change in lumbar spine-bone mineral 
density (LS-BMD) from baseline at week 52 between TVB-009P and PROLIA US treatment 
arms, regardless of intercurrent events in the target population of patients with PMO who receive 
at least one dose of IMP and have both a baseline and at least 1 post-baseline assessment of 
LS-BMD. For the submission in the US, this estimand is regarded as primary and for the 
submission in the European Union (EU), this estimand is regarded as co-primary.
The co-primary estimand for the EU filing is the difference in mean percent change in sCTX-1 
from baseline at week 26, between TVB-009P and PROLIA US treatment arms, regardless of 
intercurrent events in the target population of patients with PMO. The same analysis set will be 
used for both estimands and therefore patients who terminate before week 26 will not be 
included in the sCTX-1 analysis. For the EU submission, this estimand is regarded as 
co-primary. For the US submission, this estimand is regarded as secondary.

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2.1.1.
Justification of Primary Endpoint
The primary endpoint of the study is the percent change in LS-BMD from baseline to week 52. 
This primary endpoint was agreed with FDA and European Medicines Agency (EMA) as being 
sensitive enough to confirm that there is no relevant clinical difference in efficacy between 
TVB-009P and PROLIA US. LS-BMD is a reliable, well-established, and reproducible measure 
of bone quality and fracture resistance, and is reasonably likely to predict beneficial response to 
treatment with anti-osteoporosis drugs. The treatment duration of 52 weeks for the evaluation of 
LS-BMD is expected to be long enough to be able to evaluate comparability of the 2 study 
medications.
The percent change from baseline in the biomarker sCTX-1 at week 26 is a co-primary endpoint 
for EU submission. In several clinical studies with denosumab it was demonstrated that sCTX-1 
suppression is an indicator of denosumab effectiveness, as demonstrated by percent change from 
baseline (Wang et al 2009). Week 26 is regarded as the most appropriate time point for detecting 
difference in clinical efficacy, as for PROLIA, the difference across various drug doses in 
percent change in sCTX-1 is most evident at 6 months after start of treatment.

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3.
STUDY DESIGN
3.1.
General Study Design and Study Schematic Diagram
This is a randomized, double-blind, multinational, multicenter study to demonstrate similar 
efficacy and safety of TVB-009P compared to PROLIA US administered in 3 sc doses of 60 mg 
every 26 weeks (3 injections) in patients with PMO. This study will consist of a screening period 
(up to 4 weeks) and a 52-week double-blind main treatment period, followed by a 26-week 
double-blind transition period.
The total duration of the study for each patient is approximately 82 weeks.
Screening will take place within 4 weeks before the first dose. After informed consent is 
obtained, eligibility criteria will be reviewed and screening evaluations will be performed.
At baseline, patients will be randomized in a 1:1 ratio to receive the first 2 doses of TVB-009P or 
PROLIA US (“main treatment period"). The first dose of TVB-009P or PROLIA US will be 
administered following randomization. The second dose will be administered 26 weeks after the 
first dose.
At week 52 (26 weeks after the second dose and prior to receiving their third dose), patients in 
the PROLIA US arm will be re-randomized 1:1 to either continue with a third dose of PROLIA
US or transition to TVB-009P and receive a single dose of TVB-009P in the transition period to 
assess primarily immunogenicity and safety after a transition from PROLIA US to TVB-009P. 
All patients in the TVB-009P group will continue treatment with a third dose of TVB-009P. All 
patients who do not terminate the study before the third dose will be followed for 26 weeks after 
the third dose of study drug.
Final procedures and assessments will be performed at the end of study (EOS) visit at the end of 
the 78-week study period. Patients who withdraw from the study before completing the 78-week 
study period will have early termination (ET) procedures and assessments performed at their 
final visit. A patient who is randomized but does not complete all treatment periods will not be 
replaced. In case the assessment of LS-BMD is missing or not evaluable from more than 10% of 
the patients at the week 26 visit, the sponsor may decide to continue the recruitment of patients 
in order to increase the number of evaluable patients.
The EOS is defined as the last visit of the last patient of the transition period.
Details of study management during a COVID-19 outbreak are given in Appendix M.
The assessments and procedures performed during each study visit are detailed in Table 1
and Appendix B.
The study schematic diagram is presented in Figure 1.

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3.4.
Stopping Rules for the Study
There are no formal rules for ET of this study. During the conduct of the study, serious adverse 
events will be reviewed (Section 7.1.5) as they are reported from the investigational centers to 
identify safety concerns.
The study may be terminated by the sponsor for any reason at any time. For example, the 
sponsor should terminate the study in the event of:

new toxicological or pharmacological findings or safety issues that invalidate the 
earlier positive benefit-risk assessment

discontinuation of the development of the IMP
If the whole study or arms of the study will be stopped, the patients who are terminated early will 
be followed according to Withdrawal Criteria and Procedures for the Patient (Section 4.3).
3.5.
Schedule of Study Procedures and Assessments
Study procedures and assessments with their time points are presented in Table 1. Detailed 
descriptions of each method of procedures and assessments are provided in Section 6 (efficacy 
and pharmacodyamics assessments), Section 7 (safety assessments), and Section 8
(pharmacokinetics and immunogenicity assessments). Study procedures and assessments by visit 
are listed in Appendix B.

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p Vital signs includes pulse rate, blood pressure (systolic/diastolic), and respiratory rate. Before blood pressure and pulse are measured, the patient must rest in a supine or seated 
position for at least 5 minutes. The same position and arm should be used each time vital signs are measured for a given patient. For any abnormal vital signs value, the 
measurement should be repeated as soon as possible. In the event of suspected severe hypersensitivity (including anaphylaxis), vital signs, including oxygen saturation and 
respiration rate, will be measured.
q In case of early termination, LS-BMD DXA, total hip and femoral neck BMD DXA, and lateral spine X-ray will be assessed only in patients who terminate the study between 
the week 26 and week 52 visits. The minimum time between two DXA scans should be 3 months. These assessments will not be performed for patients who terminate the study 
earlier than week 26 or during the transition period.
r These scans will be unilateral only. For each patient, the same hip should be scanned throughout the study.
s Blood sampling for sCTX-1 and P1NP assessment should be taken in the morning hours after overnight fasting. Samples should be collected consistently at the same time of the 
day for an individual patient at all visits. Vigorous exercise should be avoided the day prior to sampling.
ADA=anti-drug antibody; BMD=bone mineral density; COVID-19=coronavirus 2019; DXA=dual-energy X-ray absorptiometry; ECG=electrocardiogram; E2=estradiol; 
EOM=end of main treatment period; EOS=end of study; ET=early termination; FSH=follicle stimulating hormone; HDL=high density lipoprotein; IMP=investigational medicinal 
product; INR=international normalized ratio; LDL=low density lipoprotein; LS-BMD=lumbar spine-bone mineral density; P1NP=procollagen type 1 N propeptide;
PK=pharmacokinetic; PPT=partial prothrombin; PT=prothrombin; sCTX-1=serum C-telopeptide cross-link of type 1 collagen; SOT=start of transition period; V=visit.

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4.
SELECTION AND WITHDRAWAL OF PATIENTS
Prospective waivers (exceptions) from study inclusion and exclusion criteria to allow patients to 
be randomized/enrolled are not granted by Teva (Appendix C).
4.1.
Patient Inclusion Criteria
Patients may be included in this study only if they meet all of the following criteria:
a.
The patient provides a signed and dated written informed consent.
b. The patient is a clinically stable, ambulatory, female postmenopausal adult (≥60 and 
≤90 years) with a diagnosis of osteoporosis.
c.
The patient is of postmenopausal status, defined as:

Spontaneous amenorrhea for >12 months, or

Spontaneous amenorrhea >6 months and serum follicle stimulating hormone 
(FSH) and estradiol (E2) in menopausal range, or

Surgical menopause at least 6 weeks before the start of screening.
d. The patient has a body weight ≥50 kg and ≤90 kg (≥110 lb and ≤198 lb) at screening.
e.
The patient agrees to be supplemented with 1000 mg calcium and at least 400 IU 
vitamin D daily from screening until the last visit.
f.
The patient has a BMD-measurement T-score of less than -2.5 but not less than -4.0 
by dual energy X-ray absorptiometry (DXA) at the lumbar spine at screening based 
on central reader assessment.
g. The patient has at least three (3) vertebrae in the L1-L4 region that are evaluable by 
DXA.
h. The patient has serum 25 (OH) vitamin D level >20 ng/mL at screening and no 
current hyper- or hypocalcemia, defined as albumin-adjusted serum calcium outside 
the normal range, as assessed by the central laboratory. Vitamin D and calcium 
supplements will be provided and patients may be rescreened once to re-evaluate 
calcium and/or vitamin D level post repletion.
i.
The patient must be willing and able to comply with study restrictions and to remain 
at the investigational center for the required duration during the study period, and 
willing to return to the investigational center for further visits, as applicable, and the 
follow-up procedures and assessments as specified in this protocol.
4.2.
Patient Exclusion Criteria
Patients will be excluded from participating in this study if they meet any of the following 
criteria:
a.
The patient has a known malabsorption of calcium or vitamin D supplements.

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b. The patient has a metabolic or bone disease (except osteoporosis) such as Paget’s 
disease, Cushing’s disease, rheumatoid arthritis, sclerosteosis, osteomalacia, 
osteogenesis imperfecta, osteopetrosis, ankylosing spondylitis, hyperprolactinemia, 
malabsorption syndrome, osteomyelitis, multiple myeloma or related 
lymphoproliferative disorder, or bone metastases.
c.
The patient has a current, uncontrolled hyperthyroidism or hypothyroidism, per 
patient report or chart review.
d. The patient has hypoparathyroidism or hyperparathyroidism (irrespective of current 
controlled or uncontrolled status).
e.
The patient has a history and/or presence of risk factors of osteonecrosis of the jaw, as 
determined by the principal investigator, (eg, unhealed open soft tissue lesions in the 
mouth, poor oral hygiene, periodontal disease, poorly fitting dentures, history of 
dental disease, recent or planned invasive dental procedures such as tooth extractions 
within the next 18 months), presence of anemia or coagulopathy at screening, and/or 
inability to maintain oral hygiene during the study.
f.
The patient has a history and/or presence of 1 severe or more than 2 moderate 
vertebral fractures (as determined by central reading of lateral spine X-ray during the 
screening period).
g. The patient has a history and/or presence of hip fracture or atypical femur fracture.
h. The patient has participated in another study of an IMP (or a medical device) within 
the previous 30 days or 5 half-lives of the IMP (whichever is longer) or longer if 
required by local regulations, or is currently participating in another study of an IMP 
(or a medical device).
i.
The patient has a known hypersensitivity to any components of the IMPs stated in this 
protocol or to calcium or vitamin D.
j.
The patient has a renal impairment manifested with an estimated glomerular filtration 
rate (eGFR) <45 mL/min.
k. The patient has cardiac disease as per investigator's discretion, including 
electrocardiogram (ECG) abnormalities at screening indicating significant risk of 
safety for patients participating in the study.
l.
The patient has a malignancy or past malignancy (except for local non-melanoma 
skin cancer fully resected).
m. The patient has a current skin infection(s).
n. The patient has infectious disease:

Acute infection and/or antibiotic treatment must be resolved 28 days prior to the 
first dose of IMP.

Any relevant chronic infection.

Ongoing hepatitis B, hepatitis C, human immunodeficiency virus (HIV) Types 1 
or 2 infection.

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
Positive test for coronavirus disease 2019 (COVID-19) during screening or 
patient reporting a recent history of confirmed COVID-19 which had not fully 
recovered more than 14 days before screening.
o. The patient has any medical condition that (treated or untreated), in the opinion of the 
investigator, could jeopardize or would compromise the patient’s safety or ability to 
participate in this study.
p. The patient has had any prior treatment with denosumab (PROLIA or XGEVA or 
biosimilars of denosumab products).
q. The patient has used intravenous bisphosphonates within less than 5 years prior to 
screening.
r.
The patient has used oral bisphosphonates within the 12 months prior to start of 
screening and/or cumulative use >3 years before the start of screening.
s.
The patient has ongoing use of any osteoporosis treatment (other than calcium and 
vitamin D supplements). The following rules for prior use of osteoporosis treatments 
have to be adhered to:

Drugs being investigated for osteoporosis, eg romosozumab: dose received at any 
time.

Strontium or fluoride (for osteoporosis): dose received at any time.

Teriparatide or any parathyroid hormone (PTH) analogs: dose received within 
12 months before the start of screening.

Calcitonin: dose received within 6 months before the start of screening.

Cinacalcet: dose received within 3 months before the start of screening.
t.
The patient has ongoing use of any bone active drugs which can affect BMD 
including:

Heparin (except topical), anti-convulsives (with the exception of 
benzodiazepines), systemic ketoconazole, adrenocorticotropic hormone, lithium, 
gonadotropin releasing hormone agonists, or anabolic steroids; dose received 
within 3 months before the start of screening.

Systemic glucocorticosteroids: total cumulative dose of ≥50 mg within 3 months 
prior to randomization.

Systemic oral or transdermal estrogen, or selective estrogen receptor modulators: 
more than 1 month of cumulative use within 6 months prior to randomization.
u. The patient is a pregnant or lactating woman, or plans to become pregnant during the 
study.
v. The patient has a history of chronic alcohol or drug abuse within the previous 
6 months.
w. The patient is vulnerable (eg, people kept in detention).

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4.3.
Withdrawal Criteria and Procedures for the Patient
Each patient is free to withdraw from the study at any time, without prejudice to their continued 
care. Patients must be withdrawn from the study if any of the following events occur:
1. Patient withdraws consent or requests withdrawal from the study for any reason.
2. Patient is noncompliant with the study procedures and assessments in the opinion of the 
investigator.
3. The sponsor requests withdrawal of the patient.
4. Patient experiences an adverse event or other medical condition which indicates to the 
investigator that continued participation is not in the best interest of the patient, for 
example, but not limited to osteonecrosis of the jaw, atypical subtrochanteric and 
diaphyseal femoral fractures, serious infections, severe dermatologic adverse reactions or 
severe musculoskeletal pain.
Patients should be treated with standard of care and should be transitioned to another 
antiresorptive agent after withdrawal from or termination of the study as appropriate.
Investigators should attempt to obtain information on patients in the case of withdrawal from the 
study. Results of any evaluations and observations, together with a narrative describing the 
reason(s) for withdrawal from the study, must be recorded in the source documents. The case 
report form (CRF) must document the primary reason for withdrawal from the study.
If a patient experiences a BMD reduction of more than 7% from baseline at any time during the 
study, the investigator needs to discuss with the patient the implications for her fracture risk, 
alternative treatment options and the option for continuing in the study and to document that 
discussion and the decision made. If alternative treatment is recommended further study drug 
administration should be discontinued and every effort should be taken to complete remaining 
study visits in the main treatment period, regardless of the type of alternative treatment chosen 
by the subject.
If a patient exhibits clinical symptoms that may indicate COVID-19 infection after entering the 
study, the patient should be tested for active COVID-19 infection. If the patient tests positive for 
active COVID-19 infection, she may continue the study following the relevant local policies and 
study procedures including use of disallowed medications.
See Appendix E for information regarding how the study will define and address lost to 
follow-up patients to help limit the amount and impact of missing data.
If the reason for withdrawal from the study is an adverse event and/or clinically significant 
abnormal laboratory test result (with clinical significance meaning any variation in assessment 
results that has medical relevance and may result in an alteration in medical care [eg, active 
observation, diagnostic or therapeutic measures]), monitoring will be continued as applicable 
(eg, until the event has resolved or stabilized, until the patient is referred to the care of a health 
care professional, or until a determination of a cause unrelated to the test IMP/device or study 
procedure is made). The specific event or test result (including repeated test results, as 
applicable) must be recorded both on the source documentation and in the CRF; both the adverse 
events page and the relevant page of the CRF will be completed at that time.

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The patient will be monitored as applicable (eg, until the event has resolved or stabilized, until 
the patient is referred to the care of a health care professional, or until a determination of a cause 
unrelated to the test IMP/device or study procedure is made). The investigator must inform the 
sponsor’s medical expert as soon as possible of each patient who is being considered for 
withdrawal due to adverse events. Additional reports must be provided when requested.
If a patient is withdrawn from the study for multiple reasons that include also adverse events, the 
relevant page of the CRF should indicate that the withdrawal was related to an adverse event. An 
exception to this requirement will be the occurrence of an adverse event that in the opinion of the 
investigator is not severe enough to warrant discontinuation but that requires the use of a 
prohibited medication, thereby requiring discontinuation of the patient. In such a case, the reason 
for discontinuation would be “need to take a prohibited medication”, not the adverse event.
In the case of patients lost to follow-up, attempts to contact the patient must be made and 
documented in the patient’s medical records and transcribed to the CRF.
4.4.
Replacement of Patients
A patient who is randomized but does not complete all treatment periods will not be replaced. In 
case the assessment of LS-BMD is missing or not evaluable from more than 10% of the patients 
at the week 26 visit, the sponsor might decide to continue the recruitment of patients in order to 
increase the number of evaluable patients. 
4.5.
Rescreening
A patient with a screening serum 25 hydroxy (OH) vitamin D level ≤20 ng/mL may be 
rescreened once to re-evaluate vitamin D level post repletion. Patients with albumin-adjusted 
serum calcium outside the normal range, as assessed by the central laboratory, may be rescreened 
once to re-evaluate calcium levels. Informed consent obtained at the beginning of the screening 
period also covers the partial rescreening for low vitamin D or for calcium; therefore 
reconsenting is not required.
4.6.
Screening Failure
Screening failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized in the study.
Selected information about patients who fail screening will be collected to comply with reporting 
and publishing requirements. This information may include, but is not limited to, demography, 
screening failure details, eligibility criteria, and any serious adverse events.

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5.
TREATMENTS
Investigational medicinal products are defined as the test IMP (TVB-009P) and reference IMP 
(PROLIA US). Patients will receive 3 injections of TVB-009P and/or PROLIA US at a dose of 
60 mg, administered by a qualified healthcare provider (according to local regulations). Patients 
will also receive Vitamin D and calcium supplements (non-IMP).
5.1.
Investigational Medicinal Products Used in the Study
5.1.1.
Test Investigational Medicinal Product
TVB-009P is provided as a sterile, preservative-free, clear to opalescent, colorless to pale yellow 
aqueous solution for sc injection. It will be supplied in a combination product consisting of a 
pre-filled syringe (PFS) with an automatically activated needle safety guard for single-use 
administration. Each PFS of TVB-009P contains 60 mg TVB-009 in 1 mL of solution.
Patients will be administered TVB-009P as a single sc injection over >5 seconds in the abdomen 
(about 8 cm lateral from the umbilicus). Patients will be observed for a minimum of 1 hour after 
dosing. If the patient develops clinical symptoms, vital signs should be recorded and the patient 
should be assessed for anaphylaxis/hypersensitivity reactions as detailed in Appendix G.
Refer to Table 2 for specific details regarding TVB-009P. Additional details may be found in the 
pharmacy manual and in the Investigator's Brochure (IB) for TVB-009P.
5.1.2.
Reference Investigational Medicinal Product
PROLIA US is supplied as a single dose PFS for sc injection with a manual needle guard. Each 
PFS of PROLIA contains 60 mg of denosumab in 1 mL of solution.
Patients will be administered PROLIA US as a single sc injection over >5 seconds in the 
abdomen (about 8 cm lateral from the umbilicus). Patients will be observed for a minimum of 
1 hour after dosing. If the patient develops clinical symptoms, vital signs should be recorded and 
the patient should be assessed for anaphylaxis/hypersensitivity reactions as detailed 
in Appendix G.
Refer to Table 2 for specific details regarding PROLIA US. Additional details may be found in 
the pharmacy manual and in the PROLIA USPI.

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Table 2:
Investigational Medicinal Products Used in the Study
IMP name
Test product
Reference product
Trade name or company-assigned number
TVB-009P
PROLIA US
Formulation
Active
60 mg/mL
60 mg/mL
Acetate
17 mM
17 mM
Sorbitol
4.7%
4.7%
Polysorbate 20
0.01%
0.01%
Sodium hydroxide
pH to 5.2
pH to 5.2
Water for injection
qs to 1 mL
qs to 1 mL
Unit dose strength(s)/Dosage level(s)
60 mg/mL
60 mg/dose
60 mg/mL 
60 mg/dose
Route of administration
sc injection
sc injection
Device
Automatically activated needle 
safety guard
Manually activated needle 
safety guard
Manufacturer
Teva Branded Pharmaceutical 
Products R&D, Inc., West 
Chester, Pennsylvania, USA
Amgen Inc., One Amgen Center 
Drive, Thousand Oaks, 
California 91320-1799, USA
Storage conditions
2°C to 8°C (36°F to 46°F) and 
protected from direct light and 
heat. Avoid vigorous shaking
2°C to 8°C (36°F to 46°F) and 
protected from direct light and 
heat. Avoid vigorous shaking
IMP=investigational medicinal product; qs=quantum satis; sc=subcutaneous; USA=United States of America
5.1.3.
Non-Investigational Medicinal Product Supplementation Treatment
Patients will be instructed to take 1000 mg calcium daily and at least 400 IU vitamin D daily 
from screening to week 78 (EOS). Calcium and vitamin D will be provided from local sources. 
If hypocalcemia is detected, and there is no additional underlying reason, this should be further 
monitored and the below can be used for the corrective treatment: 

Mild to moderate hypocalcemia (≥7.5 mg/dL, < 8.4 mg/dL adjusted calcium): 
calcium, up to 3000 mg/day (oral) at the discretion of the investigator 

Symptomatic hypocalcemia or severe asymptomatic hypocalcemia (< 7.5 mg/dL 
adjusted calcium): intravenous calcium followed by oral calcium at the discretion of 
the investigator. 
In case of continuous symptomatic or severe asymptomatic hypocalcemia the investigator should 
consider to postpone study drug administration by a maximum of 2 months and should discuss 
the situation with the medical monitor.
If hypercalcaemia is detected, supplementation with calcium and vitamin D should be interrupted 
and calcium levels should be further monitored; severe hypercalcaemia might be treated (eg, 
calcitonin or calcimimetics) at the discretion of the investigator. Patients will be allowed to 
continue treatment with study drug.

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5.1.4.
Medical Devices
The medical device for TVB-009P, manufactured by Teva and provided for use in this study is:

PFS with an automatically activated needle safety guard for single-use administration
This automatically activated needle safety guard requires no additional actions by the user to 
shield the needle after use, and thus reduces the potential for accidental needle stick injuries.
The medical device for PROLIA US, manufactured by Amgen, Inc. and provided for use in this 
study is:

PFS with manually activated needle safety guard for single-use administration
This manually activated needle safety guard requires the user to shield the needle after use.
Instructions for use of both devices are provided in the pharmacy manual.
All device-related adverse events, malfunctions etc. will be recorded; their impact relative to the 
safety and tolerability of the IMP will be evaluated (see Section 7.2 and Appendix H).
5.2.
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products
5.2.1.
Storage and Security
The investigator or designee must confirm appropriate temperature conditions have been 
maintained for all IMPs received and any discrepancies are reported and resolved before use of 
the IMPs.
The IMPs (TVB-009P and PROLIA US) must be stored at a controlled temperature (2°C to 8°C 
[36°F to 46°F]) in a secure area (eg, locked refrigerator). The site should have a process for 
monitoring the storage temperature of unused IMP.
5.2.2.
Labeling
Supplies of IMPs will be labeled according to the current ICH guidelines on GCP and Good 
Manufacturing Practice and will include any locally required statements. If necessary, labels will 
be translated into the local language.
5.2.3.
Accountability
Each IMP shipment will include a packing slip listing the contents of the shipment, return 
instructions, and any applicable forms.
The investigator is responsible for ensuring that deliveries of IMPs and other study materials 
from the sponsor are correctly received, recorded, handled, and stored safely and properly in 
accordance with the CFR or national and local regulations, and used in accordance with this 
protocol.
Only patients screened and subsequently enrolled in the study may receive IMP/non-IMP and 
only authorized staff at the investigational center may supply IMP/non-IMP or administer IMP. 
The pharmacist, designee or study drug administrator is responsible for IMP/non-IMP
accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, and final 

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disposition records). At the end of the study, a declaration will be signed stating that no 
unblinding of blinded study personnel occurred. 
A record of IMP/non-IMP accountability (ie, IMP, vitamin D and calcium supplements, and 
other study materials received, used, retained, returned, or destroyed) must be prepared and 
signed by the pharmacist, designee or study drug administrator, with an account given for any 
discrepancies. Empty, partially used, and unused IMP/non-IMP will be disposed of or returned to 
Teva or its designee.
Further guidance and information are provided in the pharmacy manual.
5.3.
Justification for Investigational Medicinal Products
5.3.1.
Justification for Dose of Test Investigational Medicinal Product
The dose of IMP to be evaluated in this double-blind study (ie, 60 mg) was selected to match the 
approved dose for PROLIA.
5.3.2.
Justification for Use of Reference Investigational Medicinal Product
TVB-009P is being developed as a potential biosimilar to the reference IMP, PROLIA. PROLIA 
US and PROLIA EU have been shown to be biosimilar in a previous 
pharmacokinetic/pharmacodynamic similarity study (see Section 1.2.2) – PROLIA US was 
selected as the reference IMP for this study.
5.4.
Treatment After the End of the Study
After study end, no IMP will be provided as PROLIA is commercially available. Patients should 
be further treated with denosumab or should be transitioned to another antiresorptive agent as 
appropriate.
5.5.
Restrictions
Patients will be required to comply with the following restrictions:

Patients must remain seated, semi-recumbent, or supine as needed for assessments or 
other procedures, including dosing.

Patients will fast overnight prior to the morning of blood sampling for sCTX-1 and 
P1NP assessment. Vigorous exercise should be avoided the day prior to sampling.

Patients will fast overnight prior to the morning of blood sampling for lipid profiling.
There are no other restrictions in this study.
5.6.
Prior and Concomitant Medication or Therapy
See Section 4.1 for patient inclusion and Section 4.2 patient exclusion criteria.
Any prior or concomitant therapy, medication (including prior osteoporosis medication), or 
procedure a patient has had from 4 weeks before screening through the end of the study will be 
recorded in the source documentation and in the CRF. Trade name and international 
nonproprietary name (INN) (if available), indication, dose, and start and end dates of the 

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administered medication or treatment will be recorded. The sponsor will encode all therapy and 
medication according to the World Health Organization Drug Dictionary (WHODrug Global).
Prohibited and restricted medications are listed in Appendix F.
At each visit at the investigational center after the screening visit the investigator will ask 
patients whether they have taken any medications, including over-the-counter medications, 
vitamins, or herbal or nutritional supplements, since the previous visit.
Concomitant medication and treatment will be recorded until the ET/EOS visit.
5.7.
Procedures for Monitoring Patient Compliance
The investigator will be responsible for monitoring patient compliance with this protocol from 
the start of the screening period through the transition period. If the investigator or the sponsor 
determines that the patient is not in compliance with the study protocol, the investigator and the 
sponsor should determine whether the patient should be withdrawn from the study. The 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) should be notified if 
required by local regulation.
5.8.
Randomization and Blinding
This is a randomized, double-blind study. Patients and investigators will remain blinded to IMP 
assignment during the study.
At baseline, patients will be randomized in a 1:1 ratio to receive the first 2 doses of TVB-009P or 
PROLIA US (“main treatment period”). The randomization will be stratified by region (US/non-
US) and any use of previous bisphosphonates (yes/no). At week 52, prior to receiving their third 
dose of study medication, patients in the PROLIA US treatment group will be re-randomized in a 
1:1 ratio to receive a third dose of PROLIA US or switch to TVB-009P (“transition period”) to 
receive a single dose of TVB-009P. The re-randomization will be stratified by region (US/non-
US) and any use of previous bisphosphonates (yes/no). All patients in the TVB-009P group will 
receive a third dose of TVB-009P at week 52.
During the main treatment period, the sponsor, investigators (and other site staff involved in 
study assessments) and patients will be blinded to the treatment assignment of all patients. To 
maintain blinding of the patients and investigators (and other site staff involved in study 
assessments) to the treatment assignment of all patients during the entire study, and maintain 
blinding of the sponsor until the main treatment period is unblinded, the re-randomization 
process will be performed for all patients, including the patients in the TVB-009P group 
(although only patients in the PROLIA US group will actually be re-randomized while patients 
in the TVB-009P group will continue to receive TVB-009P in the transition period). The 
randomization will be implemented using Randomization and Trial Supply Management 
(RTSM).
At the investigational center, only the pharmacist or designee who will dispense the study drug 
and the study drug administrator will be unblinded. These staff will not participate in any 
efficacy, pharmacokinetic, pharmacodynamic, immunogenicity, and safety assessments.

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5.9.
Maintenance of Randomization and Blinding
5.9.1.
Maintenance of Randomization
Patient randomization codes will be maintained in a secure location at the service provider 
contracted to generate the codes. At the time of final analyses, after receiving unblinding request 
from Teva statistician, the service provider will provide the unblinded IMP assignment according 
to the processes defined in the relevant Standard Operating Procedure (SOP).
5.9.2.
Blinding and Unblinding
The study drug will be prepared in a separate room by the non-blinded pharmacist or designee. 
The pharmacist or designee will place the respective original box into a neutral container that is 
suitable to maintain the blind. The original study drug box and syringe will not be visible when 
the patient or any other blinded study team member enters the room since study drug packaging 
and the syringes differ among products. In order to ensure additional patient blinding, a blindfold 
with an additional pillow at chest level (or similar device) will be used during the study drug 
injection to shield the study drug from the patient. The investigator doing the safety assessment 
will remain blinded to treatment assignment.
Staff responsible for pharmacokinetic and immunogenicity bioanalysis, population 
pharmacokinetics, and/or pharmacokinetics/pharmacodynamics model will not have access to the 
patient treatment randomization prior to unblinding the study.
During the transition period, the sponsor, investigators (and other site staff involved in study 
assessments) and patients will be blinded to the randomized treatment of patients who received 
PROLIA US in the main treatment period and are re-randomized for the transition period.
Before database lock (DBL), staff responsible for efficacy and safety analysis, pharmacokinetic 
and immunogenicity bioanalysis, population pharmacokinetic analysis, and/or 
pharmacokinetic/pharmacodynamic analysis will not have access to the patient treatment 
randomization. After last patient last visit and DBL of the main treatment period, the sponsor 
will unblind the treatments for the analysis of the main treatment period (up to and including 
week 52; not including third IMP dose and assessments following the third dose). A full CSR 
will be prepared with all data related to the first and second doses up to the week 52 end of main 
treatment phase procedures. 
Only after completion of the study (after week 78) and DBL will the transition period be fully 
unblinded and analyzed. The results will be reported separately in a CSR addendum, including 
any updates to the safety analysis of the main treatment period.
In case of an emergency, serious adverse event (see Section 7.1.5), or in cases when knowledge 
of the IMP assignment is needed to make treatment decisions, the investigator may unblind the 
patient’s IMP assignment as deemed necessary, mainly in emergency situations. Individual 
randomization codes, indicating the IMP assignment for each randomized patient, will be 
available to the investigator(s) or pharmacist(s) at the investigational center via the RTSM, both 
via telephone and internet. Breaking of the treatment code can always be performed by the 
investigator without prior approval by the sponsor; however, the sponsor should be notified 
following the breaking of the treatment code. The patient's assignment should not be revealed to 
the sponsor.

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When a blind is broken for safety reasons, the patient will be withdrawn from the study and the 
event will be recorded on the CRF. The circumstances leading to the breaking of the code should 
be fully documented in the investigator’s study files and in the patient’s source documentation. 
Assignment of IMP should not be recorded in any study documents or source document.
In blinded studies, for an adverse event defined as a suspected unexpected serious adverse 
reaction (SUSAR) (ie, reasonable possibility; see Section 7.1.4), Global Patient Safety and 
Pharmacovigilance (GPSP) may independently request that the blind code be broken (on a 
case-by-case basis) to comply with regulatory requirements. The report will be provided in an 
unblinded manner for regulatory submission. If this occurs, blinding will be maintained for the 
investigator and for other personnel involved in the conduct of the study, and analysis and 
reporting of the data.
5.9.3.
Data Monitoring Committee
There will be no Data Monitoring Committee in this study.
5.10.
Total Blood Volume
The total blood volume to be collected for each patient in this study is approximately 250 mL.
Details on blood volumes to be collected during the study are provided in the informed consent 
form (ICF) and laboratory manual.

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6.
ASSESSMENT OF EFFICACY AND PHARMACODYNAMICS
6.1.
Assessments of Efficacy
Refer to Table 1 for the timing of assessments and procedures. See Appendix B for a detailed 
description of assessments and procedures.
For screening purposes, X-rays or DXA scans taken up to 30 days prior to the beginning of the 
screening period may be used if all of the following criteria are met:

Images are to be obtained in a manner consistent with the technique specified by 
the central imaging vendor for this study (refer to the appropriate imaging 
manuals provided) and are deemed useable by the central imaging vendor

DXA images are to be obtained using the same DXA scanner that will be used for 
this study
6.1.1.
Lumbar Spine-Bone Mineral Density by Dual-Energy X-Ray Absorptiometry
LS-BMD will be measured by DXA. Hologic and GE Lunar DXA machines will be used and the 
same machine should be used for all study procedures for a particular patient for the duration of 
the study. DXA machine changes during the study are strongly discouraged; however, if a 
machine is changed during the study, the central imaging vendor will oversee the change in order 
to minimize the impact on assessments of BMD change. All LS-BMD DXA scans will be 
submitted to and analyzed by the central imaging vendor. The results of the DXA scans after 
start of treatment will be provided to the investigator after completion of the study (after 
week 78) and DBL upon request of the patient and/or due to country regulation.
Lumbar spine scans must include L1 through L4. The vertebrae on which the measurement is 
based should be consistent throughout the study on an individual patient level.
A separate procedure manual provided by the central imaging vendor will detail the DXA 
machine types including specific instructions for acquisition of scans as well as performance of 
Instrument Quality Control.
6.1.2.
Total Hip and Femoral Neck Bone Mineral Density by Dual-Energy X-Ray 
Absorptiometry
Total hip and femoral neck BMD will be measured by DXA. These scans will be unilateral only. 
For each patient, the same hip should be scanned throughout the study. Hologic and GE Lunar 
DXA machines will be used and the same machine must be used for all study procedures for a 
particular patient for the duration of the study. All hip and femoral neck bone DXA scans will be 
submitted to and analyzed by the central imaging vendor. Detailed instructions for scan 
acquisition can be found in the separate manual provided by the central imaging vendor. The 
results of the DXA scans after start of treatment will be provided to the investigator after 
completion of the study (after week 78) and DBL upon request of the patient and/or due to 
country regulation.

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6.1.3.
Lateral Spine X-Ray Vertebral Fracture Assessment
Patients will undergo a lateral spine X-ray for assessment of vertebral fractures by the central 
imaging vendor. Nominally, vertebral fracture will be assessed in all vertebrae from the fourth 
thoracic vertebra (T4) to the fourth lumbar vertebra (L4). Any new fracture should be reported as 
an adverse event (Section 7.1.2).
6.1.4.
Assessment of Nonvertebral Fractures
Information about any nonvertebral fractures and level of trauma causing the fracture during the 
study will be recorded in the CRF. A copy of radiographs or other diagnostic confirming the 
fracture and/or a copy of the report should be included in the patient’s study records. 
Additionally, any new fracture should be reported as an adverse event (Section 7.1.2).
6.2.
Pharmacodynamics Assessment
Blood samples (4 mL) for assessment of sCTX-1 and P1NP will be collected via venipuncture or 
indwelling catheter before and up to 78 weeks after administration of first IMP dose at the time 
points detailed in Table 1. Blood sampling for sCTX-1 and P1NP assessment should be taken in 
the morning hours after overnight fasting. Samples should be collected consistently at the same 
time of the day for an individual patient at all visits (see Appendix I). Vigorous exercise should 
be avoided the day prior to sampling.

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7.
ASSESSMENT OF SAFETY
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse 
events, local tolerability at the injection site, clinical laboratory test results, vital sign 
measurements, ECG findings, physical examination, and use of concomitant medication. Refer 
to Table 1 for the timing of assessments and procedures.
All assessments scheduled for baseline (day 1), week 26 and week 52 visits, with the exception 
of local tolerability, will be completed before IMP administration on those days.
Adverse events are categorized by ICH guidelines and adverse device effects are categorized and 
classified according to International Organization for Standardization (ISO) standard 
14155:2011(E).
Device deficiencies that are not associated with an adverse event as well as those that have the 
potential to cause a serious adverse event are covered in Appendix H.
7.1.
Adverse Events
7.1.1.
Definition of an Adverse Event
An adverse event is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.
In this study, any adverse event occurring after the patient has signed the ICF through the end of 
the study should be recorded and reported as an adverse event.
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of this study. 
Development of a new condition or the worsening of a pre-existing condition will be considered 
an adverse event, whether or not considered related to TVB-009P. Stable chronic conditions 
(such as arthritis) that are present before study entry and do not worsen during this study will not 
be considered adverse events.
Accordingly, an adverse event can include any of the following:

intercurrent illnesses

physical injuries

events possibly related to concomitant medication (including study provided 
medications)

significant worsening (change in nature, severity, or frequency) of pre-existing 
conditions
(Note: A condition recorded as pre-existing that is intermittently symptomatic [eg, 
headache] and that occurs during this study should be recorded as an adverse event)

drug interactions

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
events occurring during diagnostic procedures or during any washout phase of this
study

laboratory or diagnostic test abnormalities that result in the withdrawal of the patient 
from the study, are associated with clinical signs and symptoms or a serious adverse 
event, require medical treatment or further diagnostic work-up, or are considered by 
the investigator to be clinically significant. Note: Abnormal laboratory test results at 
the screening visit that preclude a patient from entering the study or receiving study 
treatment are not considered adverse events.
7.1.2.
Recording and Reporting of Adverse Events
For recording of adverse events, the study period is defined for each patient as the time period 
from signature of the ICF to the end of the study. The period for reporting treatment-emergent 
adverse events is defined as the period after the first dose of IMP is administered until the end of 
the study.
All adverse events that occur during the defined study period must be recorded both on the 
source documentation and the CRF, regardless of the severity of the event or judged relationship 
to the IMP. For serious adverse events, the serious adverse event form must be completed and 
the serious adverse event should be reported within 24 hours of when the investigator becomes 
aware of the serious adverse event (Section 7.1.5.3.1). The investigator does not need to actively 
monitor patients for adverse events after the study period defined above.
At each contact with the patient, the investigator or designee must question the patient about 
adverse events by asking an open-ended question such as “Have you had any unusual symptoms 
or medical problems since the last visit? If yes, please describe.” A precise diagnosis should be 
recorded whenever possible. When such a diagnosis is made, all related signs, symptoms, and 
any test findings will be recorded collectively as a single diagnosis on the CRF and, if it is a 
serious adverse event, on the serious adverse event form. Reported or observed signs and 
symptoms that are not manifestations of a known diagnosis should be reported individually.
The clinical course of each adverse event will be monitored at suitable intervals until resolved, 
stabilized, or returned to baseline; or until the patient is referred for continued care to a health 
care professional; or until determination of a cause unrelated to the IMP or study procedure is 
made.
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding IMP, treatment administered, and outcome for each adverse event must be 
recorded both on the source documentation and the CRF.
The relationship of each adverse event to the IMP, and the severity and seriousness of each 
adverse event, as judged by the investigator, must be recorded as described below.
7.1.3.
Severity of an Adverse Event
The severity of each adverse event must be recorded as 1 of the following:
Mild:
No limitation of usual activities
Moderate: Some limitation of usual activities

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Severe:
Inability to carry out usual activities
7.1.4.
Relationship of an Adverse Event to the Investigational Medicinal Product
The relationship of an adverse event to the IMP will be made according to the criteria in Table 3.
Table 3:
The Relationship of an Adverse Event to the Investigational Medicinal 
Product
Term
Definition
Clarification
No reasonable 
possibility
(not related)
This category applies to adverse 
events that, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc) or to adverse 
events that, after careful medical 
consideration at the time they are 
evaluated, are judged to be unrelated 
to the IMP.
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if at least 2 of the following apply:

It does not follow a reasonable temporal sequence 
from the administration of the IMP.

It could readily have been produced by the patient’s 
clinical state, environmental or toxic factors, or other 
modes of therapy administered to the patient.

It does not follow a known pattern of response to the 
IMP.

It does not reappear or worsen when the IMP is 
re-administered.
Reasonable 
possibility
(related)
This category applies to adverse 
events for which, after careful 
medical consideration at the time 
they are evaluated, a connection with 
the administration of IMP cannot be 
ruled out with certainty.
The relationship of an adverse event may be considered 
“reasonable possibility” if at least 2 of the following 
apply:

It follows a reasonable temporal sequence from 
administration of the IMP.

It cannot be reasonably explained by the known 
characteristics of the patient’s clinical state, 
environmental or toxic factors, or other modes of 
therapy administered to the patient.

It disappears or decreases on cessation or reduction in 
dose. There are important exceptions when an 
adverse event does not disappear after 
discontinuation of the IMP, yet an IMP relationship 
clearly exists.

It follows a known pattern of response to the IMP.
IMP=investigational medicinal product.
7.1.5.
Serious Adverse Events
For recording of serious adverse events, the study period is defined for each patient as the time 
period from signature of the ICF to the end of the study. Serious adverse events occurring in a 
patient after the end of the study should be reported to the sponsor if the investigator becomes 
aware of them, following the procedures described in Section 7.1.5.3.1.
Further details are given in the Safety Monitoring Plan.
7.1.5.1.
Definition of a Serious Adverse Event
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions:

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
results in death

is life-threatening adverse event (ie, the patient was at risk of death at the time of the 
event); it does not refer to an event which hypothetically might have caused death if it 
were more severe

requires inpatient hospitalization or prolongation of existing hospitalization, which 
means that hospital inpatient admission or prolongation of hospital stay were required 
for treatment of an adverse event, or that they occurred as a consequence of the event
Hospitalizations scheduled before the patient signed the ICF will not be considered 
serious adverse events, unless there was worsening of the preexisting condition 
during the patient’s participation in this study.
Likewise, hospitalizations for a social reason only (eg, the subject lives far away and 
is allowed therefore to stay in the hospital overnight) will not be considered a serious 
adverse event.

results in persistent or significant disability/incapacity (refers to a substantial 
disruption of one’s ability to conduct normal life functions)

is a congenital anomaly/birth defect

an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may jeopardize the patient and may require medical intervention 
to prevent one of the outcomes listed in this definition. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or the 
development of drug dependency or drug abuse. Note: Any suspected transmission of 
an infectious agent via a medicinal product is considered an important medical event.

All occurrences of possible drug-induced liver injury that meet Hy’s law criteria, 
defined as all of the below, must be reported by the investigator to the sponsor as a 
serious adverse event:

alanine aminotransferase (ALT) or aspartate aminotransferase (AST) increase of 
>3 × the upper limit of normal (ULN)

total bilirubin increase of >2 × ULN

absence of initial findings of cholestasis (ie, no substantial increase of alkaline 
phosphatase [ALP])
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event.
7.1.5.2.
Expectedness
In this study, the reference safety information (RSI) for TVB-009P for determination of a 
suspected serious adverse reaction is included in the IB. A serious adverse event that is not 
included in the relevant RSI by its specificity, severity, outcome, or frequency is considered an 
unexpected adverse event.

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The RSI of PROLIA US in this study is the PROLIA USPI.
The sponsor’s GPSP will determine the expectedness for all serious adverse events.
For the purpose of SUSAR reporting: if the patient is receiving TVB-009P, the version of the IB 
at the time of occurrence of the SUSAR will apply. If the patient is receiving PROLIA US, the 
PROLIA USPI effective at the time of the SUSAR occurrence will apply.
7.1.5.3.
Reporting a Serious Adverse Event
7.1.5.3.1. Investigator Responsibility
To satisfy regulatory requirements, all serious adverse events that occur during the study, 
regardless of judged relationship to administration of the IMP, must be reported to the sponsor 
by the investigator. The event must be reported within 24 hours of when the investigator learns 
about it. Completing the serious adverse event form and reporting the event must not be delayed, 
even if not all the information is available. The investigator does not need to actively monitor 
patients for adverse events once this study has ended.
Serious adverse events occurring to the patient after the end of the study (or early termination, 
whichever applies) for that patient should be reported to the sponsor if the investigator becomes 
aware of them.
The serious adverse event form should be sent to the local safety officer (LSO) or designee (a 
Contract Research Organization [CRO] in a country without a sponsor LSO) (contact
information is in the Clinical Study Personnel Contact Information section); the LSO will 
forward the report to the sponsor’s GPSP.
In addition to the serious adverse event term, the following information should be provided to 
record the event accurately and completely:

study number

investigator and investigational center identification

patient number

onset date and detailed description of adverse event

investigator’s assessment of the relationship of the adverse event to the IMP (no 
reasonable possibility, reasonable possibility, as described in Table 3)
Additional information includes:

age and sex of patient

date of first dose of IMP

date and amount of last administered dose of IMP

action taken

outcome, if known

severity

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
explanation of assessment of relatedness

concomitant medication (including study provided medications; dates, doses, routes 
of administration, doses and dosing regimens)

treatment for the event (in the narrative section)

pertinent laboratory or other diagnostic test data

medical history

results of dechallenge/rechallenge, if known

for an adverse event resulting in death

cause of death (whether or not the death was related to IMP)

autopsy findings (if available)
Each report of a serious adverse event will be reviewed and evaluated by the investigator and the 
sponsor to assess the nature of the event and the relationship of the event to the IMP.
In addition, the investigator will assess whether the etiology of the event is associated with the 
patient's primary condition, concomitant study medications (including study provided 
medications), study procedures, or underlying disease or any other condition.
Additional information (follow-up) about any serious adverse event unavailable at the initial 
reporting should be forwarded by the investigator within 24 hours of when it becomes known to 
the same address as the initial report.
For all countries, the sponsor’s GPSP will distribute the Council for International Organizations
of Medical Sciences (CIOMS) form/Extensible Markup Language (XML) file or MedWatch of 
serious adverse events to the LSO/CRO for submission to the competent authorities, IEC/IRBs, 
and investigators, according to local regulations. The investigator must ensure that the IEC/IRB 
is also informed of the event, in accordance with national and local regulations.
The sponsor’s GPSP will submit the XML of SUSARs to the EMA in an unblinded manner, 
when applicable and according to local regulations. Submission of SUSARs to the FDA using 
MedWatch forms is done in an unblinded manner by the Regulatory Affairs department upon 
receipt from the LSO.
For SUSARs occurring during the treatment period, only the LSO/unblinded personnel from the 
CRO will receive the unblinded report for regulatory submission; the others will receive a 
blinded report. If SUSARs occur after the treatment period, the sponsor will also receive an 
unblinded copy of the report.
7.1.5.3.2. Sponsor Responsibility
If a serious unexpected adverse event is believed to be related to the IMP or study procedures, 
the sponsor will take appropriate steps to notify all investigators participating in sponsored 
clinical studies of TVB-009P and the appropriate competent authorities (and IEC/IRB, as 
appropriate).
In addition to notifying the investigators and competent authorities (and IEC/IRB, as 
appropriate), other action may be required, including the following:

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
altering existing research by modifying the protocol

discontinuing or suspending the study

modifying the existing consent form and informing all study participants of new 
findings

modifying listings of expected toxicities to include adverse events newly identified as 
related to TVB-009P
7.1.6.
Protocol-Defined Adverse Events of Special Interest
No protocol-defined adverse events of special interest are identified for this study.
7.1.7.
Protocol Deviations Because of an Adverse Event
If a patient experiences an adverse event or medical emergency, deviations from the protocol 
may be allowed on a case-by-case basis. To ensure patient safety, after the event has stabilized or 
treatment has been administered (or both), the investigator or other physician in attendance must 
contact the CRO medical monitor as soon as possible to discuss the situation. The investigator, in 
consultation with the sponsor, will decide whether the patient should continue to participate in 
the study.
7.2.
Adverse Device Effects
An adverse device effect is an adverse event related to the use of an investigational medical 
device or a combination product. This includes adverse events resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, operation, or any 
malfunction of the investigational medical device, including any event resulting from user error 
or from intentional misuse of the investigational medical device.
7.2.1.
Adverse Device Effect Reporting
Adverse device effects (Figure 2) must be recorded both on the source documentation and the 
CRF.
All adverse device effects shall be reviewed by the investigator, the medical monitor, and the 
sponsor. The investigator and sponsor will record all relevant information regarding every 
adverse device effect/serious adverse device effect and will categorize each as guided in 
Section 7.2.2.1.
The investigator should make an initial determination if the adverse event may be related to a 
device deficiency. 
Adverse device effects and device deficiencies will be listed in the CSR.
7.2.2.
Serious Adverse Device Effects
A serious adverse device effect is an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event (Section 7.1.5.1).

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7.2.2.1.
Serious Adverse Device Effect Reporting
The investigator will report to the sponsor, without unjustified delay, all serious adverse device 
effects (within 24 hours); this information shall be promptly followed by detailed written reports 
as described below.
The process and contact details for serious adverse device effect reporting are the same as for 
serious adverse event reporting provided in Section 7.1.5.3.
Events shall be reported to the IEC/IRB by the investigator and to the regulatory authorities by 
the sponsor using the appropriate form according to the national and local regulations.
Figure 2:
Decision Tree for Adverse Events and Adverse Device Effects Classification
AE=adverse event; ADE=adverse device effect; CRF=case report form; IEC=Institutional ethics committee; 
IRB=Institutional Review Board; SADE=serious adverse device effect; SAE=serious adverse event.
7.3.
Clinical Laboratory Tests
All clinical laboratory test results outside of the reference range will be judged by the 
investigator as belonging to one of the following categories:

abnormal and not clinically significant

abnormal and clinically significant
A laboratory test result that is judged by the investigator as clinically significant will be recorded 
both on the source documentation and the CRF as an adverse event, and monitored as described 
in Section 7.1.2.

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Details of clinical laboratory tests are listed in Section 7.3.1 and will be referenced in the study 
laboratory manual.
7.3.1.
Serum Chemistry, Hematology, and Urinalysis
Clinical laboratory tests (serum chemistry, hematology, and urinalysis) will be performed at the 
time points detailed in Table 1. Clinical laboratory tests will be performed using the central 
laboratory (see Appendix A). Specific laboratory tests to be performed are listed in Table 4.
Table 4:
Clinical Laboratory Tests
Serum chemistry
Hematology
Urinalysis

calcium

phosphate

sodium

magnesium

potassium

chloride

bicarbonate or carbon dioxide

glucose

blood urea nitrogen (BUN)

creatinine

estimated glomerular filtration rate 
(eGFR) (using the Modification of 
Diet in Renal Disease [MDRD] 
formula)

total cholesterol (low density 
lipoprotein [LDL] and high density 
lipoprotein [HDL] HDL)

triglycerides (after overnight fasting)

uric acid

alanine aminotransferase (ALT)

aspartate aminotransferase (AST)

lactic dehydrogenase (LDH)

gamma glutamyl transpeptidase 
(GGT)

alkaline phosphatase (ALP)

creatine phosphokinase (CPK)

total protein

albumin

total bilirubin

vitamin D 

hemoglobin

hematocrit

red blood cell (RBC) count

RBC indices

platelet count

absolute neutrophil count (ANC)

white blood cell (WBC) count and 
differential count
o
polymorphonuclear leukocytes 
(neutrophils)
o
lymphocytes
o
eosinophils
o
monocytes
o
basophils

coagulation tests
o
international normalized ratio 
(INR)
o
prothrombin (PT)
o
partial prothrombin (PTT)

protein

glucose

ketones

blood (hemoglobin)

ph

nitrates

specific gravity

microscopic
o
bacteria
o
RBCs
o
WBCs
o
casts
o
crystals

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7.3.2.
Other Clinical Laboratory Tests
7.3.2.1.
Follicle Stimulating Hormone
At screening, women will have a serum FSH assessment, as applicable, to confirm 
postmenopausal status.
7.3.2.2.
Estradiol
At screening, women will have a serum E2 assessment, as applicable, to confirm postmenopausal 
status.
7.3.2.3.
Urine Pregnancy Test
At day 1 (prior to randomization), a pregnancy test (urine dipstick) will be done to confirm that 
women are not pregnant.
7.3.2.4.
Vitamin D
At screening, and at visits 6, 7, 9, 12, and EOS women will have a serum 25 (OH) vitamin D 
assessment.
7.3.2.5.
Coronavirus Disease 2019 Testing
COVID-19 testing will be performed at screening. In addition, if a patient exhibits clinical 
symptoms after entering the study that may indicate infection, the patient should be tested for 
COVID-19.
COVID-19 testing will be performed locally (if available), or centrally (if not available locally) 
and reported in the CRF.
7.4.
Physical Examinations
Physical examinations (will include, as a minimum, height in centimeters and weight in 
kilograms, and examination of head, eyes, ears, nose, and throat [HEENT], oral cavity, chest, 
cardiovascular system, abdomen, and skin) will be performed at the time points detailed in
Table 1. Oral examination will be performed to exclude risks for osteonecrosis of the jaw. If 
required by local authorities, a mandible radiograph may be carried out at screening.
Any physical examination finding that is judged by the investigator as clinically significant 
(except at the initial screening visit, which will be captured as medical history) will be 
considered an adverse event, recorded on the CRF, and monitored as described in Section 7.1.2.
7.5.
Vital Signs
Vital signs (pulse rate, blood pressure [systolic/diastolic], and respiratory rate) will be measured 
at the time points detailed in Table 1. All vital sign results outside of the reference ranges will be 
judged by the investigator as belonging to one of the following categories:

abnormal and not clinically significant

abnormal and clinically significant

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Before blood pressure and pulse are measured, the patient must rest in a supine or seated position 
for at least 5 minutes. The same position and arm should be used each time vital signs are 
measured for a given patient. For any abnormal vital signs value, the measurement should be 
repeated as soon as possible. Any vital signs value that is judged by the investigator as clinically 
significant will be recorded both on the source documentation and the CRF as an adverse event, 
and monitored as described in Section 7.1.2.
7.6.
Electrocardiography
A 12-lead ECG will be performed at the time points detailed in Table 1.
The ECG will be interpreted locally by the principal investigator (or qualified physician). All 
ECG results will be judged by the investigator (or qualified physician) as belonging to one of the 
following categories:

abnormal and not clinically significant

abnormal and clinically significant
Any ECG finding that is judged by the investigator (or qualified physician) as clinically 
significant (except at the screening visit) will be considered an adverse event, recorded on the 
source documentation and in the CRF, and monitored as described in Section 7.1.2.
7.7.
Assessment of Local Tolerability and Pain
Local tolerability at the injection site (erythema, ecchymosis, induration, tenderness, warmth, 
and swelling, and pain) will be assessed, using standardized scales. Patient reported pain at the 
injection site will be reported using a standardized 11-point pain intensity numerical response 
scale (NRS-11) where 0 is “No pain” and 10 is “Worst possible pain”, and patients will be asked 
to respond to the following question: “How much pain do you feel at the drug injection site?”.
The assessments will be performed 1 hour±10 minutes after IMP administration (Table 1).
Severity of local tolerability symptoms should be assessed as described in Table 5. Erythema, 
ecchymosis, and induration will be considered only if they reach a diameter of at least 5 mm. 
The surface diameter in millimeters should be recorded and erythema, induration, and 
ecchymosis at the injection site will be graded according to the diameter measurements: Absent, 
5 mm to ≤50 mm (mild), >50 to ≤100 mm (moderate), and >100 mm (severe). Induration must 
be assessed by careful superficial palpation avoiding pressuring or squeezing the injection site.
In the case that symptoms do not resolve, assessments will proceed as long as the patient remains 
at the study center, and thereafter at each ambulatory visit. Appropriate treatment may be 
provided if necessary, in which case it must be recorded as concomitant medication. 

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Table 5:
Severity Assessment of Local Tolerability
Test
Response
Erythema
- Absent
- Erythema surface diameter 5 mm to ≤50 mm (mild)
- Erythema surface diameter >50 to ≤100 mm (moderate)
- Erythema surface diameter >100 mm (severe)
Ecchymosis
- Absent
- Ecchymosis surface diameter 5 mm to ≤50 mm (mild)
- Ecchymosis surface diameter >50 to ≤100 mm (moderate)
- Ecchymosis surface diameter >100 mm (severe)
Induration
- Absent
- Induration surface diameter 5 mm to ≤50 mm (mild)
- Induration surface diameter >50 to ≤100 mm (moderate)
- Induration surface diameter >100 mm (severe)
Tenderness
Warmth
Swelling
- None
- Mild
- Moderate
- Severe
Injection site findings will not be captured as adverse events unless they fulfill characteristics 
that are beyond those in the specified forms/scales (eg, necrosis, abscess, etc) or fulfill 
seriousness criteria and then they must be recorded and reported as specified in Section 7.1.2.
7.8.
Pregnancy
This study is conducted in postmenopausal women. However, any female patient becoming 
pregnant during the study will discontinue IMP and will be discontinued from the study. The 
process for reporting a pregnancy is the same as that for reporting a serious adverse event but 
using the pregnancy form. Pregnant patients will be monitored for the outcome of the pregnancy 
(including spontaneous, elective, or voluntary abortion). If the pregnancy continues to term, the 
outcome (health of the infant up to 8 weeks of age), including details of birth and presence or 
absence of any birth defect, congenital abnormalities, or maternal and newborn complications,
will be reported to the sponsor. Any complication of pregnancy will be reported as an adverse 
event or serious adverse event, as appropriate.
7.9.
Medication Error and Special Situations Related to the 
Investigational Medicinal Products
Any administration of IMP that is not in accordance with the study protocol should be reported 
as a protocol deviation and in the patients’ source documents, regardless of whether or not an 
adverse event occurs as a result.
The following are types of medication errors and special situations:

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1. Medication error: Any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product while in the control of the healthcare professional, 
patient, or consumer.
2. Overdose: Administration of a quantity of a medicinal product given per administration 
or cumulatively which is above the maximum recommended dose according to the 
protocol or authorized product information. Clinical judgment should always be applied. 
Any dose of IMP (whether the test or reference IMP), whether taken intentionally or 
unintentionally, in excess of that prescribed must be immediately reported to the sponsor.
3. Misuse: Situations where the IMP is intentionally and inappropriately used not in 
accordance with the protocol or authorized product information.
4. Abuse: Persistent or sporadic, intentional excessive use of IMP which is accompanied by 
harmful physical or psychological effects.
5. Off-label use: Situations where an IMP is intentionally used for a medical purpose not in 
accordance with the protocol or authorized product information.
Occupational exposure: Exposure to an IMP, as a result of one’s professional or non-professional 
occupation.

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8.
ASSESSMENT OF PHARMACOKINETICS AND 
IMMUNOGENICITY
8.1.
Pharmacokinetic Assessment
Blood samples (4 mL) will be collected via venipuncture or indwelling catheter before and up to 
78 weeks after TVB-009P or PROLIA US administration at the time points detailed in Table 1
for measurements of serum concentration of TVB-009P and PROLIA US. The dates and times of 
IMP administration and the date and time point (24-hour clock time) of each pharmacokinetic 
sample will be recorded both on the source documentation and the CRF. 
Samples will be analyzed for concentration of TVB-009P and PROLIA US using an appropriate 
validated method. Incurred sample reanalysis may be performed (see Appendix I).
Details on sample handling, storage, shipment, and analysis are given in the pharmacy manual.
8.2.
Immunogenicity Testing
Blood samples (5 mL) for assessment of ADA response will be collected via venipuncture or 
indwelling catheter before and up to 78 weeks after TVB-009P or PROLIA US administration at 
the time points detailed in Table 1.
Additionally, efforts should be made to collect ADA samples when a severe hypersensitivity 
reaction (eg, anaphylaxis) is suspected, serious adverse event, or immunogenicity-related adverse 
event is observed as close to onset of the event as possible, resolution of event, and 30 days 
following the event onset, if possible.
When a number of assessments are to be conducted at the same time point, the immunogenicity 
blood sample should be taken after other assessments but before IMP administration. The dates 
and times of IMP administration and the date and time point of each immunogenicity sample will 
be recorded both on the source documentation and the CRF.
The detection and characterization of antibodies to TVB-009P and PROLIA US will be 
performed using validated methods by the bioanalytical lab (Appendix A). Immunogenicity 
assessment by the detection of ADA levels in serum samples will be performed using the same 
validated assay, employing a 3-tiered approach. Briefly, all samples will be screened for ADA 
using bridging enzyme-linked immunosorbent assay (ELISA) with labeled TVB-009P, the 
screening positive samples will be analyzed in a confirmatory assay, and the confirmed ADA 
positive samples will be tested for antibody titer determination. The characterization of 
confirmed ADA positive samples will include analysis for neutralization potential.
Samples may be stored if permitted by the ICF and local regulations after the last patient’s last 
visit for the study to enable potential reanalysis of immune responses to TVB-009P 
(see Appendix J).
Details on sample handling, storage, shipment, and analysis are given in the study laboratory 
manual.

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Patients who withdraw from the study prior to week 26 will not have a post-baseline LS-BMD 
measurement, and will therefore not be included in the mITT analysis set.
In the mITT analysis set, treatment will be assigned based on the treatment to which patients 
were randomized in the main treatment period, regardless of which treatment they actually 
received.
9.2.3.
Safety Analysis Set
The safety analysis set will include all patients who received at least 1 dose of IMP.
In the safety analysis set, treatment will be assigned based on the treatment patients actually 
received in the main treatment period, regardless of the treatment to which they were 
randomized. Rules for assignment of treatment in case of actual treatment error will be provided 
in the SAP.
9.2.4.
Per-Protocol Analysis Set
The per-protocol (PP) analysis set is a subset of the mITT analysis set including only patients 
who received treatment with IMP at the baseline and week 26 visit as randomized and completed 
the main treatment period without any major protocol deviations that may impact the similarity 
assessments of LS-BMD and sCTX-1.
Rules for excluding patients from the PP analysis set will be provided in the SAP. Evaluation of 
exclusion from the PP analysis set will be discussed on a case-by-case basis and documented 
prior to DBL and unblinding of the study for final analysis.
9.2.5.
Transition Intent-to-treat Analysis Set
The transition intent-to-treat (TITT) analysis set will include all patients randomized in the 
transition period.
In the TITT analysis set, treatment will be assigned based on the treatment to which patients 
were randomized in the main and transition treatment periods, regardless of which treatment they 
actually received.
9.2.6.
Transition Modified Intent-to-treat Analysis Set
The transition modified intent-to-treat (TmITT) analysis set will include all patients who 
received the third dose of IMP and had an EOS evaluation of LS-BMD.
In the TmITT analysis set, treatment will be assigned based on the treatment to which patients 
were randomized in the main and transition treatment periods, regardless of which treatment they 
actually received.
9.2.7.
Transition Safety Analysis Set
The transition safety analysis set will include all patients who received the third dose of IMP.
In the transition safety analysis set, treatment will be assigned based upon the treatment patients 
actually received in the main and transition periods, regardless of the treatment to which they 
were randomized. Rules for assignment of treatment in case of actual treatment error will be 
provided in the SAP.

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9.3.
Data Handling Conventions
For all descriptive statistics, only the observed data from the patients will be used.
9.3.1.
Handling Withdrawals and Missing Data
Missing LS-BMD or sCTX-1 assessments (either due to withdrawal from the study or for other 
reasons) are assumed to be missing at random (MAR) in this efficacy and safety biosimilar study 
in PMO.
The mITT analysis set will be used for the primary analysis. This analysis set includes only 
patients that had at least 1 post-baseline evaluation of LS-BMD (see Section 9.2.2), ie, reached 
week 26; the drop-out rate prior to week 26 is assumed to be low,
 Underlying assumptions 
are that the drop-out rate prior to week 26 will be similar in both treatment groups, and that 
drop-outs are not related to efficacy. As both treatment groups are active, and improvement in 
the underlying disease is not expected to be felt by the patient, these assumptions are considered 
reasonable. The assumption that drop-out rates are comparable between the treatment groups will 
be assessed using descriptive statistics (see Section 9.4.1).
In the primary analysis, missing LS-BMD at week 52 will be imputed based on post-baseline 
assessments using multiple imputation under the MAR assumption (see Section 9.5.4); this is a 
conservative approach for similarity testing, as missing data will be imputed within each 
treatment group separately.
Since the mITT analysis set includes only patients that reached at least week 26, missing sCTX-1 
at week 26 is expected to be negligible and will not be imputed. 
Sensitivity and supplementary analyses for missing data in the primary analysis are presented in 
Section 9.5.4.1 and Section 9.5.4.2.
9.3.2.
Handling Below the Limit of Quantitation
sCTX-1 and P1NP values below limit of quantitation (BLQ) will be imputed by the lower limit 
of quantitation (LLOQ); 0.033 ng/mL for sCTX-1 and 1.0 ng/mL for P1NP). 
Sensitivity analysis for BLQ imputation in the analysis of sCTX-1 percent change from baseline 
at week 26 is presented in Section 9.5.4.1.
9.4.
Study Population
The ITT analysis set (Section 9.2) will be used for all study population summaries unless 
otherwise specified. Summaries will be presented by treatment group and for all patients.
9.4.1.
Patient Disposition
The number of patients screened, patients screened but not randomized, and patients in the main 
treatment period and the transition period will be summarized using descriptive statistics.
For the main treatment period, the summary will include: patients randomized (ITT analysis set), 
patients in the mITT, safety, and PP analysis sets, patients that withdraw up to week 26, patients 
that withdraw after week 26, and patients that complete the main treatment period.

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For the transition period, the summary will include: patients randomized (TITT analysis set), 
patients in the TmITT and transition safety analysis sets, patients that withdraw during the 
transition period, and patients that complete the study.
Data from patients who withdraw from the study will also be summarized by reason for 
withdrawal as recorded in the disposition CRF using descriptive statistics. 
If more than 10% of the patients withdraw from the study before the end of the main treatment 
period, the number of days until study discontinuation will be analyzed using Kaplan-Meier 
methodology. In case of imbalance in withdrawal rates between treatment groups, further 
analysis to explore if the imbalance can be attributed to differences in baseline characteristics 
may be conducted as deemed necessary. 
9.4.2.
Demographic and Baseline Characteristics
Patient demographic and baseline characteristics, including but not limited to, medical history, 
prior medications and therapies, and ECG findings, will be summarized using descriptive 
statistics.
9.5.
Efficacy and Pharmacodynamic Analysis
The mITT analysis set will be used as the primary analysis set for efficacy and 
pharmacodynamics analysis in the main treatment period. The ITT and PP analysis sets will be 
used for supplementary analyses.
The TmITT analysis set will be used as the primary analysis set for efficacy and 
pharmacodynamics in the transition period.
9.5.1.
Primary Endpoint
The primary efficacy endpoint for the US filing is the percent change from baseline in LS-BMD 
at week 52, mean difference between TVB-009P and PROLIA US treatment groups.
The co-primary endpoints for the EU filing are: (1) percent change from baseline in LS-BMD at 
week 52, mean difference between TVB-009P and PROLIA US treatment groups; (2) percent 
change from baseline in sCTX-1 at week 26, mean difference between TVB-009P and PROLIA 
US treatment groups.
9.5.2.
Secondary Endpoints
The secondary efficacy and pharmacodynamic endpoints are the mean difference between 
TVB-009P and PROLIA US treatment groups in:

percent change from baseline in LS-BMD at week 26 by DXA

percent change from baseline in femoral neck BMD by DXA at week 26 and at week 
52

percent change from baseline in total hip BMD by DXA at week 26 and at week 52

percent change from baseline in sCTX-1 at all time points

sCTX-1 suppression at week 4

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For the primary analysis of s-CTX-1 percent change from baseline at week 26, values BLQ will 
be imputed as the LLOQ.
9.5.4.1.
Sensitivity/Supportive Analysis for the Primary Analysis
To assess the robustness of the primary efficacy analysis using the same estimand, sensitivity 
analyses will include:
Sensitivity analyses for the statistical model:

primary model, including only treatment group as a covariate
Sensitivity analysis for BLQ imputation:
For the primary analysis of s-CTX-1 percent change from baseline at week 26, values below 
BLQ will be imputed as the LLOQ. Sensitivity analyses for this imputation will be performed as 
follows:

two-dimensional tipping-point: for the analysis of sCTX-1 percent change from 
baseline at week 26, sensitivity analysis for the BLQ imputation will be conducted by 
repeating the analysis using different imputed values for patients in the TVB-009P 
group and the PROLIA US group, in the range of 0 to LLOQ (0.033 ng/mL).
9.5.4.2.
Supplementary Analysis for the Primary Analysis
Supplementary analyses to evaluate effect of assumptions on missing data on the results:

two-dimensional tipping point (missing not at random [MNAR]): in order to assess 
the sensitivity of the primary analysis to the MAR assumption on missing data for 
patients that have at least 1 post-baseline value, supplementary analysis for the 
primary analysis will be conducted using multiple imputation under MNAR 
assumption. In this analysis, missing LS-BMD percent change from baseline at 
week 52 will be imputed using the same predictive mean matching multiple 
imputation method as in the primary analysis, adjusted under MNAR assumption: 

the percent change from baseline in LS-BMD at week 52 in patients randomized 
to TVB-009P with missing LS-BMD at week 52 will be imputed assuming the 
treatment effect is worsened by δ1 compared to the patients who have no missing 
value (where δ1 = 0 to 2% or estimated treatment effect the TVB-009P group, 
whichever is higher);

the percent change from baseline in LS-BMD at week 52 in patients randomized 
to PROLIA US with missing LS-BMD at week 52 will be imputed assuming the 
treatment effect is worsened by δ2 compared to the patients who have no missing 
value (where δ2 = 0 to 2% or estimated treatment effect the PROLIA US group, 
whichever is higher);
The resulting complete, imputed datasets will each be analyzed using the same model 
as the primary analysis model, and the resulting statistics combined using 
methodology provided by Rubin (1987) and Little and Rubin (2002).

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
to further alleviate the concern on the uncertainty introduced by missing data, the 
following 2 separate 1-sided tests of alpha=0.05 with missing data imputed under the 
corresponding null using a multiple imputation method will be conducted:

in the first test, missing values for the TVB-009P group will be imputed under the 
non-inferiority null (the lower boundary of the equivalence margin, -1.45%) for 
testing whether it is non-inferior to PROLIA US; 

in the second test, missing values for the TVB-009P group will be imputed under 
the non-superiority null (+1.45%) for testing whether it is non-superior to 
PROLIA US. 
The resulting complete, imputed datasets will each be analyzed using the same model 
as the primary analysis model, and the resulting statistics combined using 
methodology provided by Rubin (1987) and Little and Rubin (2002).

primary analysis repeated on the ITT analysis set

two dimensional tipping point (MNAR) repeated on the ITT analysis set
Other analyses:

primary model repeated for the PP analysis set

primary model repeated for the mITT analysis set, excluding patients who received 
IMP not as randomized at baseline and/or at week 26
9.5.4.3.
Secondary Efficacy and Pharmacodynamic Analysis
No formal hypothesis testing is planned for the secondary efficacy and pharmacodynamic 
endpoints.
Descriptive statistics will be presented by treatment group. For descriptive purposes, 95% CIs for 
the difference in mean (for continuous variables) or proportion (for binary variables) between 
treatment groups will be presented.
For vertebral fractures, incidence of patients with new vertebral fractures and incidence of
patients with new non-vertebral fractures will be summarized.
9.5.4.4.
Efficacy and Pharmacodynamic Analysis in the Transition Period
No formal hypothesis testing is planned for the efficacy and pharmacodynamic endpoints in the 
transition period. 
The efficacy analyses in the transition period will be based on the TmITT analysis set, which 
will include all patients who received the third dose of IMP and had an EOS evaluation of 
LS-BMD.
Descriptive statistics will be presented by the treatment groups to which the patients were 
assigned in the main and transition periods (PROLIA US/PROLIA US, PROLIA US/TVB-009P, 
and TVB-009P/TVB-009P). In addition, the difference and 95% CI for the difference between 
the PROLIA US/PROLIA US and PROLIA US/TVB-009P treatment groups will be presented.

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9.6.
Multiple Comparisons and Multiplicity
Formal statistical analysis of similarity will be performed only on the following endpoints: 
(1) percent change from baseline to week 52 in LS-BMD
(2) percent change from baseline in sCTX-1 at week 26
For the US filing, percent change from baseline to week 52 in LS-BMD is the primary endpoint. 
Percent change from baseline in sCTX-1 at week 26 is a secondary endpoint. For this 
submission, the percent change from baseline in sCTX-1 at week 26 will be tested only if the 
primary endpoint was found to be statistically similar (ie, met the similarity criteria).
For the EU submission, percent change from baseline in LS-BMD at week 52 and percent 
change from baseline in sCTX-1 at week 26 are co-primary endpoints. For this submission, 
success will be declared if similarity is demonstrated for both co-primary endpoints.
The analysis of all other endpoints will be descriptive, therefore no control for multiplicity is 
needed.
9.7.
Safety Analysis
Safety analyses will be performed on the safety analysis set and the transition safety analysis set 
(Section 9.2.3 and Section 9.2.7).
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). In the summary tables each patient will be counted only once in each preferred term 
(PT) or system organ class (SOC) category for the analyses of safety. Summaries will be 
presented for all treatment emergent adverse events (overall and by severity), adverse events 
determined by the investigator to be related to IMP/device (ie, reasonable possibility) (defined as 
related or with missing relationship) (overall and by severity), serious adverse events, and 
adverse events causing withdrawal from the study. Summaries will be presented by treatment 
group and for all patients. For all adverse events and for serious adverse events, the summaries 
will include number of events as well as number and percent of patients with events. Patient 
listings of all adverse events, serious adverse events, and adverse events leading to withdrawal 
will be presented.
Values and change from baseline in laboratory and vital signs data will be summarized 
descriptively.
All prior/concomitant medications will be coded using WHODrug Global. The use of 
concomitant medications will be summarized by therapeutic class using descriptive statistics.
Local tolerability findings will be summarized using descriptive statistics.
For continuous variables, descriptive statistics will be provided for actual values and changes 
from baseline to each time point. For categorical variables, patient counts and percentages will 
be provided.
Incidence in abnormalities in laboratory, ECG and vital signs data will be summarized 
descriptively.
If any patient dies during the study, all relevant information will be discussed in the patient 
narrative included in the CSR; a listing of any deaths during the study will be provided.

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9.7.1.
Safety Analysis in the Main Treatment Period
Safety analyses in the main treatment period will be performed on the safety analysis set. 
Summaries will be presented by treatment group (TVB-009P, PROLIA US) and for all patients.
Summaries of adverse events in the main treatment period will be presented.
All safety variables at the week 52 visit that are assessed prior to administration of the third dose 
of IMP will be considered as occurring during the main treatment period.
9.7.2.
Safety Analysis in the Transition Period
Safety analyses in the transition period will be performed on the transition safety analysis set. 
Summaries of adverse events starting in the transition period will be presented. The analyses will 
include patients in the PROLIA US/TVB-009P, TVB-009P/TVB-009P and PROLIA 
US/PROLIA US treatment groups.
9.7.3.
Safety Analysis in the Overall Treatment Period
Safety analyses in the overall treatment period will be performed on the safety analysis set. The 
analyses will include only patients in the PROLIA US/PROLIA US and TVB-009P/TVB-009P 
treatment groups.
The analyses will be similar to the analyses of the main treatment period. Summaries will be 
presented by treatment group (PROLIA US, TVB-009P) and for all patients included in the 
analysis.
9.8.
Pharmacokinetic Analysis
The following exploratory pharmacokinetic parameters will be summarized using descriptive 
statistics:

serum concentration before next dose (Ctrough), before second and third dose, and 6 
months after third dose

serum concentration at 2 weeks postdose (C2weeks)
Details of the pharmacokinetic analysis of the area under the curve over the dosing period 
(AUC0-tau) after first dose derived from population pharmacokinetics analysis, Ctrough before 
second dose derived from population pharmacokinetics analysis, and Cmax after first dose derived 
from population pharmacokinetic analysis will be given in a separate TVB-009P population 
pharmacokinetic statistical analysis plan. The results of the population pharmacokinetic analysis 
will be provided in a separate report. 
9.9.
Immunogenicity Analysis
The immunogenicity analysis will be performed after completion of the main treatment period at 
week 52 for the of TVB-009P and PROLIA US treatment groups and after the completion of the 
transition period at week 78 (EOS) for TVB-009P and PROLIA US/TVB-009P treatment 
groups.
Results of immunogenicity assessment will be listed. 

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If more than 5 patients develop ADA anytime post-baseline, the incidence of ADA positive will 
be summarized by treatment group, and ADA positive/negative, titer level, and neutralizing 
ADA positive/negative will be summarized at each visit using descriptive statistics.
The effect of positive immunogenicity findings on efficacy and safety may be investigated, if 
applicable.
9.10.
Sequence of Final Analyses
Upon completion of the main treatment period (up to and including week 52) the sponsor will 
unblind the main treatment period (up to and including week 52; not including third IMP dosing 
and assessments following the third dosing), while keeping the investigators (and other site staff 
involved in study assessments) and the patients blinded (see Section 5.9.2). A CSR that contains 
the results of the analysis of the main treatment period (up to and including week 52) will be 
submitted with the filing of the Biologics License Application (BLA) and/or Marketing 
Authorisation Application (MAA). The results of the analysis of the transition period (up to and 
including week 78) will be included in a CSR addendum that is planned to be submitted in the 
BLA or during the 4-Month Safety Update after filing of the BLA and at the earliest opportunity 
during the MAA procedure.
9.11.
Reporting Deviations from the Statistical Plan
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the SAP, the CSR, or any combination of these, as appropriate, and in 
accordance with applicable national, local, and regional requirements and regulations.

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10.
QUALITY CONTROL AND QUALITY ASSURANCE
Refer to Appendix C for information regarding quality control and quality assurance. This 
includes information about protocol amendments, protocol deviations, responsibilities of the 
investigator to study personnel, study monitoring, and audit and inspection.
Refer to Appendix H for the definition of a clinical product complaint and investigator 
responsibilities in the management of a clinical product complaint.
11.
COMPLIANCE STATEMENT
This study will be conducted in full accordance with the ICH Harmonised Tripartite Guideline, 
Guideline for GCP E6 and any applicable national and local laws and regulations (eg, Title 21 
Code of Federal Regulations [21CFR] Parts 11, 50, 54, 56, 312, and 314, Directive 2001/20/EC 
of the European Parliament and of the Council on the approximation of the laws, regulations and 
administrative provisions of the Member States relating to the implementation of GCP in the 
conduct of clinical trials on medicinal products for human use). Any episode of noncompliance 
will be documented.
The investigator is responsible for performing the clinical study in accordance with this protocol 
and the applicable GCP guidelines referenced above for collecting, recording, and reporting the 
data accurately and properly. Agreement of the investigator to conduct and administer this 
clinical study in accordance with the protocol will be documented in separate clinical study 
agreements with the sponsor and other forms as required by national competent authorities in the 
country where each investigational center is located.
The investigator is responsible for ensuring the privacy, health, and welfare of the patients during 
and after the clinical study; and must ensure that trained personnel are immediately available in 
the event of a medical emergency. The investigator and the involved clinical study personnel 
must be familiar with the background and requirements of the study; and with the properties of 
the IMPs as described in the IB or prescribing information.
The principal investigator at each investigational center has the overall responsibility for the 
conduct and administration of the clinical study at that investigational center and for contacts 
with study management, with the IEC/IRB, and with competent authorities.
See Appendix D for the ethics expectations of informed consent, competent authorities and IEC 
and IRB, confidentiality regarding study patients, and requirements for registration of the clinical 
study.
12.
DATA MANAGEMENT AND RECORD KEEPING
See Appendix K for information regarding data management and record keeping. This includes 
direct access to source data and documents, data collection, data quality control, and archiving of 
CRFs and source documents.

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13.
FINANCING AND INSURANCE
A separate clinical study agreement, including a study budget, will be signed between each 
principal investigator and the sponsor (or the CRO designated by the sponsor) before the IMP is 
delivered.
The patients in this clinical study are insured in accordance with applicable legal provisions. The 
policy coverage is subject to the full policy terms, conditions, extensions, and exclusions. 
Excluded from the insurance coverage are eg, damages to health, and worsening of previous 
existing disease that would have occurred or continued if the patient had not taken part in the 
clinical study.
The policy of Clinical Trials Insurance will be provided to the investigational centers by the 
sponsor.
For covered clinical studies (see 21CFR54), the investigator will provide the sponsor with 
financial information required to complete FDA 3454 form. Each investigator will notify the 
sponsor of any relevant changes during the conduct of the study and for 1 year after the study has 
been completed.
14.
PUBLICATION POLICY
See Appendix L for information regarding the publication policy.

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15.
REFERENCES
Amgen. A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate AMG 162 in the 
Treatment of Bone Loss in Subjects Undergoing Aromatase Inhibitor Therapy for 
Non-metastatic Breast Cancer. clinicaltrials.gov; 2018 Oct. Report No.: NCT00089661.
Amgen. A Randomized, Double-Blind Study to Evaluate AMG 162 in the Prevention of 
Postmenopausal Osteoporosis. clinicaltrials.gov; 2010 Dec. Report No.: NCT00091793.
Amgen. A Study to Evaluate Denosumab in the Treatment of Postmenopausal Osteoporosis 
FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months). 
clinicaltrials.gov; 2020 Jul. Report No.: NCT00089791.
Bone HG, Bolognese MA, Yuen CK, et al. Effects of Denosumab on Bone Mineral Density and 
Bone Turnover in Postmenopausal Women. J Clin Endocrinol Metab. 2008;93(6):2149–57.
Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s Guide to Prevention and Treatment of 
Osteoporosis. Osteoporos Int. 2014;25(10):2359–81.
Cummings SR, Martin JS, McClung MR, et al. Denosumab for Prevention of Fractures in 
Postmenopausal Women with Osteoporosis. N Engl J Med. 2009;361(8):756–65.
European Union (EU) Summary of Product Characteristics (SPC) for XGEVA, 2020. Available 
from: 
https://www.ema.europa.eu/en/documents/product-information/xgeva-epar-product-information_
en.pdf. Accessed 23 June 2020.
European Union (EU) Summary of Product Characteristics (SPC) for PROLIA, 2020. Available 
from: 
https://www.ema.europa.eu/en/documents/product-information/prolia-epar-product-information_
en.pdf. Accessed 23 June 2020.
FDA Centre for Drug Evaluation and Research. Medical Review for PROLIA. 2010. Application 
No.: 125320.
Heitjan DF, Little RJA. Multiple Imputation for the Fatal Accident Reporting System. Journal of 
the Royal Statistical Society: Series C (Applied Statistics). 1991;40(1):13–29. 
International Committee of Medical Journal Editors (ICMJE). Recommendations for the 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, 2019. 
Available from: http://www.icmje.org/recommendations/. Accessed 23 June 2020.
Little RJA, Rubin DB. Bayes and Multiple Imputation. Statistical Analysis with Missing Data. 
John Wiley & Sons; 2002. p. 200–20.
Little RJ, Rubin DB. Statistical Analysis with Missing Data. John Wiley & Sons; 2019. 
McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in Postmenopausal Women with Low 
Bone Mineral Density. N Engl J Med. 2006;354(8):821-31.
Orwoll E, Teglbjærg CS, Langdahl BL, et al. A Randomized, Placebo-Controlled Study of the 
Effects of Denosumab for the Treatment of Men with Low Bone Mineral Density. J Clin 
Endocrinol Metab. 2012;97(9):3161–9.

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PROLIA (denosumab) Injections; US Prescribing Information. Thousand Oaks, California, USA: 
Amgen Inc; Updated 03/2020. Available from: 
https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/prolia/prolia_pi.pdf. 
Accessed 23 June 2020.
PROLIA Summary of Product Characteristics. EMA, 2020. Available at: 
https://www.ema.europa.eu/en/documents/product-information/prolia-epar-product-information_
en.pdf. Accessed on 12 November 2020.
Riggs BL. The Mechanisms of Estrogen Regulation of Bone Resorption. J Clin Invest. 
2000;106(10):1203-4.
Rubin DB. Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons; 1987.
Rubin DB. Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons; 2004. 
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second Symposium on the Definition and 
Management of Anaphylaxis: Summary Report-Second National Institute of Allergy. J Allergy 
Clin Immunol 2006;117(2):391-7.
Schenker N, Taylor JMG. Partially Parametric Techniques for Multiple Imputation. 
Computational Statistics & Data Analysis. 1996;22(4):425–46. 
Sohn W, Simiens MA, Jaeger K, et al. the Pharmacokinetics and Pharmacodynamics of 
Denosumab in Patients with Advanced Solid Tumours and Bone Metastases: a Systematic 
Review. Br J Clin Pharmacol 2014;78(3):477-87.
Streicher C, Heyny A, Andrukhova O, et al. Estrogen Regulates Bone Turnover by Targeting 
RANKL Expression in Bone Lining Cells. Sci Rep. 2017;7(1):6460.
Wang J, Lee J, Burns D, Doherty D, Brunner L, Peterson M, et al. “Fit-For-Purpose” Method 
Validation and Application of a Biomarker (C-Terminal Telopeptides of Type 1 Collagen) in 
Denosumab Clinical Studies. The AAPS Journal 2009;11(2):385-94.
WHODrug Global. https://www.who-umc.org/whodrug/whodrug-portfolio/whodrug-global/
Accessed on 20 August 2020.
World Health Organization (WHO). Who Scientific Group on the Assessment of Osteoporosis at 
Primary Health Care Level: Summary Meeting Report. 2004. Available from: 
https://www.who.int/chp/topics/Osteoporosis.pdf. Accessed 19 August 2020.
XGEVA (denosumab) Injection for Subcutaneous Use; US Prescribing Information. Thousand 
Oaks, California, USA: Amgen Inc.; Updated 06/2020. Available from: 
https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/xgeva/xgeva_pi.pdf. 
Accessed 23 June 2020.

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16.
SUMMARY OF CHANGES TO THE PROTOCOL
16.1.
Protocol Amendment 02 dated 29 June 2021
The primary reason for this global amendment is to implement changes requested by FDA and 
also to implement the changes from Local Amendment 01 (Section 16.2) globally. All major 
changes to the protocol body are listed below in the table and are reflected in the synopsis and 
Table 1 (Study Procedures and Assessments), as applicable. Minor editorial changes have been 
made.

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Reason/Justification for 
change
3.
STUDY DESIGN
Section 3.5, Table 1; other Section affected by this change: Appendix B (visit 12)
Footnote q
In case of early termination, LS BMD DXA, total hip and 
femoral neck BMD DXA, and lateral spine X ray will be assessed 
only in patients who terminate the study between the week 26 
and week 52 visits. The minimum time between two DXA scans 
should be 3 months. These assessments will not be performed for 
patients who terminate the study earlier than week 26 or during 
the transition period.
Footnote q
In case of early termination, LS BMD DXA, total hip and 
femoral neck BMD DXA, and lateral spine X ray will be 
assessed only in patients who terminate the study between the 
week 26 and week 52 visits. The minimum time between two 
DXA scans should be 3 months. These assessments will not be 
performed for patients who terminate the study earlier than 
week 26 or during the transition period.
Specified minimum time 
between two DXA scans
4.
SELECTION AND WITHDRAWAL OF PATIENTS
Section 4.3
Each patient is free to withdraw from the study at any time,
without prejudice to their continued care. Patients must be 
withdrawn from the study if any of the following events occur:
1.
Patient withdraws consent or requests withdrawal from 
the study for any reason.
2.
Patient is noncompliant with the study procedures and 
assessments in the opinion of the investigator.
3.
The sponsor requests withdrawal of the patient.
4.
Patient experiences an adverse event or other medical 
condition which indicates to the investigator that 
continued participation is not in the best interest of the 
patient, for example, but not limited to osteonecrosis of 
the jaw, atypical subtrochanteric and diaphyseal femoral 
fractures, serious infections, severe dermatologic 
adverse reactions or severe musculoskeletal pain.
…
Investigators should attempt to obtain information on patients in 
the case of withdrawal from the study. Results of any evaluations 
and observations, together with a narrative describing the 
reason(s) for withdrawal from the study, must be recorded in the 
source documents. The case report form (CRF) must document 
Each patient is free to withdraw from the study at any time, 
without prejudice to their continued care. Patients must be 
withdrawn from the study if any of the following events occur:
1.
Patient withdraws consent or requests withdrawal from 
the study for any reason.
2.
Patient is noncompliant with the study procedures and 
assessments in the opinion of the investigator.
3.
The sponsor requests withdrawal of the patient.
4.
Patient experiences an adverse event or other medical 
condition which indicates to the investigator that 
continued participation is not in the best interest of the 
patient, for example, but not limited to osteonecrosis of 
the jaw, atypical subtrochanteric and diaphyseal 
femoral fractures, serious infections, severe 
dermatologic adverse reactions or severe 
musculoskeletal pain.
…
Investigators should attempt to obtain information on patients in 
the case of withdrawal from the study. Results of any 
evaluations and observations, together with a narrative 
describing the reason(s) for withdrawal from the study, must be 
Included examples for 
events leading to study 
discontinuation and 
provided instructions for 
the management of BMD 
reduction of more than 
7% from baseline

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the primary reason for withdrawal from the study.
If a patient experiences a BMD reduction of more than 7% from 
baseline at any time during the study, the investigator needs to 
discuss with the patient the implications for her fracture risk, 
alternative treatment options and the option for continuing in the 
study and to document that discussion and the decision made. If 
alternative treatment is recommended further study drug 
administration should be discontinued and every effort should be 
taken to complete remaining study visits in the main treatment 
period, regardless of the type of alternative treatment chosen by 
the subject.
If a patient exhibits clinical symptoms that may indicate 
COVID-19 infection after entering the study, the patient should 
be tested for active COVID-19 infection...
recorded in the source documents. The case report form (CRF) 
must document the primary reason for withdrawal from the 
study.
If a patient experiences a BMD reduction of more than 7% from 
baseline at any time during the study, the investigator needs to 
discuss with the patient the implications for her fracture risk, 
alternative treatment options and the option for continuing in the 
study and to document that discussion and the decision made. If 
alternative treatment is recommended further study drug 
administration should be discontinued and every effort should 
be taken to complete remaining study visits in the main 
treatment period, regardless of the type of alternative treatment 
chosen by the subject.
If a patient exhibits clinical symptoms that may indicate 
COVID-19 infection after entering the study, the patient should 
be tested for active COVID-19 infection...
Section 4.5, other Section affected by this change: Section 3.5 (Table 1)
A patient with a screening serum 25 hydroxy (OH) vitamin D 
level <≤20 ng/mL may be rescreened once to re evaluate vitamin 
D level post repletion. Patients with albumin adjusted serum 
calcium outside the normal range, as assessed by the central 
laboratory, may be rescreened once to re evaluate calcium levels. 
Informed consent obtained at the beginning of the screening 
period also covers the partial rescreening for low vitamin D or for 
calcium; therefore reconsenting is not required.
A patient with a screening serum 25 hydroxy (OH) vitamin D 
level ≤20 ng/mL may be rescreened once to re evaluate vitamin 
D level post repletion. Patients with albumin adjusted serum 
calcium outside the normal range, as assessed by the central 
laboratory, may be rescreened once to re evaluate calcium 
levels. Informed consent obtained at the beginning of the 
screening period also covers the partial rescreening for low 
vitamin D or for calcium; therefore reconsenting is not required.
Correction (per inclusion 
criterion h patients have 
to have a serum 25 (OH) 
vitamin D level >20 
ng/mL at screening)
5.
TREATMENTS
Section 5.1.3
Patients will be instructed to take 1000 mg calcium daily and at 
least 400 IU vitamin D daily from screening to week 78 (EOS). 
Calcium and vitamin D will be provided from local sources. 
If hypocalcemia is detected, and there is no additional underlying 
reason, the investigator may decide to treat with additional 
calcium supplementation if appropriate. this should be further 
monitored and the below can be used for the corrective treatment: 
Patients will be instructed to take 1000 mg calcium daily and at 
least 400 IU vitamin D daily from screening to week 78 (EOS). 
Calcium and vitamin D will be provided from local sources. 
If hypocalcemia is detected, and there is no additional 
underlying reason, this should be further monitored and the 
below can be used for the corrective treatment: 

Mild to moderate hypocalcemia (≥7.5 mg/dL, 
Included instructions for 
the management of 
hypocalcemia and 
hypercalcaemia

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
Mild to moderate hypocalcemia (≥7.5 mg/dL, < 8.4 
mg/dL adjusted calcium): calcium, up to 3000 
mg/day (oral) at the discretion of the investigator 

Symptomatic hypocalcemia or severe asymptomatic 
hypocalcemia (< 7.5 mg/dL adjusted calcium): 
intravenous calcium followed by oral calcium at the 
discretion of the investigator. 
In case of continuous symptomatic or severe asymptomatic 
hypocalcemia the investigator should consider to postpone study 
drug administration by a maximum of 2 months and should 
discuss the situation with the medical monitor.
If hypercalcaemia is detected, supplementation with calcium and 
vitamin D should be interrupted and calcium levels should be 
further monitored; severe hypercalcaemia might be treated (eg, 
calcitonin or calcimimetics) at the discretion of the investigator. 
Patients will be allowed to continue treatment with study drug.
< 8.4 mg/dL adjusted calcium): calcium, up to 
3000 mg/day (oral) at the discretion of the 
investigator 

Symptomatic hypocalcemia or severe 
asymptomatic hypocalcemia (< 7.5 mg/dL 
adjusted calcium): intravenous calcium followed 
by oral calcium at the discretion of the 
investigator. 
In case of continuous symptomatic or severe asymptomatic 
hypocalcemia the investigator should consider to postpone study 
drug administration by a maximum of 2 months and should 
discuss the situation with the medical monitor.
If hypercalcaemia is detected, supplementation with calcium 
and vitamin D should be interrupted and calcium levels should 
be further monitored; severe hypercalcaemia might be treated 
(eg, calcitonin or calcimimetics) at the discretion of the 
investigator. Patients will be allowed to continue treatment with 
study drug.
Section 5.8 (last paragraph)
At the investigational center, only the pharmacist or designee 
who will dispense the study drug and the study drug 
administrator will be unblinded. These staff will not participate in 
any efficacy, pharmacokinetic, pharmacodynamic, 
immunogenicity, and safety assessments.
At the investigational center, only the pharmacist or designee 
who will dispense the study drug and the study drug 
administrator will be unblinded. These staff will not participate 
in any efficacy, pharmacokinetic, pharmacodynamic, 
immunogenicity, and safety assessments.
Clarified that staff 
involved in study drug 
preparation/administratio
n will not be involved in 
any study assessments
6.
ASSESSMENT OF EFFICACY AND PHARMACODYNAMICS
Section 6.1.1, other Section affected by this change: 6.1.2
LS-BMD will be measured by DXA. Hologic and GE Lunar 
DXA machines will be used and the same machine should be 
used for all study procedures for a particular patient for the 
duration of the study. DXA machine changes during the study are 
strongly discouraged; however, if a machine is changed during 
the study, the central imaging vendor will oversee the change in 
order to minimize the impact on assessments of BMD change. 
All LS-BMD DXA scans will be submitted to and analyzed by 
LS-BMD will be measured by DXA. Hologic and GE Lunar 
DXA machines will be used and the same machine should be 
used for all study procedures for a particular patient for the 
duration of the study. DXA machine changes during the study 
are strongly discouraged; however, if a machine is changed 
during the study, the central imaging vendor will oversee the 
change in order to minimize the impact on assessments of BMD 
change. All LS-BMD DXA scans will be submitted to and 
Clarified that DXA 
results after start of 
treatment will be 
provided to the 
investigator after study 
completion 

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the central imaging vendor. The results of the DXA scans after 
start of treatment will be provided to the investigator after 
completion of the study (after week 78) and DBL upon request of 
the patient and/or due to country regulation.
Lumbar spine scans must include L1 through L4. The vertebrae 
on which the measurement is based should be consistent 
throughout the study on an individual patient level.
…
analyzed by the central imaging vendor. The results of the DXA 
scans after start of treatment will be provided to the investigator 
after completion of the study (after week 78) and DBL upon 
request of the patient and/or due to country regulation.
Lumbar spine scans must include L1 through L4. The vertebrae 
on which the measurement is based should be consistent 
throughout the study on an individual patient level.
…
Section 6.1.2; other Section affected by this change: Section 3.5 (Table 1)
Total hip and femoral neck BMD will be measured by DXA. 
These scans will be unilateral only. For each patient, the same hip 
should be scanned throughout the study. Hologic and GE Lunar 
DXA machines will be used and the same machine must be used 
for all study procedures for a particular patient for the duration of 
the study. All hip and femoral neck bone DXA scans will be 
submitted to and analyzed by the central imaging vendor. …
Total hip and femoral neck BMD will be measured by DXA. 
These scans will be unilateral only. For each patient, the same 
hip should be scanned throughout the study. Hologic and GE 
Lunar DXA machines will be used and the same machine must 
be used for all study procedures for a particular patient for the 
duration of the study. All hip and femoral neck bone DXA scans 
will be submitted to and analyzed by the central imaging 
vendor. …
Specified that total hip 
and femoral neck BMD 
will be measured by 
unilateral DXA
Section 6.1.3, other Section affected by this 6.1.4
Patients will undergo a lateral spine X-ray for assessment of 
vertebral fractures by the central imaging vendor. Nominally, 
vertebral fracture will be assessed in all vertebrae from the fourth 
thoracic vertebra (T4) to the fourth lumbar vertebra (L4). Any 
new fracture should be reported as an adverse event (Section 
7.1.2).
Patients will undergo a lateral spine X-ray for assessment of 
vertebral fractures by the central imaging vendor. Nominally, 
vertebral fracture will be assessed in all vertebrae from the 
fourth thoracic vertebra (T4) to the fourth lumbar vertebra (L4). 
Any new fracture should be reported as an adverse event
(Section 7.1.2).
Clarified that any new 
fracture should be 
reported as an adverse 
event.
7.
ASSESSMENT OF SAFETY
Section 7.3.2, other sections affected by this change: Table 1 in Section 3 and Appendix B (visit 2)
Added new subsection for urine pregnancy test:
7.3.2.3. Urine Pregnancy Test
At day 1 (prior to randomization), a pregnancy test (urine 
dipstick) will be done to confirm that women are not pregnant.
7.3.2.3. Urine Pregnancy Test
At day 1 (prior to randomization), a pregnancy test (urine 
dipstick) will be done to confirm that women are not pregnant.
Added a pregnancy test 
(urine dipstick) at day 1
9.
STATISTICS

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Section 9.5.4.2
Supplementary analyses to evaluate effect of assumptions on 
missing data on the results:

…
The resulting complete, imputed datasets will each be 
analyzed using the same model as the primary analysis model, 
and the resulting statistics combined using methodology 
provided by Rubin (1987) and Little and Rubin (2002).

to further alleviate the concern on the uncertainty 
introduced by missing data, the following 2 separate 1-
sided tests of alpha=0.05 with missing data imputed under
the corresponding null using a multiple imputation method 
will be conducted:

in the first test, missing values for the TVB-009P 
group will be imputed under the non-inferiority null 
(the lower boundary of the equivalence margin, -
1.45%) for testing whether it is non-inferior to 
PROLIA US; 

in the second test, missing values for the TVB-009P 
group will be imputed under the non-superiority null 
(+1.45%) for testing whether it is non-superior to 
PROLIA US. 
The resulting complete, imputed datasets will each be 
analyzed using the same model as the primary analysis model, 
and the resulting statistics combined using methodology 
provided by Rubin (1987) and Little and Rubin (2002).
…
Supplementary analyses to evaluate effect of assumptions on 
missing data on the results:

…
The resulting complete, imputed datasets will each be 
analyzed using the same model as the primary analysis 
model, and the resulting statistics combined using 
methodology provided by Rubin (1987) and Little and Rubin 
(2002).

to further alleviate the concern on the uncertainty 
introduced by missing data, the following 2 separate 1-
sided tests of alpha=0.05 with missing data imputed 
under the corresponding null using a multiple imputation 
method will be conducted:

in the first test, missing values for the TVB-009P 
group will be imputed under the non-inferiority null 
(the lower boundary of the equivalence margin, -
1.45%) for testing whether it is non-inferior to 
PROLIA US; 

in the second test, missing values for the TVB-009P 
group will be imputed under the non-superiority null 
(+1.45%) for testing whether it is non-superior to 
PROLIA US. 
The resulting complete, imputed datasets will each be 
analyzed using the same model as the primary analysis 
model, and the resulting statistics combined using 
methodology provided by Rubin (1987) and Little and Rubin 
(2002).
…
Added additional 
supplementary analyses 
to further alleviate the 
concern on the 
uncertainty introduced by 
missing data
Appendix A
Sponsor’s Medical Expert/Contact Point designated by the 
Sponsor for Further Information on the Study
For serious adverse events:
Send by email to the address of the local safety officer/contract 
research organization (LSO/CRO) provided on the serious 
Sponsor’s Medical Expert/Contact Point designated by the 
Sponsor for Further Information on the Study
For serious adverse events:
Send by email to the address of the local safety officer/contract 
research organization (LSO/CRO) provided on the serious 
Update

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Appendix B.
STUDY PROCEDURES AND ASSESSMENTS BY VISIT
Visits 3, 4, 5, 6, 8, 10 and 11 may be conducted at the patient's home should circumstances 
dictate.
1. Visit 1: Screening (Up to 4 weeks before Visit 2)
The screening visit (visit 1) will take place not more than 4 weeks before the baseline visit 
(visit 2). The following procedures will be performed at visit 1:

obtain signed and dated informed consent before any study-related procedures are 
performed

review inclusion and exclusion criteria

demographics/medical history

dispense Vitamin D and calcium supplements

document prior medication and treatment history

clinical laboratory test sampling:

serum chemistry

hematology

serum follicle stimulating hormone (FSH) if applicable

serum estradiol (E2) if applicable

estimated glomerular filtration rate (eGFR) (using the Modification of Diet in 
Renal Disease [MDRD] formula)

serum vitamin D

physical examination (including height and weight)

12-lead electrocardiogram (ECG)

vital signs measurement

lumbar spine-bone mineral density assessment (LS-BMD) by dual-energy X-ray 
absorptiometry (DXA)

total hip and femoral neck bone mineral density (BMD) assessment by DXA

lateral spine X-ray

inquire about adverse events

inquire about concomitant medications

inquire about coronavirus disease 2019 (COVID-19)

COVID-19 viral test (test can be performed any time during the study that the patient 
displays symptoms)

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
inform patients of study restrictions and compliance requirements
2. Visit 2: Baseline (Day 1)
Patients who meet the inclusion and exclusion criteria at visit 1 will continue to visit 2, when 
baseline assessments will be conducted.
The following procedures will be performed at visit 2, prior to investigational medicinal 
product (IMP) administration:

review inclusion and exclusion criteria

pregnancy test (urine dipstick) (prior to randomization)

assign randomization/treatment numbers and enter in case report form (CRF)

document prior medication and treatment history

clinical laboratory test sampling

serum chemistry

hematology

coagulation (international normalized ratio [INR], prothrombin [PT] and partial 
prothrombin [PPT])

cholesterol (low density lipoprotein [LDL], high density lipoprotein [HDL], 
HDL/total)

fasting triglycerides

urinalysis

immunogenicity sampling

serum anti-drug antibody (ADA)

12-lead ECG

vital signs measurement

pharmacokinetics sampling

serum concentration of IMP

pharmacodynamics sampling

fasting serum C-telopeptide cross-link of type 1 collagen (sCTX-1) and 
procollagen type 1 N propeptide (P1NP)

inquire about adverse events

inquire about concomitant medications

inquire about COVID-19

inform patients of study restrictions and compliance requirements

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Patients will have IMP administered by qualified site staff. The following procedure will be 
performed at visit 2, following IMP administration:

local tolerability at the injection site

record device-related adverse events
3. Visits 3 through 8: Main Treatment Period
a. Visit 3: Main Treatment Period (Day 15±3 days)
The following procedures will be performed:

immunogenicity sampling 

serum ADA

vital signs measurement

pharmacokinetics sampling

serum concentration of IMP

pharmacodynamics sampling

fasting serum sCTX-1 and P1NP

inquire about adverse events

inquire about concomitant medications

inquire about COVID-19

inform patients of study restrictions and compliance requirements
b. Visit 4: Main Treatment Period (Week 4±3 days)
The following procedures will be performed:

clinical laboratory tests sampling

serum chemistry

hematology

immunogenicity sampling 

serum ADA

vital signs measurement

pharmacokinetics sampling

serum concentration of IMP

pharmacodynamics sampling

fasting serum sCTX-1 and P1NP

inquire about adverse events

inquire about concomitant medications

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
inquire about COVID-19

inform patients of study restrictions and compliance requirements
c.
Visit 5: Main Treatment Period (Week 8±5 days)
The following procedures will be performed:

immunogenicity sampling

serum ADA

vital signs measurements

pharmacokinetics sampling

serum concentration of IMP

pharmacodynamics sampling

fasting serum sCTX-1 and P1NP

inquire about adverse events

inquire about concomitant medications

inquire about COVID-19

inform patients of study restrictions and compliance requirements
d. Visit 6: Main Treatment Period (Week 12±7 days)
The following procedures will be performed:

clinical laboratory tests:

serum chemistry

hematology

immunogenicity sampling 

serum ADA

vital signs measurement

pharmacokinetics sampling

serum concentration of IMP

pharmacodynamics sampling

fasting serum sCTX-1 and P1NP

inquire about adverse events

inquire about concomitant medications

inquire about COVID-19

inform patients of study restrictions and compliance requirements

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e.
Visit 7: Main Treatment Period (Week 26±7 days)
The following procedures will be performed at visit 7, prior to IMP administration:

clinical laboratory tests:

serum chemistry

hematology

coagulation (INR, PT and PPT)

cholesterol (LDL, HDL, HDL/total)

fasting triglycerides

urinalysis

immunogenicity sampling 

serum ADA

physical examination (including height and weight)

12-lead ECG

vital signs measurement

LS-BMD by DXA

total hip and femoral neck BMD assessment by DXA

pharmacokinetics sampling

serum concentration of IMP

pharmacodynamics sampling

fasting serum sCTX-1 and P1NP

inquire about adverse events

inquire about concomitant medications

inquire about COVID-19

inform patients of study restrictions and compliance requirements
Patients will have IMP administered by qualified site staff. The following procedure will be 
performed at visit 7, following IMP administration:

local tolerability at the injection site

record device-related adverse events
f.
Visit 8: Main Treatment Period (Week 39±14 days)
The following procedures will be performed:

clinical laboratory tests:

serum chemistry

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
hematology

immunogenicity sampling 

serum ADA

vital signs measurements

pharmacokinetics sampling

serum concentration of IMP

pharmacodynamics sampling

fasting serum sCTX-1 and P1NP

inquire about adverse events

inquire about concomitant medications

inquire about COVID-19

inform patients of study restrictions and compliance requirements
4. Visit 9: End of Main Treatment Period and Start of Transition Period 
(Week 52±14 days)
The following procedures will be performed at visit 9, prior to IMP administration:

clinical laboratory tests:

serum chemistry

hematology

coagulation (INR, PT and PPT)

cholesterol (LDL, HDL, HDL/total)

fasting triglycerides

urinalysis

immunogenicity sampling 

serum ADA

physical examination (including height and weight)

12-lead ECG

vital signs measurement

LS-BMD by DXA

Total hip and femoral neck BMD by DXA 

lateral spine X-ray

pharmacokinetics sampling

serum concentration of IMP

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
pharmacodynamics sampling

fasting serum sCTX-1 and P1NP

inquire about adverse events

inquire about concomitant medications

inquire about COVID-19

inform patients of study restrictions and compliance requirements

randomization for the transition period. Patients in the PROLIA US treatment group 
will be re-randomized in a 1:1 ratio to receive a third dose of PROLIA US or switch 
to TVB-009P and receive a single dose of TVB-009P in the transition period. Patients 
who were initially randomized to TVB-009P will continue to receive TVB-009P; 
however, to maintain blinding, the randomization process will be performed for all 
patients (although only patients in the PROLIA US arm will actually be 
re-randomized). Randomization will not be applied to patients where this visit is for 
early termination.
Patients will have IMP administered by qualified site staff. The following procedure will be 
performed at visit 9, following IMP administration:

local tolerability at the injection site

record device-related adverse events
5. Visit 10: Transition Period (Week 54, 2 weeks±3 days after Visit 9)
The following procedures will be performed:

immunogenicity sampling 

serum ADA

vital signs measurement

pharmacokinetics sampling

serum concentration of IMP

pharmacodynamics sampling

fasting serum sCTX-1 and P1NP

inquire about adverse events

inquire about concomitant medications

inquire about COVID-19

inform patients of study restrictions and compliance requirements
6. Visit 11: Transition Period (Week 65, 13 weeks±14 days after Visit 9)
The following procedures will be performed:

clinical laboratory tests:

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
serum chemistry

hematology

immunogenicity sampling

serum ADA

vital signs measurement

pharmacokinetics sampling

serum concentration of IMP

pharmacodynamics sampling

fasting serum sCTX-1 and P1NP

inquire about adverse events

inquire about concomitant medications

inquire about COVID-19

inform patients of study restrictions and compliance requirements
7. Visit 12: End of Study/Early Termination (Week 78, 26 weeks±14 days after Visit 9) 
The following procedures will be performed:

clinical laboratory tests:

serum chemistry

hematology

immunogenicity sampling 

serum ADA

physical examination (including height and weight)

12-lead ECG

vital signs measurement

total hip and femoral neck BMD assessment by DXA (assessment will not be 
performed for patients where this visit is for early termination, unless early 
termination occurs between the week 26 and week 52 visits [the minimum time 
between two DXA scans should be 3 months])

lateral spine X-ray (assessment will not be performed for patients where this visit is 
for early termination, unless early termination occurs between the week 26 and week 
52 visits)

LS-BMD by DXA (assessment will not be performed for patients where this visit is 
for early termination, unless early termination occurs between the week 26 and week 
52 visits [the minimum time between two DXA scans should be 3 months])

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
pharmacokinetics sampling

serum concentration of IMP

pharmacodynamics sampling

fasting serum sCTX-1 and P1NP

inquire about adverse events

inquire about concomitant medications

inquire about COVID-19
8. Unscheduled Visits
An unscheduled visit may be performed at any time during the study at the patient’s request 
and as deemed necessary by the investigator. The date and reason for the unscheduled visit 
will be recorded on the CRF as well as any other data obtained from procedures and 
assessments.
Procedures performed during unscheduled visits include:

vital signs measurement

inquire about adverse events

inquire about concomitant medication

inquire about COVID-19

inform patients of study restrictions and compliance requirements
Other procedures and assessments may be performed at the discretion of the investigator.

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APPENDIX C. QUALITY CONTROL AND QUALITY ASSURANCE
Protocol Amendments and Protocol Deviations
Protocol Amendments
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the Independent Ethics Committee 
(IEC)/ Institutional Review Board (IRB) and national and local competent authorities, as 
applicable, except when necessary to address immediate safety concerns to the patients or when 
the change involves only logistics or administration. The principal investigator at each 
investigational center, the coordinating investigator (if applicable), and the sponsor will sign the 
protocol amendment.
Important Protocol Deviations
Any deviation from the protocol that affects, to a significant degree, (a) the safety, physical, or 
mental integrity of the patients in the study and/or (b) the scientific value of the study will be 
considered an important protocol deviation. Important protocol deviations may include 
non-adherence on the part of the patient, the investigator, or the sponsor to protocol-specific 
inclusion and exclusion criteria, primary objective variable criteria, or good clinical practice 
(GCP) guidelines; noncompliance to investigational medicinal product (IMP) administration; use 
of prohibited medications. Important protocol deviations will be identified and recorded by 
investigational center personnel. All important protocol deviations will be reported to the 
responsible IEC/IRB, as required.
When an important protocol deviation is reported, the sponsor will determine whether to 
withdraw the patient from the study or permit the patient to continue in the study, with 
documented approval from the medical expert. The decision will be based on ensuring the safety 
of the patient and preserving the integrity of the study.
If a patient experiences an adverse event or medical emergency, deviations from the protocol 
may be allowed on a case-by-case basis. To ensure patient safety, after the event has stabilized or 
treatment has been administered (or both), the investigator or other physician in attendance must 
contact the physician identified in the Clinical Study Personnel Contact Information section of 
this protocol as soon as possible to discuss the situation. The investigator, in consultation with 
the sponsor, will decide whether the patient should continue to participate in the study.
Changes in the inclusion and exclusion criteria of the protocol are not prospectively granted by 
the sponsor. If investigational center personnel learn that a patient who did not meet protocol 
inclusion and exclusion criteria was entered in a study, they must immediately inform the 
sponsor of the important protocol deviation. If such patient has already completed the study or 
has withdrawn early, no action will be taken but the deviation will be recorded.
Information to Study Personnel
The investigator is responsible for giving information about the study to all personnel members 
involved in the study or in any element of patient management, both before starting the study and 
during the course of the study (eg, when new personnel become involved). The investigator must 
ensure that all study personnel are qualified by education, experience, and training to perform 

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their specific task. These study personnel members must be listed on the investigational center 
authorization form, which includes a clear description of each personnel member’s 
responsibilities. This list must be updated throughout the study, as necessary.
The study monitor is responsible for explaining the protocol to all study personnel, including the 
investigator, and for ensuring they comply with the protocol.
Study Monitoring
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form (ICF) and the study is 
conducted according to applicable SOPs, the protocol, and other written instructions and 
regulatory guidelines.
The study monitor is the primary association between the sponsor and the investigator. The main 
responsibilities of the study monitor are to visit the investigator before, during, and after the 
study to ensure adherence to the protocol, that all data are correctly and completely recorded and 
reported, and that informed consent is obtained and recorded for all patients before they 
participate in the study and when changes to the consent form are warranted, in accordance with 
IEC/IRB approvals.
The study monitor will contact the investigator and visit the investigational center according to 
the monitoring plan. The study monitor will be permitted to review and verify the various 
records (case report forms [CRF]s and other pertinent source data records, including specific 
electronic source document relating to the study) to verify adherence to the protocol and to 
ensure the completeness, consistency, and accuracy of the data being recorded.
As part of the supervision of study progress, other sponsor personnel may, on request, 
accompany the study monitor on visits to the investigational center. The investigator and 
assisting personnel must agree to cooperate with the study monitor to resolve any problems, 
errors, or possible misunderstandings concerning the findings detected during the course of these 
monitoring visits or provided in follow-up written communication.
For COVID-19 updates, refer to Appendix M.
Audit and Inspection
The sponsor may audit the investigational center to evaluate study conduct and compliance with 
protocols, standard operating procedures (SOP)s, GCP guidelines, and applicable regulatory 
requirements. The sponsor’s Global Clinical Quality Assurance, independent of Global Specialty 
Development, is responsible for determining the need for (and timing of) an investigational 
center audit.
The investigator must accept that competent authorities and sponsor representatives may conduct 
inspections and audits to verify compliance with GCP guidelines.
For COVID-19 updates, refer to Appendix M.

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APPENDIX D. ETHICS
Informed Consent
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient of all pertinent aspects of the study, including the written information approved by the 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB). All written and oral 
information about the study will be provided in a language as nontechnical as practical to be 
understood by the patient. The patient should be given ample time and opportunity to inquire 
about details of the study and to decide whether or not to participate in the study. The above 
should be detailed in the source documents.
Written informed consent will be obtained from each patient before any study specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained. The patient’s willingness to participate in the study will be 
documented in the informed consent form (ICF), which will be signed and personally dated by 
the patient and by the person who conducted the informed consent discussion. The investigator 
will keep the original informed consent forms, and copies will be given to the patients. It will 
also be explained to the patients that the patient is free to refuse participation in the study and 
free to withdraw from the study at any time without prejudice to future treatment.
Adult patients with a legally acceptable representative should provide informed consent 
according to national and local requirements.
Competent Authorities and Independent Ethics Committees/Institutional Review Boards
Before this study starts, the protocol will be submitted to the national competent authority and to 
the respective IEC/IRB for review. As required, the study will not start at a given investigational 
center before the IEC/IRB and competent authority (as applicable) for the investigational center 
give written approval or a favorable opinion.
Confidentiality Regarding Study Patients
The investigator must ensure that the privacy of the patients, including their identity and all 
personal medical information, will be maintained at all times. In case report forms (CRF)s and 
other documents or image material submitted to the sponsor, patients will be identified not by 
their names, but by an identification number.
Personal medical information may be reviewed for the purpose of patient safety or for verifying 
data in the source and the CRF. This review may be conducted by the study monitor, properly 
authorized persons on behalf of the sponsor, Global Quality Assurance (GCA), or competent 
authorities. Personal medical information will always be treated as confidential.
Registration of the Clinical Study
In compliance with national and local regulations and in accordance with Teva standard 
procedures, this clinical study will be registered on trials registry websites.

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APPENDIX E. LOST TO FOLLOW-UP
A patient will be considered lost to follow-up if she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the investigational center.
The following actions must be taken if a patient fails to return to the investigational center for a 
required study visit:

The investigational center must attempt to contact the patient and reschedule the 
missed visit as soon as possible, counsel the patient on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the patient wishes to and/or 
should continue in the study.

In cases in which the patient is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the patient (where possible, 3 telephone 
calls and, if necessary, a certified letter to the patient’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
patient’s medical record.

Should the patient continue to be unreachable, she will be considered to have 
withdrawn from the study with a primary reason of ‘lost to follow-up’.

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Appendix F.
LIST OF PROHIBITED MEDICATIONS
Any osteoporosis treatment (other than calcium and vitamin D supplements) or ongoing use of 
any bone active drugs are prohibited during study.

denosumab, other than the study drug

romosozumab

strontium

fluoride (for treatment of osteoporosis)

intravenous (iv) bisphosphonates

oral bisphosphonates

teriparatide or any parathyroid hormone (PTH) analogs

tibolone or any systemic oral or transdermal estrogen or selective estrogen receptor 
modulators (SERM)s

calcitonin

cinacalcet

prolonged (ie, >2 months) systemic glucocorticoid therapy

heparin (except topical)

anti-convulsives (with the exception of benzodiazepines)

systemic ketoconazole

adrenocorticotropic hormone

lithium

gonadotropin releasing hormone agonists, or anabolic steroids

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APPENDIX G. CLINICAL CRITERIA FOR DIAGNOSING 
ANAPHYLAXIS
As detailed by Sampson et al 2006, anaphylaxis is broadly defined as, “a serious allergic reaction 
that is rapid in onset and may cause death.” Diagnostic criteria defined by the National Institute 
of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network during the second 
symposium on the definition and management of anaphylaxis, modified from Sampson et al 
2006, are as follows:
Anaphylaxis is highly likely when any 1 of the following 3 criteria is fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue, 
uvula) and at least 1 of the following:

respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow [PEF], hypoxemia)

reduced blood pressure or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):

involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula)

respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia)

reduced blood pressure (BP) or associated symptoms (eg, hypotonia [collapse], 
syncope, incontinence)

persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to a known allergen for that patient (minutes to several 
hours):

adults: systolic BP of <90 mm Hg or >30% decrease from that person’s baseline
In the event of suspected severe hypersensitivity (including anaphylaxis), vital signs, including 
oxygen saturation and respiration rate, will be measured. Other assessments will be performed at 
the discretion of the investigator.

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APPENDIX H. PRODUCT COMPLAINTS
1. Clinical Product Complaints/Device Deficiency
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical investigational medicinal product (IMP) supplies or clinical 
device supplies used in a clinical research study sponsored by Teva. Examples of a product 
complaint include but are not limited to:

suspected contamination

questionable stability (eg, color change, flaking, crumbling, etc.)

defective components

missing or extra units (eg, primary container is received at the investigational center 
with more or less than the designated number of units inside)

incorrect packaging, or incorrect or missing labeling/labels

device not working correctly or appears defective in some manner
Each investigational center will be responsible for reporting a possible clinical product 
complaint/device deficiency by completing the product complaint form provided by Teva and 
emailing it to clinical.productcomplaints@tevapharm.com within 48 hours of becoming aware of 
the issue.
For complaints involving a device, combination product (CP) or other retrievable item, it is 
required that the device/CP (or item) be sent back to the sponsor for investigative testing 
whenever possible. For complaints involving an IMP, all relevant samples (eg, the remainder of 
the patient’s IMP supply) should be sent back to the sponsor for investigative testing whenever 
possible.
Product Complaint Information Needed from the Investigational Center
In the event that the product complaint form cannot be completed, the investigator will provide 
the following information, as available:

investigational center number and principal investigator name

name, phone number, and address of the source of the complaint

clinical protocol number

patient identifier (patient study number) and corresponding visit numbers, if 
applicable

patient number for double-blind studies

product available for return: Yes/No

product was taken or used according to protocol: Yes/No

description or nature of complaint

associated serious adverse event or serious adverse device event: Yes/No

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
device deficiency that could lead to a serious adverse event: Yes/No

clinical supplies unblinded (for blinded studies): Yes/No

date and name of person receiving the complaint
Note: Reporting a product complaint/device deficiency must not be delayed even if not all the 
required information can be obtained immediately. Known information must be reported 
immediately. The sponsor will collaborate with the investigator to obtain any outstanding 
information.
Handling of Investigational Medicinal Product(s) and Devices at the Investigational 
Center(s)
The investigator is responsible for retaining the product or device in question in a location 
separate from the investigator’s clinical study supplies. The sponsor may request that the 
investigator return the product for further evaluation and/or analysis. If this is necessary, the 
clinical study monitor or designee will provide the information needed for returning the 
IMP/device.
If it is determined that the investigational center must return all IMP/devices, the sponsor will 
provide the information needed to handle the return.
The integrity of the randomization code and corresponding blinded clinical supplies will be 
maintained whenever possible. A serious adverse event or the potential for a product quality 
problem existing beyond the scope of the complaint may be a reason to unblind the clinical 
supplies for an affected patient.
Adverse Events or Serious Adverse Events Associated with a Product Complaint
If there is an adverse event or serious adverse event due to product complaint, the protocol 
should be followed for recording and reporting (Section 7.1.2 and Section 7.1.5.3, respectively).
Documenting a Product Complaint
The investigator will record in the source documentation a description of the product complaint, 
the initial determination if the deficiency could have led to a serious adverse event, and any 
actions taken to resolve the complaint and to preserve the safety of the patient. Once the 
complaint has been investigated by the sponsor and the investigator, if necessary, an event 
closure letter may be sent to the investigational center where the complaint originated or to all 
investigational centers using the product or device.
Medical device incidents, including those resulting from malfunctions of the device, must be 
detected, documented, and reported by the investigator throughout the study.
1. Assessment of Device Performance 
Device performance will be assessed by device deficiencies and product complaints.
A device deficiency is any inadequacy of an investigational medical device with respect to its 
identity, quality, durability, reliability, safety, or performance that has not led to an adverse event 
(Figure 3). This definition includes malfunctions, use errors, inadequate labeling 
(eg, unintelligible label, incorrect expiry date).

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The investigator should try to determine whether the device deficiency could have led to a 
serious adverse event and include this assessment in the product complaint form.
Device deficiencies with potential serious adverse device effect are deficiencies that might have 
led to a serious adverse device effect if:

suitable action had not been taken (or)

intervention had not been made (or)

if circumstances had been less fortunate
These device deficiencies shall be reported to the IEC/IRB by the investigator and to the 
regulatory authorities by the sponsor according to the national and local regulations.
Figure 3:
Decision Tree for Device Deficiencies
IEC=Institutional ethics committee; IRB=Institutional Review Board; SAE=serious adverse event.

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APPENDIX I.
PHARMACOKINETICS AND PHARMACODYNAMICS
Specimen Sampling and Handling
For serum collection, samples will be collected in vacutainer tubes containing no anticoagulant 
and allowed to set at room temperature for between 1 and 1.5 hours to allow for serum separation 
to occur. Samples will then be centrifuged (1500g, approximately 10 minutes, at 4 to 8°C). 
Separated serum will be transferred in approximately equal portions into 2 opaque, labeled, 
polypropylene tubes (Sets A and B).
Labels for samples should include study number, patient randomization number, period, nominal 
collection time, Set A or B, and indication that they are pharmacokinetic/pharmacodynamic 
samples. Samples will be stored at a temperature -80°C (nominal) in an upright position until 
they are shipped to the bioanalytical laboratory (
) for analysis.
Shipment and Analysis of Samples
Serum samples for all patients will be shipped from the investigational center to the GBT, in dry 
ice with temperature data logger. The bioanalytical laboratory (
) will be notified before the 
shipment of the samples and the shipping information will be sent when the samples are shipped. 
An electronic file containing sample demographics will be emailed to the bioanalytical 
laboratory and the sponsor’s representatives from bioanalytical departments for each shipment.
Set A samples will be transported with a temperature data logger and frozen with dry ice 
sufficient for 4 days, by next-day courier to the bioanalytical laboratory (
).
Set B samples will be sent to the same laboratory as that for Set A samples on a subsequent day 
by next-day courier. Instructions as to the disposition of the Set B samples will be provided by 
the sponsor.
Samples should not be shipped on a holiday. Samples are not to arrive on the 
 weekend or a 
holiday.
Samples will be analyzed using an appropriate validated method. Timing of the initiation of 
sample analysis will be determined by the sponsor’s representatives of bioanalytical departments 
responsible for the bioanalysis while keeping the study blinding intact.

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APPENDIX J.
IMMUNOGENICITY SAMPLES
Blood Sampling and Handling
For serum collection, samples will be collected in vacutainer tubes containing no anticoagulant, 
and allowed to set at room temperature for between 1 and 1.5 hours to allow for serum separation 
to occur. Samples will then be centrifuged (1500g, approximately 10 minutes, at 4 to 8°C). 
Separated serum will be transferred in approximately equal portions into 2 opaque, labeled, 
polypropylene tubes (Sets A and B).
Label of samples should include study number, patient randomization number, period, nominal 
collection time, Set A or B, and indication that they are anti-drug antibodies (ADA) samples. 
Serum samples will be stored at a temperature of -80°C (nominal) in an upright position until 
they are shipped to the bioanalytical laboratory 
Shipment and Analysis of Samples
Serum samples for all patients will be shipped from the investigational center to the bioanalytical 
laboratory (
), in dry ice with a temperature data logger. The bioanalytical laboratory (
) 
will be notified before the shipment of the samples and the shipping information will be sent 
when the samples are shipped. An electronic file containing sample demographics will be 
emailed to the bioanalytical laboratory and the sponsor’s representatives from bioanalytical 
departments for each shipment.
Set A samples will be transported with a temperature data logger and frozen with dry ice 
sufficient for 4 days, by next-day courier to the bioanalytical laboratory 
).
Set B samples will be sent to the same laboratory as that for Set A samples on a subsequent day 
by next-day courier. Instructions as to the disposition of the Set B samples will be provided by 
the sponsor.
Samples should not be shipped on a holiday. Samples are not to arrive on the 
 weekend or a 
holiday.
Samples will be analyzed using an appropriate validated method. Timing of the initiation of 
sample analysis will be determined by the sponsor’s representatives of bioanalytical departments 
responsible for the bioanalysis while keeping the study blinding, if any, intact.

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APPENDIX K. DATA MANAGEMENT AND RECORD KEEPING
Direct Access to Source Data and Documents
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed to the case report form (CRF). Data may not be recorded 
directly on the CRF and considered as source data unless the sponsor provides written 
instructions specifying which data are permitted to be recorded directly to the CRF.
If data are processed from other institutions or by other means (eg, clinical laboratory, central 
image center, or electronic diary data) the results will be sent to the investigational center, where 
they will be retained but not transcribed to the CRF, unless otherwise noted in the protocol. 
These data may also be sent electronically to the sponsor (or organization performing data 
management).
The medical experts, study monitors, auditors, Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB), and inspectors from competent authority (or their agents) will be given 
direct access to source data and documents (eg, medical charts/records, laboratory test results, 
printouts, videotapes) for source data verification, provided that patient confidentiality is 
maintained in accordance with national and local requirements.
The investigator must maintain the original records (ie, source documents) of each patient’s data 
at all times. The investigator must maintain a confidential patient identification list that allows 
the unambiguous identification of each patient.
Data Collection
Data will be collected using CRFs that are specifically designed for this study. The data collected 
on the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in 21 Code of Federal Regulations (CFR) Part 11 (United 
States of America) and documents of other concerned competent authorities. Before using the 
CDMS, it will be fully validated and all users will receive training on the system and 
study-specific training. After they are trained, users will be provided with individual system 
access rights.
Data will be collected at the investigational center by appropriately designated and trained 
personnel, and CRFs must be completed for each patient who provided informed consent. Patient 
identity should not be discernible from the data provided on the CRF.
If data are processed from other sources (eg, central laboratory, bioanalytical laboratory, central 
image center, electronic diary data, electronic patient-reported outcome tablet), these data will be 
sent to the investigational center, where they will be retained but not transcribed to the CRF, 
unless otherwise noted in the protocol. These data may also be sent electronically to the sponsor 
(or organization performing data management). All patient data must have supportive original 
source documentation in the medical records, or equivalent, before they are transcribed to the 
CRF. Data may not be recorded directly on the CRF and considered as source data unless the 
sponsor provides written instructions specifying which data are permitted to be recorded directly 
to the CRF.

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For patients who enter a study but do not meet entry criteria, at a minimum, data for screening 
failure reason, demography, and adverse events from the time of informed consent will be 
entered in the CRF.
Data Quality Control
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this study. Oversight will be carried out as described in the 
sponsor’s standard operating procedures (SOP)s for clinical studies. Day to day data 
management tasks for this study are delegated to a contract organization, and these functions 
may be carried out as described in the SOPs for clinical studies at that organization. These SOPs 
will be reviewed by the sponsor before the start of data management activities.
Data will be verified by the study monitor using the data source, and reviewed by data 
management using both automated logical checks and manual review. Data identified as 
erroneous, or data that are missing, will be referred to the investigational center for resolution 
through data queries. Any necessary changes will be made in the clinical database, and data 
review and validation procedures will be repeated as needed. Data from external sources will be 
compared with the information available in the CDMS and any discrepancies will be queried.
Applicable terms will be coded according to the coding conventions for this study.
At the conclusion of the study, the CDMS and all other study data will be locked to further 
additions or corrections. Locking the study data represents the acknowledgment that all data have 
been captured and confirmed as accurate. All data collected will be approved by the investigator 
at the investigational center. This approval acknowledges the investigator’s review and 
acceptance of the data as being complete and accurate.
Archiving of Case Report Forms and Source Documents
Sponsor Responsibilities
The original CRFs will be archived by the sponsor. Investigational center-specific CRFs will be 
provided to the respective investigational centers for archiving.
Investigator Responsibilities
The investigator must maintain all written and electronic records, accounts, notes, reports, and 
data related to the study and any additional records required to be maintained under country, 
state/province, or national and local laws, including, but not limited to:

full case histories

signed informed consent forms (ICF)s

patient identification lists

CRFs for each patient on a per-visit basis

data from other sources (eg, central laboratory, bioanalytical laboratory, central image 
center, electronic diary)

safety reports

financial disclosure reports/forms

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
reports of receipt, use, and disposition of the investigational medicinal product 
(IMP)s

copies of all correspondence with sponsor, the Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB), and any competent authority
The investigator will retain all records related to the study and any additional records required, as 
indicated by the protocol and according to applicable laws and regulations, until the Clinical 
Research Organization (CRO) or sponsor notifies the institution in writing that records may be 
destroyed. If, after 25 years from study completion, or earlier in the case of the investigational 
center closing or going out of business, the investigator reasonably determines that study record 
retention has become unduly burdensome, and sponsor has not provided written notification of 
destruction, then the investigator may submit a written request to sponsor at least 60 days before 
any planned disposition of study records. After receipt of such request, the sponsor may make 
arrangements for appropriate archival or disposition, including requiring that the investigator 
deliver such records to the sponsor. The investigator shall notify the sponsor of any accidental 
loss or destruction of study records.

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APPENDIX L. PUBLICATION POLICY
All unpublished information given to the investigator by the sponsor shall not be published or 
disclosed to a third party without the prior written consent of the sponsor.
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments.
The sponsor will comply with the requirements for publication of study results: 
“Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in 
Medical Journals” (International Committee of Medical Journal Editors [ICMJE] 2019). 
Publication of the results will occur in a timely manner according to applicable regulations. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual investigational 
center data. In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements:

substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work

drafting the work or revising it critically for important intellectual content

final approval of the version to be published

agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved
The publications committee established by the sponsor will oversee this process. Additional 
publications may follow. Policies regarding the publication of the study results are defined in the 
financial agreement.
No patent applications based on the results of the study may be made by the investigator nor may 
assistance be given to any third party to make such an application without the written 
authorization of the sponsor.

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APPENDIX M. MANAGEMENT OF STUDY ACTIVITIES DURING 
COVID-19 OUTBREAKS
This appendix is to address the modifications to the protocol that will be effective during 
Coronavirus Disease 2019 (COVID-19) outbreaks that affect the conduct of the study. When the 
situation at specific sites/countries allows the return to regular study activities, this appendix will 
be void for those sites/countries.
Section 3.1. General Study Design and Study Schematic Diagram; Section 3.5. Schedule of 
Study Procedures and Assessments
In the event of an emergency situation (eg, COVID-19 outbreaks), in case a patient cannot return 
to the clinic for the scheduled visits (eg, due to quarantine, isolation, patient’s concern, active 
COVID-19 infection, or closure of the site clinic) remote assessment of safety via telephone 
and/or videoconference (VC), with VC being the preferred method, may be allowed. 
Modifications to other procedures and assessments, electrocardiogram (ECG), laboratory sample 
collection (including pharmacokinetics, immunogenicity, and pharmacodynamics, etc.) might be 
performed per implemented contingency measures according to sponsor instructions and the 
corresponding manual. For example, if central laboratory samples cannot be collected for safety 
assessments, sites may have patients visit a local reference laboratory or dispatch a home health 
nurse to perform the assessments, but only after consultation with the sponsor, see Sections 7 and 
Section 8 below for details.
If pharmacokinetics, immunogenicity, and pharmacodynamics cannot be collected at site, sites 
may use a home health nurse to collect these blood samples, but only after consultation with the 
sponsor, see Sections 7 and Sections 7.4-7.8 below for details. The same collection process and 
equipment will be used in these circumstances. 
For dual-energy X-ray absorptiometry (DXA) and X-ray procedures, see Section 6 below.
In addition, the investigational medicinal product (IMP) may be administered according to the 
schedule outlined in the protocol by blinded study personnel, or home care service providers 
trained according to study specifications, via visits to the patient's place of residence. The 
patient's consent to the home visit will be collected in advance. The IMP will be transported, 
prepared, and administered in a blinded fashion per the conditions specified in the pharmacy 
manual and the injection instructions.
If the patient does not continue in the study due to site closure, the patient status should be NOT 
COMPLETED DUE TO: Other COVID-19 logistical reasons prevented patient's continuation in 
the study.
These measures will be implemented on a case-by-case basis, and only when and where they are 
warranted due to the emergency situation. Preferably, the original protocol instructions will be 
followed whenever the new instructions are not required.
Section 4.3.Withdrawal Criteria and Procedures for the Patient
If a patient exhibits clinical symptoms that may indicate COVID-19 infection after entering the 
study, the patient should be tested for active COVID-19. If the patient tests positive for active 

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COVID-19, she may continue for scheduled visits when recovered (ie, tests negative for active 
COVID-19).
Section 6. Assessment of Efficacy
In the event of an emergency situation (eg, COVID-19 outbreaks), in case a patient cannot return 
to the clinic/site for the scheduled visits (eg, due to quarantine, isolation, patient’s concern, 
active COVID-19 infection, or closure of the site clinic), DXA and X-ray procedures should be 
performed if the responsible location is not affected by the restrictions. If the responsible 
location used for DXA and X-ray cannot be visited due to special circumstances it should be 
evaluated if another location might be used after consultation and approval by the sponsor.
These measures will be implemented on a case-by-case basis, and only when and where they are 
warranted due to the emergency situation. Preferably, the full protocol instructions will be 
followed whenever the modified instructions are not required.
Section 7. Assessment of Safety
In the event of an emergency situation (eg, COVID-19 outbreaks), in case a patient cannot return 
to the clinic for the scheduled visits (eg, due to quarantine, isolation, patient’s concern, active 
COVID-19 infection, or closure of the site clinic), remote assessment of safety (as well as 
inquiries regarding adverse events and use of concomitant medication) via telephone call and/or 
VC, with VC being the preferred method, may be allowed. The results will be directly entered 
into the case report form (CRF) per the usual process.
Modifications to other procedures and assessments (ECG, laboratory sample collection, etc.) 
might be performed per implemented contingency measures according to sponsor instructions. 
For example, if central laboratory samples cannot be collected for safety assessments, sites may 
have patients visit a local reference laboratory or dispatch a home health nurse to perform the 
assessments, but only after consultation with the sponsor.
These measures will be implemented on a case-by-case basis, and only when and where they are 
warranted due to the emergency situation. These measures will not be implemented for patients 
known to be COVID-19 positive. Preferably, the original protocol instructions will be followed 
unless the instructions in this appendix are implemented by the sponsor. 
Section 7.3. Clinical Laboratory Tests
If central laboratory samples cannot be collected for safety assessments sites may have patients 
visit a local reference laboratory or arrange a home health visit to perform the assessments after 
discussion with and approval by the sponsor. If any patient has clinical laboratory samples 
collected at a local laboratory, the site will be responsible for collection of reference ranges from 
that laboratory. 
Section 7.4. Physical Examinations; Section 7.5. Vital Signs; Section 7.6. 
Electrocardiography; Section 7.7. Assessment of Local Tolerability and Pain
At-home health visits may be used to perform safety assessments such as physical examinations, 
vital signs, ECG, and local tolerability to determine any new adverse events.

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Section 8. Assessments of Pharmacokinetics and Immunogenicity; Section 6.2. 
Pharmacodynamics Assessment 
If pharmacokinetic, pharmacodynamic, and immunogenicity samples cannot be collected due to 
limitations in ability to carry out the procedure or limitations in storage and shipments, the 
samples will not be collected for those respective visits. Study samples collected from confirmed 
COVID-19 positive patients during the study, with confirmation either before or after the sample 
collection, will be kept at the central laboratory and will not be shipped to Teva bioanalytical 
laboratories nor analyzed. Teva bioanalytical laboratories will be informed within approximately 
1 week of any COVID-19 positive patients confirmed after samples being collected.
Section 10. Quality Control and Quality Assurance; Appendix C. Quality Control and 
Quality Assurance
Deviations from the study conduct due to emergency situations (eg, COVID-19 outbreaks), 
including implemented contingency measures and their impact (eg, patient discontinuation from 
the study, alternative procedures used to collect critical safety and/or efficacy data, etc.), will be 
described in the appropriate sections of the clinical study report (CSR).