Clinical trial NCT03700658
Conditions: Contraception
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2019-01-15; Completion date: 2020-10-02
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to evaluate the local tolerability associated with the SC administration of TV-46046, and inform next steps of the TV-46046 development program.

Detailed description:
Eligible participants will be enrolled and receive 1 of each of the 4 SC study injections in each abdominal quadrant approximately 1 hour apart: 120 milligrams (mg)/0.3 milliliter (mL) of TV-46046, 60 mg/0.3 mL of 1:1 saline diluted TV-46046, 0.3 mL of TV-46046 Placebo and 104 mg/0.65 mL Depo-subQ 104 per the assigned sequence.

Arms: arm 1: Participants will receive TV-46046 undiluted (120 mg/0.3 mL of 400 mg/mL) SC injection as a test formulation in a crossover design with the other 3 SC study drug injections. The 4 study drug injections will be administered approximately 1 hour apart. arm 2: Participants will receive TV-46046 saline-diluted (60 mg/0.3 mL of 200 mg/mL) SC injection as a test formulation in a crossover design with the other 3 SC study drug injections. The 4 study drug injections will be administered approximately 1 hour apart. arm 3: Participants will receive TV-46046 placebo (0.3 mL) SC injection in a crossover design with the other 3 SC study drug injections. The 4 study drug injections will be administered approximately 1 hour apart. arm 4: Participants will receive Depo-subQ 104 (medroxyprogesterone acetate injectable suspension; 104 mg/0.65 mL) SC injection as a reference formulation in a crossover design with the other 3 SC study drug injections. The 4 study drug injections will be administered approximately 1 hour apart.
Interventions: intervention 1: TV-46046 intervention 2: Depo-subQ 104 intervention 3: TV-46046 Placebo
Intervention descriptions: intervention 1: TV-46046 will be administered per dose and schedule specified in the arm. intervention 2: Depo-subQ 104 will be administered per dose and schedule specified in the arm. intervention 3: TV-46046 Placebo will be administered per schedule specified in the arm.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
 
 
A Randomized Crossover Study to Evaluate Local Tolerability Following 
Subcutaneous Administration of TV-46046 
 
Study Number TV46046-WH-10147 
 
 
NCT03700658   
 
 
Protocol with Amendment 04 Approval Date: 18 May 2020 


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TITLE PAGE
Clinical Study Protocol with Amendment 04
Study Number TV46046-WH-10147
FHI 360 Study Number: 1191167
A Randomized Crossover Study to Evaluate Local Tolerability Following Subcutaneous 
Administration of TV-46046
Phase 1
IND number: 126249
Amendment 04 Approval Date: 18 May 2020
Amendment 03 Approval Date: 19 November 2019
Amendment 02 Approval Date: 11 April 2019 
Amendment 01 Approval Date: 02 July 2018 
Original Protocol Approval Date: 15 May 2018 
Sponsor 
Monitor
Teva Branded Pharmaceutical
Products R&D, Inc.
145 Brandywine Pkwy, 
West Chester, PA 19380
United States
FHI 360 
359 Blackwell Street, Suite 200
Durham, North Carolina 27701
United States
Authorized Representative
Vice President, Global Specialty R&D, Respiratory TA Head
Teva Branded Pharmaceutical Products R&D, Inc.
145 Brandywine Pkwy, 
West Chester, PA 19380
United States
+1-610-738-6557
Sponsor’s Medical Expert
Sponsor’s Safety Representative 
VP, PK and ClinPharm
Nuventra, Inc.™
2525 Meridian Parkway, Suite 280
Durham, North Carolina 27713
+1-919-667-7976
Safety Physician, Medical Scientific Unit – US
Teva Branded Pharmaceutical Products R&D, 
Inc.
400 Interpace Pkwy, Bldg. A, Suite 367
Parsippany, NJ 07054
+1-973-658-0378


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Information regarding 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 and FHI 360’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/or its affiliates. The recipient agrees that no information 
contained herein may be published or disclosed without written approval from the sponsor.
© 2020 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved.


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AMENDMENT HISTORY
The protocol for Study TV46046-WH-10147 (original protocol dated 15 May 2018) has been 
amended and reissued as follows:
Amendment 04
18 May 2020
27 subjects have been enrolled to date
Amendment 03
19 November 2019
27 subjects have been enrolled to date.
Amendment 02
11 April 2019
13 subjects have been enrolled to date.
Amendment 01
02 July 2018
No subjects have been enrolled to date.
Details about the changes and reason/justification for each change are provided in Section 16.


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INVESTIGATOR AGREEMENT


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CLINICAL STUDY PROTOCOL SYNOPSIS 
With Amendment 04
Study: TV46046-WH-10147
Title of Study: A Randomized Cross-over Study to Evaluate Local Tolerability Following 
Subcutaneous Administration of TV-46046
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Investigational New Drug (IND) Number: 126249 
EMA Decision number of Pediatric Investigation Plan: Article 45 or 46 of 1901/2006 does 
not apply
Name of Test Investigational Medicinal Product (IMP): Depot Medroxyprogesterone Acetate 
(DMPA [TV-46046])
Active Substance: Medroxyprogesterone acetate (MPA)
EudraVigilance (EV) code for the IMP, if applicable: NA
Type of Study: Safety/Tolerability
Phase of Clinical Development: 1
Number of Investigational Centers Planned: 1
Countries Planned: Dominican Republic
Planned Study Period: The study is expected to start in Q3 2018 and have a duration period of 
approximately 24 months including approximately 6 months of recruitment and up to 18 months 
of follow-up.
Primary Objective(s): The primary objective is to evaluate and compare local tolerability 
associated with subcutaneous administration of 120 mg/0.3 mL of TV-46046, 60 mg/0.3 mL of 
1:1 saline-diluted TV-46046, 0.3 mL of TV-46046 Placebo, and 104 mg/0.65 mL of Depo-subQ 
Provera 104® (medroxyprogesterone acetate injectable suspension, 104 mg/0.65 mL, hereafter 
referred to as Depo-subQ 104).
Secondary Objective(s): The secondary objectives are: 
1. To evaluate and compare injection site pain associated with subcutaneous administration 
of 120 mg/0.3 mL of TV-46046, 60 mg/0.3 mL of 1:1 saline-diluted TV-46046, 0.3 mL 
of TV-46046 Placebo, and 104 mg/0.65 mL of Depo-subQ 104
2. To evaluate the overall safety of subcutaneous same-day administration of 
120 mg/0.3 mL of TV-46046, 60 mg/0.3 mL of 1:1 saline diluted TV-46046, 0.3 mL of 
TV-46046 Placebo, and 104 mg/0.65 mL of Depo-subQ 104
Exploratory and Other Objectives: NA
General Study Design and Methodology:
This is a randomized, crossover, single-center, Phase 1 study to evaluate local tolerability 
following subcutaneous administration of TV-46046 in 24 healthy female subjects 18 to 50 years 
of age. After signing the informed consent form, eligible subjects will be enrolled in the study 
and receive a subcutaneous injection of each of the four study drugs: 120 mg/0.3 mL of 


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TV-46046, 60 mg/0.3 mL of 1:1 saline-diluted TV-46046, 0.3 mL of TV-46046 Placebo, and 
104 mg/0.65 mL of Depo-subQ 104. Injections will be administered in different quadrants of the 
abdomen, each separated by approximately 1 hour. Subjects will be randomized to one of 24 
different injection sequences (one subject per sequence) to counterbalance potential effects of 
injection order or abdominal quadrant on study outcomes. 
All subjects will be followed for at least 6 months after receiving their injections. Local 
tolerability will be assessed by evaluating ISRs at least twice on the day of the study drug 
injection (Day 0: immediately after [ie, as soon as possible but no later than 10 minutes upon 
removing the needle] and 1 hour [±5 minutes] after the injection), at Days 1, 3, 7, and 14; at 
Months 3 and 6; and at other visits, if indicated. Subjects with unresolved ISR(s) will be 
followed monthly through the resolution of ISR(s) or Month 18, whichever comes first. Subjects 
will assess their injection site pain using an 11-point Numeric Rating Scale (NRS) (0 = no pain at 
all; 10 = worst pain) twice on the day of injection (Day 0: immediately after [ie, as soon as 
possible but no later than 10 minutes upon removing the needle] and 1 hour [±5 minutes] after 
the injection, but prior to any subsequent injection). In addition, 1 hour after the fourth (final) 
injection subjects will rank administrations from least [1] to most [4] painful. Thereafter, 
injection site pain will be assessed by self-reports at Days 1, 3, 7, and 14; at Months 3 and 6; and 
other visits, if indicated. Adverse events and concomitant medications will be recorded 
throughout the study. Vital signs and weight will be measured at baseline, Month 6, and at study 
exit.
In the ongoing TV46046-WH-10147 study, several cases of hypopigmentation had a later onset 
(ie, approximately 6 months post-injection) than observed in Study TV46046-WH-10075. In 
order to identify any late onset ISRs, subjects who have exited the study at Month 6 with no new 
or ongoing ISRs and who agree to return for a single follow-up visit between Months 9 and 12, 
will undergo ISR, adverse event, and concomitant medication evaluation, and vital sign and 
weight measurements at that time. 
Investigational Medicinal Products (IMPs): Dose, Pharmaceutical Form, Route of 
Administration, and Administration Rate 
Test IMP: DMPA (120 mg/0.3 mL of TV-46046)
Reference IMP: Medroxyprogesterone acetate injectable suspension (104 mg/0.65 mL)
Placebo IMP: TV-46046 Placebo (vehicle only)
Study Population and Number of Subjects Planned: Approximately 24 women will be 
enrolled. Subjects will not be replaced in this study. Subjects may be added if more than 2 
women fail to complete the treatment sequence or discontinue before Month 6. 
Duration of Subject Participation: Total duration of the study for each subject is expected to 
be 6 to 18 months including 1 day for screening, enrollment and administration of treatment, and 
6 to 18 months of follow-up. 
Main Criteria for Inclusion: Subjects may be included in the study if they meet all of the 
following criteria: 
a.
has a low risk of pregnancy (ie, sterilized, in exclusively same-sex partnership, in 
menopause and/or post-menopausal, abstinent, in monogamous relationship with 
vasectomized partner, using nonhormonal intrauterine device (IUD) or consistent use 
of condoms) 


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b. is in good general health as determined by a medical history
c.
is 18 to 50 years of age (inclusive)
d. is willing to provide informed consent and follow all study requirements
e.
is not pregnant and does not have desire to become pregnant in the subsequent 
18 months
f.
had a normal mammogram within the last year, if 40 years or older
g. has no skin disorders or skin allergies
Main Criteria for Exclusion: Subjects will be excluded from participating in this study if they 
meet any of the following criteria: 
a.
has hypertension, 

systolic blood pressure (BP) ≥160 mm Hg or diastolic BP ≥100 mm Hg or

vascular disease
b. has ischemic heart disease or a history of ischemic heart disease
c.
has a history of stroke
d. has a history of thromboembolic event (s) 
e.
has systemic lupus erythematosus or

positive (or unknown) antiphospholipid antibodies or

severe thrombocytopenia
f.
has rheumatoid arthritis and is undergoing immunosuppressive therapy
g. has migraine with aura
h. has unexplained vaginal bleeding
i.
has diabetes
j.
has a strong family history of breast cancer (defined as one or more first degree 
relatives, breast cancer occurring before menopause in three or more family members, 
regardless of degree of relationship, or any male family member with breast cancer), 
or current or history of breast cancer, or undiagnosed mass detected by breast exam 
k. has cervical cancer or a history of cervical cancer
l.
has severe cirrhosis (decompensated) or liver tumors
m. has known significant renal disease
n. has a history of diagnosed clinical depression or bipolar disorder, with or without 
suicidal ideation, and/or history of suicide attempt
o. has, in the last two years, a history of either hospitalization or medication 
management for a psychiatric disorder that in the opinion of the investigator would 
make study participation unsafe, would interfere with adherence to study 
requirements or complicate data interpretation


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p. is currently using hormonal contraception
q. had an injection of DMPA (Depo-Provera CI or Depo-subQ 104) in the past 
12 months; or combined injectable in the last 3 months
r.
has a known sensitivity to MPA or any inactive ingredients
s.
is chronically using pain medication
t.
has a plan to move to another location in the next 18 months
u. has, in the opinion of the investigator, a potentially elevated risk of human 
immunodeficiency virus (HIV) infection (eg, HIV-positive partner, intravenous (IV) 
drug use by self or by partner)
v. has any condition (social or medical), which in the opinion of the investigator would 
make study participation unsafe, would interfere with adherence to the clinical study 
requirements, or would complicate data interpretation
Study Evaluations
Safety and Tolerability Assessments
Local Tolerability
Local tolerability will be assessed by occurrence of ISRs including but not limited to erythema 
(redness), swelling, pruritus (itching), bleeding, bruising, injection site discoloration (eg, 
hypopigmentation), or atrophy (ie, dimple). The site of injection will be evaluated for possible 
ISRs after each of the four injections at least twice during the enrollment/injection visit (Day 0: 
immediately after (ie, as soon as possible but no later than 10 minutes upon removing the needle) 
and 1 hour (±5 minutes) after each injection (right before the next injection). Thereafter, 
injection sites will be monitored for the progress of ongoing and/or occurrence of new ISRs at 
Days 1, 3, 7, and 14; at Months 3 and 6, and at other visits, if indicated. 
Injection Site Pain
Injection site pain will be evaluated twice on the day of the study drugs injection (Day 0): 
immediately after (ie, as soon as possible but no later than 10 minutes upon removing the needle) 
and 1 hour (±5 minutes) after each injection (right before the next injection). Subjects will assess 
their injection site pain using an 11-point NRS (0 = no pain at all; 10 = worst pain). In addition, 1 
hour after the fourth (final) injection subjects will provide an overall ranking of all four 
administrations from least [1] to most [4] painful. 
Thereafter, injection site pain will be evaluated by self-reports on Days 1, 3, 7, and 14, Month 3 
and 6, and at additional visits, if appropriate. If the subject reports injection site pain, she will be 
asked to use the NRS to evaluate the intensity of pain in order to determine if it meets the 
definition of an adverse event. 
Overall Safety 
Overall safety will be assessed by occurrence of adverse events, use of concomitant medications, 
and changes in vital signs and weight compared to baseline. 


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Statistical Methods
Sample Size Determination: The study size of 24 subjects (N=24) will provide at least 80% 
power to detect differences in ISR rates of the magnitude (>40%) observed in recent non-
comparative studies of TV-46046 and Depo-subQ 104. Although not designed to obtain precise 
estimates of less frequent ISR rates (eg, injection site discoloration [hypopigmentation]), there is 
a high (>90%) probability of detecting one or more specific ISR types if the true rate of such 
events is at least 10%. No randomized subjects will be replaced. However, if more than two 
subjects fail to receive all four injections or discontinue before Month 6, then additional subjects 
may be enrolled to help ensure that there are at least 22 subjects who complete the treatment 
sequence and are evaluable for at least 6 months. 
Primary Measure:

ISR 
Secondary Measure: 

Injection site pain evaluated using NRS
Analyses
Safety Analysis: Safety and tolerability will be evaluated based on the following measures:

ISRs 

Injection site pain

Subjects’ perception of pain

Occurrence of adverse events

Use of concomitant medications

Change in vital signs and weight


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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
AMENDMENT HISTORY .............................................................................................................3
INVESTIGATOR AGREEMENT...................................................................................................4
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................5
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................16
1.
BACKGROUND INFORMATION...........................................................................18
1.1.
Introduction.................................................................................................................18
1.2.
Findings from Nonclinical and Clinical Studies.........................................................18
1.2.1.
Nonclinical Studies.....................................................................................................18
1.2.2.
Clinical Studies...........................................................................................................19
1.3.
Known and Potential Benefits and Risks....................................................................19
1.3.1.
Overall Potential Benefits and Risks..........................................................................19
1.3.2.
Known and Potential Risks of TV-46046 and Depo-subQ 104 .................................19
1.3.2.1.
Pregnancy ...................................................................................................................19
1.3.2.2.
Injection Site Reactions..............................................................................................20
1.3.2.3.
Menstrual Changes .....................................................................................................20
1.3.2.4.
Weight Gain................................................................................................................21
1.3.2.5.
Risk of Human Immunodeficiency Virus...................................................................21
1.3.2.6.
Return to Fertility .......................................................................................................21
1.3.2.7.
Bone Mineral Density.................................................................................................22
1.3.2.8.
Dose of MPA..............................................................................................................22
1.3.2.9.
Other ...........................................................................................................................23
1.4.
Study Design Rationale ..............................................................................................24
1.4.1.
General Study Design Rationale.................................................................................24
1.4.2.
Dosage Rationale........................................................................................................24
2.
STUDY OBJECTIVES AND MEASURES/PARAMETERS...................................26
2.1.
Study Objectives.........................................................................................................26
2.1.1.
Primary Objective.......................................................................................................26
2.1.2.
Secondary Objectives .................................................................................................26
2.2.
Study Endpoints..........................................................................................................26
2.2.1.
Primary Endpoint........................................................................................................26


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2.2.2.
Secondary Endpoints ..................................................................................................26
2.2.2.1.
Injection Site Pain.......................................................................................................26
2.2.2.2.
Overall Safety.............................................................................................................27
3.
INVESTIGATIONAL PLAN.....................................................................................28
3.1.
General Study Design.................................................................................................28
3.2.
Subject Eligibility.......................................................................................................28
3.2.1.
Subject Inclusion Criteria ...........................................................................................28
3.2.2.
Subject Exclusion Criteria..........................................................................................29
3.3.
Duration of Subject Participation ...............................................................................30
3.4.
Study Procedures ........................................................................................................30
3.4.1.
Procedures for Screening Visit...................................................................................33
3.4.2.
Procedures for Enrollment/Injections Visit ................................................................33
3.4.3.
Follow-up/Final Visits................................................................................................34
3.4.4.
Unscheduled Visits .....................................................................................................35
3.4.5.
Post-6 Month Follow-up.............................................................................................35
4.
TREATMENT OF SUBJECTS..................................................................................36
4.1.
Investigational Medicinal Products Administered During the Study.........................36
4.1.1.
Test Investigational Medicinal Product......................................................................36
4.1.2.
Reference Investigational Medicinal Product.............................................................36
4.1.3.
Placebo Investigational Medicinal Product ................................................................36
4.2.
Treatment of Subjects.................................................................................................36
4.3.
Blinding/Unblinding...................................................................................................39
4.3.1.
Unblinding During the Study......................................................................................39
4.4.
Stopping Rules and Discontinuation Criteria .............................................................39
4.5.
Interim Data Reviews .................................................................................................40
4.6.
Prior and Concomitant Therapy or Medication..........................................................40
4.6.1.
Subject Withdrawal Criteria and Procedures..............................................................41
4.7.
Procedures for Monitoring Subject Compliance ........................................................41
4.8.
Withdrawal of Subjects...............................................................................................41
4.8.1.
Lost to Follow-up .......................................................................................................41
5.
SAFETY AND TOLERABIILITY MEASUREMENTS AND 
ASSESSMENTS.........................................................................................................42
5.1.
Safety and Tolerability Measurements .......................................................................42


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5.1.1.
Local Tolerability .......................................................................................................42
5.1.2.
Injection Site Pain.......................................................................................................42
5.2.
Safety Assessments.....................................................................................................43
5.2.1.
Definition of an Adverse Event ..................................................................................43
5.2.2.
Recording and Reporting Adverse Events..................................................................44
5.2.3.
Severity of an Adverse Event .....................................................................................45
5.2.4.
Relationship of an Adverse Event to the IMP ............................................................45
5.2.5.
Serious Adverse Events..............................................................................................46
5.2.5.1.
Definition of a Serious Adverse Event .......................................................................46
5.2.5.2.
Expectedness...............................................................................................................47
5.2.5.3.
Reporting a Serious Adverse Event............................................................................47
5.2.6.
Protocol Defined Adverse Events for Expedited Reporting.......................................48
5.2.7.
Weight and Vital Signs...............................................................................................49
5.2.8.
Medication Error and Special Situations Related to the Investigational 
Medicinal Products.....................................................................................................49
5.2.9.
Protocol Deviations Because of an Adverse Event ....................................................50
5.2.10.
Pregnancy ...................................................................................................................50
6.
PHARMACOKINETIC MEASUREMENTS AND ASSESSMENTS......................51
7.
PHARMACODYNAMIC, PHARMACOGENOMIC,
IMMUNOGENICITY, AND BIOMARKER MEASUREMENTS AND 
ASSESSMENTS.........................................................................................................52
7.1.
Pharmacodynamics.....................................................................................................52
7.2.
Pharmacogenomic Assessments.................................................................................52
7.3.
Immunogenicity..........................................................................................................52
7.4.
Assessment of Exploratory Biomarkers .....................................................................52
8.
STATISTICS ..............................................................................................................53
8.1.
Sample Size and Power Considerations .....................................................................53
8.2.
Method of Randomization..........................................................................................53
8.3.
Analysis Sets...............................................................................................................54
8.4.
Data Handling Conventions........................................................................................54
8.5.
Study Population.........................................................................................................54
8.5.1.
Subject Disposition.....................................................................................................54
8.5.2.
Demographic and Baseline Characteristics ................................................................54


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8.6.
Analysis of Primary Endpoints...................................................................................54
8.6.1.
Local Tolerability .......................................................................................................54
8.7.
Analysis of Secondary Endpoints...............................................................................55
8.7.1.
Injection Site Pain.......................................................................................................55
8.7.2.
Overall Safety.............................................................................................................55
9.
INVESTIGATIONAL MEDICINAL PRODUCT INFORMATION........................57
9.1.
Investigational Medicinal Product Storage and Security............................................57
9.2.
Investigational Medicinal Product Accountability.....................................................57
10.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................58
10.1.
Protocol Amendments, Protocol Deviations, and Important Protocol 
Deviations...................................................................................................................58
10.1.1.
Protocol Amendments ................................................................................................58
10.1.2.
Important Protocol Deviations....................................................................................58
10.2.
Study Monitoring........................................................................................................58
10.3.
Clinical Product Complaints.......................................................................................59
10.3.1.
Product Complaint Information Needed from the Investigational Center..................59
10.3.2.
Handling the Product Complaint IMP at the Investigational Center..........................60
10.3.3.
Documenting a Product Complaint ............................................................................60
10.4.
Data Quality Control...................................................................................................60
10.5.
Audit and Inspection...................................................................................................61
11.
ETHICAL AND REGULATORY CONSIDERATIONS..........................................62
11.1.
Investigator Responsibilities.......................................................................................62
11.2.
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards.........................................................................................................................62
11.3.
Informed Consent .......................................................................................................63
11.4.
Subject Confidentiality...............................................................................................63
11.5.
Declaration of the End of the Clinical Study..............................................................63
11.6.
Registration of the Clinical Study...............................................................................63
12.
STUDY DOCUMENTATION...................................................................................64
12.1.
Source Data and Case Report Forms..........................................................................64
12.2.
Archiving of Study Documentation............................................................................64
12.2.1.
FHI 360 Responsibilities ............................................................................................64
12.2.2.
Investigator Responsibilities.......................................................................................65


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13.
FINANCING AND INSURANCE.............................................................................66
14.
REPORTING AND PUBLICATION OF RESULTS................................................67
15.
REFERENCES ...........................................................................................................68
16.
SUMMARY OF CHANGES TO PROTOCOL .........................................................70
16.1.
Protocol Amendment 04 Dated 18 May 2020 ............................................................70
16.2.
Protocol Amendment 03 Dated 19 November 2019...................................................72
16.3.
Protocol Amendment 02 Dated 11 April 2019...........................................................78
16.4.
Protocol Amendment 01 Dated 02 July 2018.............................................................79
APPENDIX A.
STUDY RESPONSIBILITIES..........................................................................83


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LIST OF TABLES
Table 1:
Study Procedures and Assessments............................................................................31
Table 2:
Investigational Medicinal Products Used in the Study...............................................38
Table 3:
ISR Rates (per injection) ............................................................................................53


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term 
BMD
bone mineral density
BP 
blood pressure
CDMS
clinical data management system 
CFR
Code of Federal Regulations (US)
CI
Contraceptive Injection
CRF
case report form (refers to any media used to collect study data [ie, paper or electronic])
CRO
contract research organization
DSS
docusate sodium sulfosuccinate
DMPA
depot medroxyprogesterone acetate
EC
Ethics Committee
EMA
European Medicines Agency
EU
European Union
FDA
Food and Drug Administration (US)
FIH
first in human
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
IB
Investigator’s Brochure 
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IM
intramuscular
IMP
investigational medicinal product
IRB
Institutional Review Board
ISR
injection site reaction
IUD
intrauterine device
IV
intravenous
MEC
Medical Eligibility Criteria
MPA
Medroxyprogesterone acetate
NDA
New Drug Application
NRS
Numerical Rating Scale
OTC
over-the-counter


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Abbreviation
Term 
PDAE
protocol defined- adverse event 
PHSC
Protection of Human Subjects Committee
RSI
Reference safety information
SAE
serious adverse event
SC
subcutaneous
SOP
standard operating procedure
SPC
Summary of Product Characteristics 
SRC
study review committee
SUSAR
suspected unexpected serious adverse reaction
US
United States (of America)
WHO
World Health Organization


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1.
BACKGROUND INFORMATION
Teva and FHI 360 are in collaboration to develop a new formulation of depot 
medroxyprogesterone acetate (DMPA), TV-46046, for the prevention of pregnancy when 
injected every 6 months.
1.1.
Introduction
Teva has been conducting a Phase 1 pharmacodynamic (PD) and pharmacokinetic (PK) study to 
identify a dose of medroxyprogesterone acetate (MPA) injectable suspension 400 mg/mL 
(TV-46046) (within the range of 80 to 300 mg) that is both safe and consistent with a high 
degree of contraceptive efficacy when injected every 6 months (A Two-part, Phase 1, 
Exploratory and Dose-range Finding Study to Evaluate Suppression of Ovulation and 
Pharmacokinetics of Medroxyprogesterone Acetate Following a Single Subcutaneous 
Administration of TV-46046 in Women with Ovulatory Cycle [TV46046-WH-10075]). The 
interim data from Part 1 of this first in human (FIH) non-comparative study suggested that the 
single 120 mg dose of TV-46046 injected subcutaneously in the abdomen may be associated 
with a higher rate of local irritation when compared to the historical data for the reference Depo-
subQ Provera 104® (hereafter referred to as Depo-subQ 104). This comparison should be 
interpreted with caution due to its non-direct nature, the small sample size, and the potential data 
collection biases of Study TV-46046-WH-10075. Teva (the sponsor) and FHI 360 propose to 
conduct a local tolerability study to directly evaluate and compare local tolerability and injection 
pain following subcutaneous administration of TV-46046 and Depo-subQ 104. 
1.2.
Findings from Nonclinical and Clinical Studies
1.2.1.
Nonclinical Studies 
The sponsor’s current nonclinical safety program for TV-46046 consists of four in vivo 
nonclinical studies: a Good Laboratory Practice (GLP) female rabbit subcutaneous local 
tolerance/distant target organ tissue evaluation with long term toxicokinetic study (Study DS-
2015-009); a GLP murine local lymph node assay study (Study DS-2015-017); a non-GLP 
murine local lymph node assay study (Study DS-2014-064); and a non-GLP female rabbit 
subcutaneous pharmacokinetic and gross tolerability study (Study DP-2014-135).
No significant injection site reactions (ISRs) occurred following treatment with TV-46046 in the 
9-month local tolerability study in rabbits (Study DS-2015-009). Between days 43 and 90, 
grade 1 hypopigmentation was observed intermittently in 2 rabbits given 104 mg/0.65 mL of 
Depo-subQ 104, and in 3 rabbits given 300 mg/mL of TV-46046. Between days 92 and 180, 
hypopigmentation was observed in 2 rabbits given Depo-subQ 104 and in 5 rabbits given 
TV-46046. Between days 183 and 246 hypopigmentation was observed in 1 rabbit only in the 
TV-46046 group. There were no significant injection site differences in microscopic findings 
between TV-46046 and the reference Depo-subQ 104.
Based on the results of the IND-enabling nonclinical investigation, the sponsor did not anticipate 
the rate of ISRs associated with the subcutaneous administration of TV-46046 in humans to be 


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higher than that of Depo-subQ 104. However, careful evaluation of the risk of ISRs was planned 
in Study TV-46046-WH-10075.
1.2.2.
Clinical Studies
Based on the interim analysis of safety data from the TV-46046-WH-10075 study on 28 August 
2017, eleven out of 12 study subjects reported at least one sign or symptom consistent with an 
ISR that included but was not limited to pain, redness, tenderness, swelling, bruising, itching and 
sense of pressure during injection. Nine of the reported ISRs met the per protocol definition of an 
adverse event. All nine adverse events were mild in severity, lasted on average 4 to 5 days and 
resolved without sequelae. Two women had hypopigmentation of skin at the site of injection (ie, 
injection site discoloration) that appeared between 3 and 4 months after the injection, 
respectively. Both areas of hypopigmentation were approximately 2 cm in diameter and both 
were still present 6 months after the injection. More detailed information on the results of the 
Phase 1 study may be found in the current investigational brochure (IB).
1.3.
Known and Potential Benefits and Risks 
In addition to the benefit and risk information described in this section, please refer to the current 
IB (Section 3, Section 6.3, and Section 7).
1.3.1.
Overall Potential Benefits and Risks
The study will be conducted in healthy subjects; no direct health benefits are expected in this 
study population. The study design, inclusion/exclusion criteria, and procedures have been 
developed in a manner to protect subject safety. The results of this study may facilitate the 
development of a new longer-acting injectable contraceptive. 
1.3.2.
Known and Potential Risks of TV-46046 and Depo-subQ 104 
The contraceptive dose, as well as the duration of contraceptive effects, of TV-46046 are 
unknown. Therefore, all necessary precautions will be taken to minimize the risk of pregnancy 
among study subjects. Only women who are not pregnant, not wanting to become pregnant in the 
next 18 months, and who are at low risk of pregnancy because they are sterilized, in exclusively 
same-sex partnership, in menopause, and/or postmenopausal, abstinent, in a monogamous 
relationship with vasectomized partner, using a nonhormonal IUD, or consistently using 
condoms (see Section 3.2.1 for Inclusion Criteria) will be enrolled in this study. During the 
study, pregnancy testing will be performed if the woman is experiencing any symptoms or signs 
of pregnancy, or if she thinks she may be pregnant.
1.3.2.1.
Pregnancy
Although no contraceptive injectables should be used during pregnancy, there appears to be little 
or no increased risk of birth defects in women who have inadvertently been exposed to MPA 
injections in early pregnancy. Neonates exposed to MPA in-utero and followed to adolescence 
showed no evidence of any adverse effects on their health including their physical, intellectual, 
sexual, or social development (Depo-Provera CI US Prescribing Information 2016). According 
to the prescribing information, women who are breastfeeding should not have their first injection 
until the sixth postpartum week (Depo-Provera CI US Prescribing Information 2016). However, 


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neonates and infants exposed to MPA from breast milk have been studied for developmental and 
behavioral effects through puberty, and no adverse effects have been noted. According to the 
Centers for Disease Control and Prevention (CDC) US Medical Eligibility Criteria (MEC) for 
Contraceptive Use, all progestin-only hormonal methods, including progestin-only pills, DMPA, 
and implants, are safe for postpartum women, including women who are breastfeeding, and can 
be initiated immediately postpartum (Curtis 2016).
1.3.2.2.
Injection Site Reactions
In 5 clinical studies involving 2325 women using Depo-subQ 104 (282 treated for up to 
6 months, 1780 treated for up to 1 year and 263 treated for up to 2 years, ie, 8 injections), 5% 
reported ISRs, and 1% had persistent skin changes, typically described as small areas of 
induration or atrophy (Depo-subQ 104 US Prescribing Information 2016). One of these studies 
found more injection site reactions (which were all mild to moderate in severity) in the Depo-
subQ 104 (subcutaneous injection) group (8%) than in the Depo-Provera CI (intramuscular 
injection) group (0.4%), an expected finding for the subcutaneous route of administration 
(Kaunitz et al 2009).
Based on the nonclinical data, Teva did not anticipate the rate of ISRs associated with the 
subcutaneous administration of TV-46046 in humans to be higher than that of Depo-subQ 104 
but planned for the careful evaluation of the risk of ISRs in Study TV-46046-WH-10075. The 
interim results from Study TV-46046-WH-10075 indicated higher rates of local irritation 
associated with TV-46046 (eg, pain, redness, swelling, itching) compared to the historical data 
for Depo-subQ 104 (Depo-subQ 104 US Prescribing Information 2016). Eleven out of 12 
participants reported at least one sign or symptom consistent with an ISR that included but was 
not limited to pain, redness, tenderness, swelling, bruising, itching and sense of pressure during 
injection. Nine of the reported ISRs met the per protocol definition of an adverse event. All nine 
adverse events were mild in severity, lasted on average 4 to 5 days and resolved without 
sequelae. Two women had hypopigmentation of skin at the site of injection (ie. injection site 
discoloration) that appeared between 3 and 4 months after the injection, respectively. Both areas 
of hypopigmentation were approximately 2 cm in diameter and both were still present 6 months 
after the injection. Based on interim results from Study TV-46046-WH-10075, there are no 
safety concerns associated with the subcutaneous administration of TV-46046. However, all 
subjects will be fully informed of the potential risk of ISRs including injection site discoloration 
(hypopigmentation) before joining the study.
1.3.2.3.
Menstrual Changes
Most women using Depo-Provera CI or Depo-subQ 104 experience disruption of menstrual 
bleeding patterns. Altered menstrual bleeding patterns include amenorrhea, irregular or 
unpredictable bleeding or spotting, prolonged spotting or bleeding, and heavy bleeding. As 
women continue using Depo-Provera CI or Depo-subQ 104, fewer experience irregular 
menstrual bleeding and more experience amenorrhea. In three contraception trials, 39.0% of 
women experienced amenorrhea during month 6, and 56.5% experienced amenorrhea during 
month 12 (Depo-subQ 104 US Prescribing Information 2016). 
In the ongoing study (Study TV-46046-WH-10075), the effect of a single subcutaneous 
administration of TV-46046 on bleeding pattern was consistent with that of Depo-Provera CI or 


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Depo-subQ 104. At 3 months post-injection, 3 out of 6 subjects experienced spotting. At 7.5 
months post-injection, 2 out of 4 subjects reported spotting, and the other 2 reported irregular 
bleeding. When asked about their overall opinion on the bleeding pattern, most of the women 
responded that it was acceptable. 
All subjects will be informed before joining the local tolerability study that their bleeding pattern 
is likely to be irregular. Changes in menstrual bleeding patterns and its acceptability will not be 
evaluated.
1.3.2.4.
Weight Gain
Women tend to gain weight while using both Depo-Provera CI and Depo-subQ 104. From an 
initial average body weight of 136 pounds, women who completed 1 year of treatment with 
Depo-Provera CI (ie, 4 intramuscular injections resulting in a cumulative dose of 600 mg) gained 
an average of 5.4 pounds (Depo-Provera CI US Prescribing Information 2016). In three large 
clinical trials using Depo-subQ 104, the mean weight gain was 3.5 pounds in the first year of use 
(Depo-subQ 104 US Prescribing Information 2016). 
It is anticipated that change in weight in the proposed local tolerability study will be less than the 
weight gain associated with the chronic use of the approved 3-month contraceptives. Body 
weight will be measured at baseline and study exit.
1.3.2.5.
Risk of Human Immunodeficiency Virus
Depo-Provera CI and Depo-subQ 104 provide no protection against sexually transmitted
infections, including human immunodeficiency virus (HIV). While some observational data have 
suggested an association between the use of Depo-Provera CI and an increased risk of HIV 
acquisition (Morrison et al 2015, Ralph et al 2015, Polis et al 2016), the data are inconsistent and 
causality has not been established. In light of the inconclusive evidence, the World Health 
Organization (WHO) recently revised their MEC for contraceptive use (WHO 2017); per the 
revised criteria, women at low risk of HIV can continue using all hormonal methods of 
contraception including DMPA without restriction. Women who are at high risk of HIV, 
however, can use DMPA if they are informed of the possible increased risk of HIV acquisition 
among DMPA users, the uncertainty over a causal relationship, and how to minimize their risk of 
acquiring HIV. This study will not recruit women at high risk for HIV, but the information on 
how to minimize risk of acquiring HIV as well as the recommendation to use condoms for 
protection against HIV and sexually-transmitted infections will be provided to all subjects in this 
study. 
1.3.2.6.
Return to Fertility
Return to ovulation is delayed after stopping DMPA. Among 15 women who received multiple 
doses of Depo-subQ 104, the median time to ovulation was 10 months after the last injection; the 
earliest return to ovulation was 6 months after the last injection; and 12 women (80%) ovulated 
within 1 year of the last injection (Depo-subQ 104 US Prescribing Information 2016). 
Subcutaneous administration of DMPA is associated with a more delayed return to ovulation 
compared to the intramuscular route. In a comparative study, median time to return of ovulation 
after a single intramuscular injection of Depo-Provera CI (150 mg) and a single injection of 


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Depo-subQ (104 mg) were 183 and 212 days, respectively (although the difference was not 
statistically significant) (Jain et al 2004).
Return to fertility is also delayed. On the basis of the prescribing information, 68% of women 
who stop use may conceive within 12 months, 83% may conceive within 15 months, and 93% 
may conceive within 18 months from the last injection of Depo-Provera CI (Depo-Provera CI US
Prescribing Information 2016). Among 28 women using Depo-subQ 104 for contraception who 
stopped treatment to become pregnant, only 1 became pregnant within a year of last injection and 
a second became pregnant 443 days after the last injection (7 women were lost to follow-up) 
(Depo-subQ 104 US Prescribing Information 2016). 
In the local tolerability study, return to ovulation after the same-day administration of MPA in 
the total dose of 284 mg is likely to be delayed. Therefore, only women who are at low risk of 
pregnancy and who do not desire pregnancy for a minimum of 18 months will be enrolled into 
this study. Women will not be followed to assess return of ovulation.
1.3.2.7.
Bone Mineral Density
In 2004, a boxed warning regarding skeletal health was added to the label of Depo-subQ 104 
indicating that women who use these methods may lose significant bone mineral density (BMD) 
(Depo-subQ 104 US Prescribing Information 2016). The warning states that bone loss is greater 
with increasing duration of use and may not be completely reversible. It is unknown if use of 
Depo-subQ 104 during adolescence or early adulthood, a critical period of bone accretion, will 
reduce peak bone mass and increase the risk for osteoporotic fracture in later life. The label also 
states that Depo-subQ 104 should not be used as a long-term birth control method (ie, longer 
than 2 years) unless other birth control methods are considered inadequate. A similar boxed 
warning was added to the Depo-Provera CI prescribing information.
However, existing evidence indicates that the changes in BMD are largely reversible and 
comparable to the changes associated with the hypoestrogenism that occurs with pregnancy and 
lactation. Also, there is no evidence that long term use is actually associated with increased risk 
of fracture, the clinically relevant outcome (Kaunitz and Grimes 2011).
In the local tolerability study, any permanent adverse impact on BMD is unlikely. However, 
since the loss of BMD associated with the chronic use of Depo Provera CI and Depo-subQ 104 is 
of particular concern during adolescence and early adulthood, a critical period of bone accretion. 
Women younger than 18 years of age will not be eligible for this study.
1.3.2.8.
Dose of MPA 
The same-day administration of 120 mg/0.3 mL of TV-46046, 60 mg/0.3 mL of 1:1 saline 
diluted TV-46046, 0.3 mL of TV-46046 Placebo and 104 mg/0.65 mL of Depo-subQ 104 will 
result in a total dose of MPA of 284 mg; less than the 300 mg that was approved as a maximum 
dose of TV-46046 in Study TV-46046-WH-10075 and less than the dose of 300 mg used in an 
ongoing study sponsored by FHI 360 (Study #702179; IND 127097). 
Several worldwide clinical studies have demonstrated that Depo-Provera CI at a dose of up to 
450 mg, when administered by intramuscular injection, was safe and well-tolerated. Specifically, 
a clinical study in 61 women was conducted in Australia to determine the safety and efficacy of 
DMPA administered as 6-monthly intramuscular injections of 300 mg. Side effects were varied 


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but mild and generally related to changes in menstrual bleeding pattern (Mackay et al 1971). In 
the 4- and 5 ½-year-long clinical studies conducted in Thailand, 991 and 1132 women received 
Depo-Provera by intramuscular injection in doses of 300 and 400 mg every 6 months, 
respectively. In both studies, mild side effects included spotting, amenorrhea, and irregular 
menses (Schwallie and Assenzo 1972, McDaniel and Pardthaisong 1974). In a comparative 
clinical study in 1000 South African women, doses of 150 and 450 mg intramuscular injections 
of DMPA administered every 3 or 6 months, respectively, to 500 women each were 
well-tolerated with fewer women discontinuing the treatment in the 6-month group (Castle et al 
1978). Depo-Provera is also currently approved in Canada as an intramuscular (im) injectable 
formulation at a dose of 50 mg weekly or 100 mg every 2 weeks intramuscularly for at least 
6 months for the treatment of endometriosis (PRDepo-Provera and PRDepo-Provera-SC Product 
Monograph Canada 2013).
The safety of subcutaneous administration of a 300 mg dose of MPA has been demonstrated in 
an ongoing study (Study #702179; IND 127097) that compared the subcutaneous administration 
of 150 mg/mL (n=24) and 300 mg/mL (n=9) of Depo Provera CI with Depo-subQ 104 (n=9). 
Based on the interim analysis conducted when all enrolled subjects completed at least 7.5 months 
of follow-up, there were no serious adverse events and only two severe adverse events in the 
300 mg group, both of which were considered not related to the product (an upper respiratory 
infection and thermal burn). As of April 2018, all nine women in the 300 mg group completed 
the study, and eight of them returned to ovulation within 18 months after the injection. Based on 
the interim data, the majority of participants in all groups had no clinically meaningful change 
from baseline in blood pressure or weight at Month 7.5. Possible suppression of adrenal function 
was evaluated by measuring serum cortisol levels throughout the study. There were no 
significant differences in cortisol levels observed in any of the three treatment groups.
In conclusion, the subcutaneous administration of MPA at the total dose of 284 mg proposed in 
the current study is expected to be safe. Vital signs, weight, adverse events and concomitant 
medications will be monitored during the study.
1.3.2.9.
Other
According to the US Depo-subQ 104 and Depo-Provera CI labels, women with a strong family 
history of breast cancer should be carefully monitored when receiving DMPA. Five large case-
control studies assessed the association between DMPA use and the risk of breast cancer: three 
studies suggested a slightly increased risk of breast cancer in the overall population of users (Lee
et al 1987, WHO 1991, Shapiro et al 2000), and two studies demonstrated a statistically 
significant increased risk of breast cancer among recent DMPA users (Li et al 2012, Paul et al
1989). Women 40 years or older must have normal mammogram results in the last year prior to 
enrollment to be eligible for this study. If a woman 40 years or older has not had a mammogram 
in the past year, one will be scheduled between screening and enrollment.
Infrequent reports of anaphylaxis and anaphylactoid reaction have been associated with the use 
of Depo-Provera CI. On the day of the study, subjects will remain at the investigational center 
for observation for at least 1 hour after the last injection and receive counseling of possible signs 
of anaphylactic reaction prior to leaving the investigational center. The investigational centers 
will have an epinephrine injection on hand and easy access to emergency care in the unlikely 
event of an anaphylactic reaction.


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Additional information regarding risks to human subjects related to TV-46046 may be found in 
the current IB.
Additional information regarding risks to subjects related to Depo-subQ 104 may be found in the
Depo-subQ 104 Prescribing Information (Depo-subQ 104 US Prescribing Information 2016).
1.4.
Study Design Rationale
1.4.1.
General Study Design Rationale 
Interim data from Study TV-46046-WH-10075 suggested that the subcutaneous administration 
of TV-46046 may be associated with a higher rate of ISRs than Depo-subQ 104. The lack of a 
direct comparison, the small sample size and the potential differences in ISR ascertainment 
complicate the interpretation of these results. The study described here will allow assessment and 
direct comparison of local tolerability between 120 mg/0.3 mL of TV-46046 and the reference 
drug, Depo-subQ 104. Inclusion of 60 mg/0.3mL of the 1:1 saline-diluted TV-46046 will enable 
investigation of a potential dose-dependent effect.
The proposed study is a single-group cross-over design in which 24 women will receive one of 
each of the four subcutaneous study injections in different quadrants of the abdomen 
approximately 1 hour apart (considered to be sufficient to eliminate carry-over effect of pain 
from previous injection). Each woman will serve as her own control to minimize the variability 
of treatment comparisons. Women will be randomized to one of 24 possible injection sequences 
(one subject per sequence) to counterbalance potential effects of injection order or abdominal 
quadrant on outcomes. 
This study will recruit healthy subjects to eliminate confounding factors (comorbidities, 
comedications). Since TV-46046 is a hormonal contraceptive, only women will be enrolled into 
the study. Since the contraceptive dose and duration of TV-46046 action are unknown, 
enrollment will include women who are in menopause, or are premenopausal and are not 
pregnant, not wanting to become pregnant in the next 18 months, or at a low risk of pregnancy 
because they are sterilized, in an exclusively same-sex partnership, abstinent, in a monogamous 
relationship with a vasectomized partner, using non- hormonal IUD, or consistently using 
condoms. 
In the ongoing TV46046-WH-10147 study, several cases of hypopigmentation had a later onset 
(ie, approximately 6 months post-injection) than observed in Study TV46046-WH-10075. In 
order to identify any late onset ISRs, subjects who have exited the study at Month 6 with no new 
or ongoing ISRs and who agree to return for a single follow-up visit between Months 9 and 12, 
will undergo ISR, adverse event, and concomitant medication evaluation, and vital sign and 
weight measurements at that time (see Section 3.4.5 for more detail).
1.4.2.
Dosage Rationale
A 120 mg/0.3 mL dose of undiluted TV-46046 (containing 120 mg of MPA and 0.45 mg of 
docusate sodium sulfosuccinate [DSS]), will be used in this study. Based on interim data of the 
Phase 1 study (TV-46046-WH-10075), the PK/PD response of this dose appears consistent with 
the desired 6-month contraceptive protection and therefore may be similar to the dose used in 
future efficacy evaluations. The TV-46046 Placebo will be administered at a volume of 0.3 mL 
(containing 0.45 mg of DSS) to match the dose of DSS in the undiluted TV-46046 group. The 


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dose of 60 mg/0.3 mL of the 1:1 saline-diluted TV-46046 (containing 60 mg of MPA and 0.225 
mg of DSS) was selected to evaluate if any treatment effect is potentially dose-dependent. 
Depo-subQ 104 will serve as an active control and will be administered at a dose of 
104 mg/0.65 mL. 


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2.
STUDY OBJECTIVES AND MEASURES/PARAMETERS
The purpose of this study is to evaluate the local tolerability associated with the subcutaneous 
administration of TV-46046, and inform next steps of the TV-46046 development program.
2.1.
Study Objectives
2.1.1.
Primary Objective
The primary objective is to evaluate and compare local tolerability associated with subcutaneous 
administration of 120 mg/0.3 mL of TV-46046, 60 mg/0.3 mL of 1:1 saline-diluted TV-46046, 
0.3 mL of TV-46046 Placebo, and 104 mg/0.65 mL of Depo-subQ Provera 104® 
(medroxyprogesterone acetate injectable suspension, 104 mg/0.65 mL, hereafter referred to as 
Depo-subQ 104).
2.1.2.
Secondary Objectives
The secondary objectives of the study are the following:

To evaluate and compare injection site pain associated with subcutaneous 
administration of 120 mg/0.3 mL of TV-46046, 60 mg/0.3 mL of 1:1 saline-diluted 
TV-46046, 0.3 mL of TV-46046 Placebo, and 104 mg/0.65 mL of Depo-subQ 104

To evaluate the overall safety of subcutaneous, same-day administration of 
120 mg/0.3 mL of TV-46046, 60 mg/0.3 mL of 1:1 saline diluted TV-46046, 0.3 mL 
of TV-46046 Placebo, and 104 mg/0.65 mL of Depo-subQ 104
2.2.
Study Endpoints
2.2.1.
Primary Endpoint
The primary endpoint is ISR, excluding injection site pain, as assessed by self-reports and direct 
observation for each injection at least twice on the day of injection (Day 0: immediately after [ie, 
as soon as possible but no later than 10 minutes upon removing the needle] and 1 hour 
[±5 minutes] after the injection), at Days 1, 3, 7 and 14, at Months 3 and 6, and at additional 
visits, if indicated. 
2.2.2.
Secondary Endpoints
2.2.2.1.
Injection Site Pain

Injection site pain for each injection assessed by:

Numerical Rating Scale (NRS) score twice on the day of injection (Day 0: 
immediately [ie, as soon as possible but no later than 10 minutes upon removing 
the needle] after and 1 hour [±5 minutes] after the injection)

Self-reports using the NRS on Days 1, 3, 7 and 14, at Months 3 and 6, and at 
additional visits, if indicated


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
Subjects’ perception of injection site pain as assessed by an overall ranking of the 4 
study injections from least [1] to most [4] painful on the day of injection (Day 0)
2.2.2.2.
Overall Safety

Occurrence of adverse events

Use of concomitant medications

Change in vital signs and weight


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3.
INVESTIGATIONAL PLAN
3.1.
General Study Design 
This is a randomized, crossover, single-center, Phase 1 study to evaluate and compare local 
tolerability following subcutaneous administration of TV-46046, diluted TV-46046, TV-46046 
Placebo, and Depo-subQ 104, in 24 healthy female subjects 18 to 50 years of age. After signing 
the informed consent form, eligible subjects will be enrolled and receive one of each of the four 
subcutaneous study injections in each abdominal quadrant: 120 mg/0.3 mL of TV-46046, 
60 mg/0.3 mL of 1:1 saline diluted TV-46046, 0.3 mL of TV-46046 Placebo and 
104 mg/0.65 mL Depo-subQ 104 per the assigned sequence. Injections will be administered in 
different quadrants of the abdomen, each separated by approximately 1 hour (sufficient time to 
eliminate carry-over effect of pain at previous injection). Subjects will be randomized to one of 
24 different injection sequences (one subject per sequence) to counterbalance potential effects of 
injection order or abdominal quadrant on study outcomes. 
All subjects will be followed for at least 6 months after receiving their injections. Local 
tolerability will be assessed by evaluating ISRs at least twice on the day of the study injections 
(Day 0: immediately after [ie, as soon as possible but no later than 10 minutes upon removing the 
needle] and 1 hour [±5 minutes] after the injection), at Days 1, 3, 7, and 14; at Months 3 and 6; 
and at other visits, if indicated. Subjects with unresolved ISR(s) will be followed monthly 
through the resolution of ISR(s) or Month 18, whichever comes first. 
Subjects will assess their injection site pain using an 11-point NRS (0 = no pain at all; 10 = worst 
pain) twice on the day of injection (Day 0: immediately after [ie, as soon as possible but no later 
than 10 minutes upon removing the needle] and 1 hour [±5 minutes] after the injection). In 
addition, 1 hour after the fourth (final) injection subjects will provide an overall ranking of 
administrations from least [1] to most [4] painful. Thereafter, injection site pain will be assessed 
by self-reports at all subsequent visits. Adverse events and concomitant medications will be 
recorded throughout the study. Vital signs and weight will be measured at baseline, Month 6, and 
study exit.  The assessments and procedures performed during each study visit are detailed in 
Table 1 and Section 3.4.
3.2.
Subject Eligibility
Prospective waivers (exceptions) from study eligibility criteria to allow subjects to enter a study 
are not granted by Teva (see Section 10.1.2).
3.2.1.
Subject Inclusion Criteria
Subjects may be included in the study if they meet all of the following criteria: 
a.
has a low risk of pregnancy (ie, sterilized, in exclusively same-sex partnership, in 
menopause and/or post-menopausal, abstinent, in monogamous relationship with 
vasectomized partner, using non-hormonal intrauterine device (IUD), or consistent 
use of condoms)
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c.
is 18 to 50 years of age (inclusive)
d. is willing to provide informed consent and follow all study requirements
e.
is not pregnant and does not have desire to become pregnant in the subsequent 
18 months
f.
had a normal mammogram within the last year, if 40 years or older
g. has no skin disorders or skin allergies
3.2.2.
Subject Exclusion Criteria
Subjects will be excluded from participating in this study if they meet any of the following 
criteria: 
a.
has hypertension, 

systolic blood pressure (BP) ≥160 mm Hg or diastolic BP ≥100 mm Hg or

vascular disease
b. has ischemic heart disease or a history of ischemic heart disease
c.
has a history of stroke
d. has a history of thromboembolic event(s) 
e.
has systemic lupus erythematosus or

positive (or unknown) antiphospholipid antibodies or

severe thrombocytopenia
f.
has rheumatoid arthritis and is undergoing immunosuppressive therapy
g. has migraine with aura
h. has unexplained vaginal bleeding
i.
has diabetes
j.
has a strong family history of breast cancer (defined as one or more first degree 
relatives, breast cancer occurring before menopause in three or more family members, 
regardless of degree of relationship, or any male family member with breast cancer), 
or current or history of breast cancer, or undiagnosed mass detected by breast exam 
k. has cervical cancer or a history of cervical cancer
l.
has severe cirrhosis (decompensated) or liver tumors
m. has known significant renal disease
n. has a history of diagnosed clinical depression or bipolar disorder, with or without 
suicidal ideation, and/or history of suicide attempt
o. has, in the last two years, a history of either hospitalization or medication 
management for a psychiatric disorder that in the opinion of the investigator would 


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make study participation unsafe, would interfere with adherence to study 
requirements or complicate data interpretation
p. is currently using hormonal contraception
q. had an injection of DMPA (Depo-Provera CI or Depo-subQ 104) in the past 12 
months; or combined injectable in the last 3 months
r.
has a known sensitivity to MPA or any inactive ingredients
s.
is chronically using pain medication
t.
has a plan to move to another location in the next 18 months
u. has, in the opinion of the investigator, a potentially elevated risk of HIV infection (eg, 
HIV-positive partner, IV drug use by self or by partner)
v. has any condition (social or medical), which in the opinion of the investigator would 
make study participation unsafe, would interfere with adherence to the clinical study 
requirements or would complicate data interpretation
3.3.
Duration of Subject Participation 
Screening for eligibility, enrollment, randomization and administration of study treatments can 
occur on the same day or may be split between two visits for logistical reasons. This will be 
followed by a treatment period of 6 months. If subjects have unresolved ISR(s) at Month 6, they 
will be followed until ISR resolution or Month 18, whichever comes first. Therefore, the 
minimal duration of subject participation is 6 months and the maximum is 18 months after the 
study treatment. See Section 11.5 for the definition of the end of the study.
3.4.
Study Procedures
Before implementation, the protocol and all relevant study documents including recruiting 
materials will be approved by the investigational center’s local Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) and by FHI 360’s Protection of Human Subjects 
Committee (PHSC).
Description and timing of study procedures and assessments are summarized in Table 1. Detailed 
visit-specific information is provided in this section. Detailed descriptions of each assessment are 
provided in Section 5.1 and Section 5.2.


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Table 1:
Study Procedures and Assessments
Procedures and 
Assessments
Screening
Treatment Day
Scheduled Follow-Up Period
Additional Follow-Up 
Period, if Indicated
Day 
-1
Day 0
Injection 
1
Injection 
2
Injection 
3
Injection 
4
Days 
1, 3, 7, 14
Months 
1, 2, 4, 5
Months 
3 and 6a  
Months 7, 8, 9, 10, 11, 12, 
13, 14, 15, 16, 17, 18b
Informed consent
X
Medical history
X
Contraceptive 
history
X
Inclusion and 
exclusion criteria
X
X
Urine pregnancy 
test 
X
[X]
[X]
[X]
[X]
Blood pressure
X
Vital Signs 
(Blood pressure, 
pulse, respiration 
rate, 
temperature)c  
X
X
[X]
Weight c
X
X
[X]
Mammogram d
[X]
Breast exam
X
Randomization
X
IMP injection
X
X
X
X
Injection site 
pain NRS 
assessment e
X
X
X
X
X
[X]
[X]
ISR evaluation f
X
X
X
X
X
[X] 
X
X


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Procedures and 
Assessments
Screening
Treatment Day
Scheduled Follow-Up Period
Additional Follow-Up 
Period, if Indicated
Day 
-1
Day 0
Injection 
1
Injection 
2
Injection 
3
Injection 
4
Days 
1, 3, 7, 14
Months 
1, 2, 4, 5
Months 
3 and 6a  
Months 7, 8, 9, 10, 11, 12, 
13, 14, 15, 16, 17, 18b
Adverse event 
assessment f,g
[X]
[X] 
[X] 
[X] 
[X] 
[X]
X
X
[X]
Concomitant 
medication 
assessment g
X
[X]
X
X
[X]
a If the subject does not have any ISRs at Month 6 and subject does not agree to return for an additional post-6 month follow up visit, Month 6 will be her final 
visit. In addition to ISR, adverse event, and concomitant medication evaluation, her weight and vital signs will be measured at that time. Subjects who complete 
the study at Month 6 will be instructed to contact the clinic if any ISRs develop after their final visit. If the subject is reported to have ISR(s) at Month 6, she 
will be instructed to return to the clinic monthly until ISR resolution or Month 18, whichever is earlier. In this case, the Month 6 procedures will be repeated at 
her final visit.
b Subjects who have exited the study with no new or ongoing ISRs at Month 6 and who agree (providing written informed consent) to return for a single follow-
up visit between Months 9 and 12, will undergo ISR, adverse event, and concomitant medication evaluation, and vital sign and weight measurements at that 
time. If the subject does not have any ISRs at this visit, it will be her final visit and the subject will be instructed to contact the clinic if any ISRs develop after 
their final visit. If the subject does have ISR(s) at this visit, she will be instructed to return to the clinic monthly until the ISR resolution or Month 18, 
whichever is earlier. In this case, ISR, adverse event, and concomitant medication evaluation, and vital sign and weight measurements will be repeated at her 
final visit.
c Vital signs and weight will be measured on Enrollment/Injection Day (Day 0) and Month 6, and at study exit.
d Normal mammogram within 1 year prior to enrollment, if 40 years or older.
e For each injection, injection site pain will be evaluated twice on the day of the study drug injection (Day 0: immediately after [ie, as soon as possible but no 
later than 10 minutes upon removing the needle] and 1 hour (±5 minutes) after the injection using NRS. For all subsequent visits, NRS will be used only if 
injection site pain is self-reported. One hour after the fourth (final) injection subjects will provide an overall ranking of all four administrations from least [1] to 
most [4] painful. 
f For each injection, ISR will be evaluated at least twice on the day of the study drug injection (Day 0: immediately after [ie, as soon as possible but no later than 
10 minutes upon removing the needle] and 1 hour (±5 minutes) after the injection, and on Days 1, 3, 7, and 14, Months 3 and 6, and at additional visits if 
indicated. Each injection site will be marked at the time of the injection and a photo taken for reference after the fourth injection.
g Study staff will inquire about adverse events and concomitant medications at Months 1, 2, 3, 4, 5 and 6 and at study exit, but will document adverse events and 
concomitant medications at any visit where the subject reports any new or changed adverse events or concomitant medications. For subjects who have 
previously exited the study at Month 6 and who agree to return for a single follow-up visit between Months 9 and 12, study staff will inquire about adverse 
events and concomitant medications during this visit and at study exit.
IMP=investigational medicinal product; NRS=Numerical Rating Scale; ISR=injection site reaction
NOTE: X=required, [X]=if indicated


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3.4.1.
Procedures for Screening Visit
Women may be recruited through various channels, including via regular informational sessions 
held at the study clinic where patients are informed about potential research opportunities. 
Women who express interest to participate will undergo an informed consent process 
administered by trained staff members including information about the study objectives, design 
and procedures, and potential risks and benefits of participation. A signed and dated informed 
consent form (ICF) will be obtained before screening procedures commence (see Section 11.3). 
After informed consent is obtained, the subject will be assigned a subject identification number 
in successive order of inclusion. Demographic information will be collected, a breast exam and 
blood pressure measurement will be performed and other eligibility criteria verified including 
medical and contraceptive history. The investigational center may conduct clinical procedures 
per investigational center-specific standard of care that are not required per the study protocol 
(eg, pelvic exam). 
If the participant has not had a mammogram in the past year and is 40 years or older, one will be 
scheduled prior to enrollment. In consultation with FHI 360, a subject who is screened and does 
not meet eligibility criteria may be considered for re-screening if the non-met criteria change
3.4.2.
Procedures for Enrollment/Injections Visit
On the day of enrollment, a urine pregnancy test will be performed; weight and vital signs will 
be measured (ie, blood pressure, pulse rate, respiration rate and temperature). Mammogram 
results from the prior year will be verified for women 40 years and older. Subject eligibility will 
be confirmed and enrollment/randomization procedures will be performed.
After eligibility is confirmed, the subject will be enrolled into the study and any ongoing 
medication will be documented as a concomitant medication. The enrolled subject will be 
randomized to a treatment sequence. An unblinded study staff member will enter subject 
information into OpenClinica’s RANDOMISE module, which will display the randomly selected 
treatment sequence. Date and time of randomization will be recorded on the study source 
documentation and case report form (CRF). All unblinded staff involved in randomization 
procedures will conceal the study drug sequence assignment and all records containing allocation 
sequence from the subject and the blinded staff (See Section 4.3 on Blinding/Unblinding for 
more detail). 
The subject will receive one of each of the four injections per the assigned sequence separated by 
approximately 1 hour: 120 mg/0.3 mL of TV-46046 injected with 23G needle, 60 mg/0.3 mL of 
1:1 saline-diluted TV-46046 injected with 23G needle, 0.3 mL of TV-46046 Placebo injected 
with 23G needle, and 104 mg/0.65 mL of Depo-subQ 104 injected with 26G needle. Shielding 
the needle and syringe from the view of the subject, an unblinded study staff member qualified 
and experienced in administering parenteral drugs, will administer all four injections 
subcutaneously in four abdominal quadrants starting with the subject’s right upper quadrant 
(injection A) and progressing in a clockwise manner to the left upper quadrant (injection B), left 
lower quadrant (injection C), and right lower quadrant (injection D). Each injection site will be 
marked at the time of the injection and a photo taken for reference after the fourth injection. For 
each injection, ISRs and injection site pain will be evaluated immediately after (ie, as soon as 
possible but no later than 10 minutes upon removing the needle) and 1 hour (±5 minutes) after 


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each injection (right before the next injection). In addition, 1 hour after the fourth (final) 
injection subjects will provide an overall ranking of administrations from least [1] to most [4] 
painful. See Section 5.1.1 for more information on assessment of ISRs and injection site pain. In 
addition, detailed instructions for NRS assessment and documentation will be provided in the 
Study Manual.
In summary, the following procedures will be conducted on the Enrollment/Injection Visit 
(Day 0):

eligibility confirmed

urine pregnancy test performed

vital signs and weight measured

adverse events documented if occurring after ICF is signed

concomitant medications recorded

treatment sequence allocation obtained

study drug injections administered per treatment sequence allocation 

injection sites evaluated for ISRs

injection site pain assessed by NRS 

all four injections ranked from least [1] to most [4] painful 

photo of the four marked injection sites taken
3.4.3.
Follow-up/Final Visits
All subjects will return to the clinic on Day 1, Day 3, Day 7, Day 14, Month 1 and then monthly 
through Month 6. During Days 1, 3, 7, and 14 and Months 3 and 6 visits, ISRs and injection site 
pain for each of the four study injections will be evaluated following procedures outlined in 
Section 5.1. In addition, at monthly visits between Months 1 and 6, information on adverse event 
and concomitant medications will be collected. If the subject does not have any ISRs at Month 6, 
Month 6 will be her final visit, unless she agrees to return for additional follow up as detailed in 
Section 3.4.5.  In addition to ISR, adverse event, and concomitant medication evaluation, her 
weight and vital signs will be measured at that time. Subjects who complete the study at Month 6 
will be instructed to contact the clinic if any ISRs develop after their final visit. If any ISRs are 
identified or still ongoing at Month 6, monthly follow-up visits for ISR evaluation will be 
scheduled until the ISR is resolved or Month 18, whichever is earlier. In this case, the Month 6 
procedures will be repeated at her final visit. 
The following procedures will be performed during Follow-up/Final visits:

injection sites evaluated for ongoing and/or new ISRs (Days 1, 3, 7, and 14 and Months 3 
and 6 and at study exit)

injection site pain assessed if self-reported (Days 1, 3, 7, and 14 and Months 3 and 6, and 
other visits if appropriate)


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
adverse event and concomitant medication inquiry conducted (at Months 1, 2, 3, 4, 5 and 
6 and at study exit)

vital signs and weight measured (Month 6 and at study exit)
3.4.4.
Unscheduled Visits
An unscheduled visit may be performed at any time during the study at the subject’s request or 
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, if applicable (eg, ISRs, adverse events, 
concomitant medications and treatments, and results from procedures or tests). 
3.4.5.
Post-6 Month Follow-up 
In order to identify any late onset ISRs, subjects who have exited the study with no new or 
ongoing ISRs at Month 6 and who agree (providing written informed consent) to return for a 
single follow-up visit between Months 9 and 12, will undergo ISR, adverse event and 
concomitant medication evaluation, and vital sign and weight measurements at that time. If any 
ISRs are identified or still ongoing at this additional visit between Months 9 and 12, monthly 
follow-up visits for ISR evaluation will be scheduled until the ISR is resolved or Month 18, 
whichever is earlier. In this case, ISR, adverse event, and concomitant medication evaluation, 
and vital sign and weight measurements will be repeated at her final visit. If the subject reports 
injection site pain at any of these visits, she will be asked to use the NRS to evaluate the intensity 
of pain in order to determine if it meets the definition of an adverse event. If the subject does not 
have any ISRs at this visit, it will be her final visit. However, the subject will be instructed to 
return to the clinic if any ISRs develop after her final visit. In that case, she will be consented, 
her status will change from completed the study to active and she will be followed until ISR 
resolution or Month 18, whichever is earlier, as described above.


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4.
TREATMENT OF SUBJECTS
4.1.
Investigational Medicinal Products Administered During the Study 
The IMPs used in this study will be supplied by the sponsor and are described in Table 2.
4.1.1.
Test Investigational Medicinal Product
Medroxyprogesterone acetate injectable suspension 400 mg/mL (TV-46046) will be provided by 
the sponsor as a sterile suspension. TV-46046 will be used at 2 different concentrations: 0.3 mL 
of 400 mg/mL (undiluted) and 0.3 mL of 200 mg/mL (saline diluted). To obtain the 200 mg/mL 
concentration, TV-46046 will be diluted with sterile saline by the delegated study staff following 
the sponsor’s recommendations. Saline will be provided to the site by either the contract research 
organization or the sponsor. Dilution procedures will be followed per the Pharmacy Manual.
Each TV-46046 dose will be presented in a 3 mL United States Pharmacopeia (USP) Type 1 
clear glass vial, with a 13-mm rubber stopper, and a 13-mm aluminum seal covered with a green 
cap (STERI TAMP® single-use tamper evident sticker). The test IMP will be administered with a 
23 gauge, 3/8” safety needle. 
4.1.2.
Reference Investigational Medicinal Product 
Depo-subQ 104 is the reference IMP. It is indicated for prevention of pregnancy at a dose of 
104 mg administered every 3 months by a 0.65 mL subcutaneous injection. For this study, 
Depo-subQ will be supplied as a single-unit dose of 104 mg/0.65 mL prefilled glass syringes pre-
packaged with 26 gauge 3/8” needle. Detailed composition and injection instructions are 
contained in the Depo-subQ 104 Prescribing Information (Depo-subQ 104 US Prescribing 
Information 2016).
4.1.3.
Placebo Investigational Medicinal Product 
Medroxyprogesterone acetate injectable suspension 400 mg/mL (TV-46046), Placebo (or 
TV-46046 Placebo) will be supplied in a 2 mL clear glass vial (filling volume 1.2 mL), with a 
rubber stopper and covered with a white cap.
Similar to TV-46046, 0.3 mL of TV-46046 Placebo will be administered with a 23 gauge, 3/8” 
safety needle.
4.2.
Treatment of Subjects 
Subjects will receive all four study injections (120 mg/0.3 mL of TV-46046, 60 mg/0.3 mL of 
1:1 saline-diluted TV-46046, 0.3 mL of TV-46046 Placebo and 104 mg/0.65 mL of Depo subQ 
104) on the same day approximately 1 hour apart. The four injections will be administered 
subcutaneously in four abdominal quadrants starting with the subject’s right upper quadrant 
(injection A) and progressing in a clockwise manner to the left upper quadrant (injection B), left 
lower quadrant (injection C), and right lower quadrant (injection D), per the assigned sequence. 
The study staff administering the injections will be instructed not to apply bandages, and to avoid 
touching or massaging the injection site. In case of bleeding, a gentle application of the cotton 
ball for several minutes will be recommended (ie, no application of ice or bandages). Subjects 


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will remain at the investigational center for at least 1 hour after the last injection. The 
investigational center will have an epinephrine injection available and easy access to emergency 
care in the unlikely event of anaphylaxis or anaphylactoid reaction.


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Table 2:
Investigational Medicinal Products Used in the Study
IMP name
TV-46046
TV-46046 Placebo
Reference IMP
Trade name and INN, if 
applicable, or company 
assigned number
Medroxyprogesterone acetate
TV-46046 Placebo
Medroxyprogesterone acetate injectable 
suspension
 
 
 
 
 
 
 
 
 
 
Unit dose strength(s)/ 
Dosage level(s)
120 mg/0.3 mL
(diluted TV-46046: 60 mg/0.3 mL)
0.3 mL
104 mg/0.65 mL
Route of administration
SC injection 
(Sol Care Safety syringe 0.5 ml,
with fixed needle 23G x 3/8”
[0.6mm x 10mm]
SC injection
(Sol Care Safety syringe 0.5 ml,
with fixed needle 23G x 3/8”
[0.6mm x 10mm] 
SC injection with 26G needle
IMP=investigational medicinal product; INN=international proprietary name; NA=not applicable; anh=anhydrous; qs=quantify sufficient; SC=subcutaneous; 
G=gauge. 


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4.3.
Blinding/Unblinding
The study will be partially blinded due to differences in appearance and volume of the 
treatments. Designated unblinded study staff will conduct randomization procedures. The staff 
preparing and administering injections will also be unblinded to treatment sequence but will be 
trained to shield the syringe prior to and at the time of injection from view of the subject and 
study staff assessing ISRs. Additional study staff will be unblinded to provide quality assurance 
and oversight of injection preparation and administration. These individuals will not be involved 
in any additional conduct of study procedures, collection of ISR data, or assessment of any 
adverse events.
Study subjects and staff conducting follow-up interviews, and recording of complaints, 
symptoms and clinical findings, will be unaware of sequence assignments throughout the study. 
Specifically, blinded study staff will be responsible for evaluating ISRs, adverse events, 
concomitant medication use, and measuring vital signs and weight at all appropriate study 
timepoints. Injection site pain will be assessed in a blinded manner by subjects themselves. 
Records of treatment sequence assignment will be maintained in a secure manner accessible only 
to unblinded study staff. FHI 360 will assign a blinded clinical monitor to conduct routine 
investigational center monitoring visits and a separate unblinded clinical monitor to reconcile 
study supplies dispensed and maintained at the investigational center, and review randomization 
and dosing documentation during the study. FHI 360 and sponsor project team members 
involved in assessment of adverse events, data analysis, or results interpretation will be blinded 
to treatment sequence until at least the first interim analysis, at which time results may be 
reviewed by treatment to inform decisions whether to stop enrollment or modify the study.
4.3.1.
Unblinding During the Study
Because of the cross-over design of one day treatment only and long-term follow-up/observation 
nature of the study drugs, emergency unblinding for medical reasons will be of limited (if any) 
value, and therefore no prior plans for emergency unblinding will be put in place.
For adverse events that are defined as a Suspected Unexpected Serious Adverse Reaction 
(SUSAR) (ie, reasonable possibility that adverse event is related to treatment; Section 5.2.5), 
Global Patient Safety and Pharmacovigilance (GPSP) will request that the treatment code be 
revealed 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, analysis, and reporting of the data.
All cases of inadvertent unblinding will be handled per FHI 360’s SOPs.
4.4.
Stopping Rules and Discontinuation Criteria
The investigational center will be advised to pause enrollment if at any time two or more ISRs 
graded as severe adverse events, two cases of injection site discoloration (hypopigmentation) 
ongoing for more than 7 days, or two serious and related adverse events are reported in the study 
across all injection sites. Such occurrences will trigger an unplanned review of interim data by a 
Study Review Committee (SRC), at which time a recommendation to halt the study or to 
reinitiate enrollment may be made. Other planned reviews will take place as scheduled (see 


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Section 4.5), at which time the SRC could advise that the study stop or be modified based on 
concerns for safety of subjects or definitive conclusions.
Since most of the study drugs are expected to remain in the body months after injection, study 
discontinuation will not be the same as treatment discontinuation. Study staff will explain to 
subjects who wish to discontinue the study early that it is important to stay in the study until 
safety assessments are completed. However, a subject may discontinue participation in the study 
at any time for any reason (eg, withdrawal of consent or an adverse event) without loss of other 
benefits or services to which they may be entitled. All subjects who discontinue early will be 
followed according to Subject Withdrawal Criteria and Procedures (Section 4.6.1). Reasons for 
discontinuation from the study will be recorded on the appropriate CRF.
Others reasons the study may be stopped include:

FHI 360’s PHSC recommends terminating the study

Local IRB(s)/IEC(s) recommend terminating the study

The FDA requests that the study be discontinued or placed on hold.

The sponsor decides to reduce the scope (eg, reduce sample size, drop one or more 
study groups) or terminate the study. The sponsor may terminate the study at any time 
for any reason. 
If the whole study is stopped, the subjects that are terminated early will be followed according to 
Subject Withdrawal Criteria and Procedures (Section 4.6.1).
4.5.
Interim Data Reviews
The study will be overseen by an internal SRC, the composition and responsibilities of which 
will be detailed in a separate SRC Operational Plan. In addition to unplanned reviews that may 
be triggered by the occurrence of ISRs, serious and related adverse events, and/or injection site 
discoloration (hypopigmentation) events, the SRC may convene for a single planned review of 
interim data when approximately 50% of study subjects have been enrolled and treated. If, 
however, enrollment is predicted to take less than 2 months, then the interim review may instead 
be scheduled to occur after all subjects have been treated. At the time of any planned or 
unplanned interim review of data, the SRC may recommend that the trial be modified or halted 
to ensure the safety and well-being of study subjects. There will be no adjustment to type I error 
to account for any interim reviews of study data. 
4.6.
Prior and Concomitant Therapy or Medication
Any medication a subject uses between the enrollment and final visit will be recorded as a 
concomitant on the appropriate CRF. During scheduled Months 1, 2, 3, 4, 5 and 6 visits the 
investigator will ask subjects whether they have taken any medications, including 
over-the-counter medications, vitamins, or herbal or nutritional supplements, since the previous 
visit. During all other scheduled and unscheduled visits information on the use of concomitant 
medications will be documented only if reported by the subject. Generic or trade name, 
indication, route of IMP administration, dosage, and start and end dates will be recorded.


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Subjects who are taking pain medications on a chronic basis will not be eligible for the study. 
There will be no prohibited medications during the study; however, application of bandages to 
injection sites will be discouraged. 
4.6.1.
Subject Withdrawal Criteria and Procedures
In accordance with the Declaration of Helsinki, each subject is free to withdraw from the study at 
any time. The investigator also has the right to withdraw a subject from the study in the event of 
intercurrent illness, adverse events, pregnancy (see Section 5) or other reasons concerning the 
health or well-being of the subject, or in the event of lack of cooperation. 
Should a subject decide to withdraw from the study, or should the investigator decide to 
withdraw the subject, every reasonable effort will be made to assess information relevant to the 
endpoints at the time of discontinuation. In this study this mainly includes assessment of ISRs. 
The final visit procedures will be followed for all subjects who withdraw, if possible (see 
Section 3.4.3).
The reason for and date of withdrawal from the study must be recorded on the source 
documentation and transcribed onto the CRF. If a subject withdraws consent, every attempt will 
be made to determine the reason. 
If the investigator determines that an adverse event is related to the test IMP, monitoring will 
continue until the adverse event has resolved or stabilized, the subject exited the study or the 
subject has reached the end of the follow-up period. The investigator must inform FHI 360 as 
soon as possible of all subjects who are being considered for withdrawal due to adverse events. 
Additional reports must be provided when requested.
The study product remains in the body months after the injections, therefore, prompt withdrawal 
from the study treatment is not possible, and discontinuation from the study will not be the same 
as withdrawal from treatment. Study staff will explain to subjects who wish to discontinue from 
the study early that it is impossible to discontinue the treatment and that it is important to stay in 
the study until safety assessments are completed.
4.7.
Procedures for Monitoring Subject Compliance
All IMPs will be injected by the investigator or other clinical personnel at the investigational 
center; therefore, monitoring of subject compliance will not be necessary. 
4.8.
Withdrawal of Subjects
4.8.1.
Lost to Follow-up
If a subject fails to appear for a scheduled visit, at least 3 attempts to contact the subject will be 
made. If she does not return to clinic while the study is ongoing then she will be considered 
“presumed lost to follow-up”, but her file will remain open until study closeout. If the subject 
does not return before the study is closed, she will be classified as lost to follow-up. The lost to 
follow-up designation will not be made for any subject until the closing date of the study.


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5.
SAFETY AND TOLERABIILITY MEASUREMENTS AND 
ASSESSMENTS
5.1.
Safety and Tolerability Measurements
5.1.1.
Local Tolerability 
The four study injections will be administered in different quadrants of the abdomen, each 
separated by approximately 1 hour (sufficient time to eliminate carry-over effect of pain at 
previous injection). The injections will be administered subcutaneously in four abdominal 
quadrants starting with the subject's right upper quadrant (injection A) and progressing in a 
clockwise manner to the left upper quadrant (injection B), left lower quadrant (injection C), and 
right lower quadrant (injection D), per the randomized sequence. Each injection site will be 
marked at the time of the injection and a photo will be taken of all four injection sites for future 
identification.
In this study local tolerability will be assessed by occurrence of ISRs including but not limited to 
erythema (redness), swelling, pruritus (itching), bleeding, bruising, injection site discoloration 
(eg, hypopigmentation), or atrophy (ie, dimple). Injection site pain will be evaluated and 
analyzed as a separate study endpoint (see Section 5.1.2). 
The site of injection will be evaluated for possible ISRs after each of the four injections at least 
twice during the enrollment/injection visit (Day 0) immediately after (ie, as soon as possible but 
no later than 10 minutes upon removing the needle) and 1 hour (±5 minutes) after each injection 
(right before the next injection). Given the study design and assessment schedule, injection sites 
for the first, second and third injections may be evaluated more than twice. Thereafter, injection 
sites will be monitored for the progress of ongoing and/or occurrence of new ISRs at Days 1, 3, 
7, and 14; at Months 3 and 6 and at other visits, if indicated. Subjects with no new or ongoing 
ISRs at their final visit will complete the study but be instructed to contact the clinic if new ISRs 
develop after their final visit (see Section 3.4.3 and Section 3.4.5). Subjects with ISRs at their 
final visit will be followed monthly until ISR resolution or Month 18, whichever comes first. 
ISRs will be evaluated at all study visits by subject’s self-reports and visual examination of the 
site of injection by blinded study staff. The study staff will be instructed to use non-leading 
questions (eg, how does the injection site feel, do you have any new complaints about the 
injection site since last visit) for ISR ascertainment. All findings will be recorded for each of the 
four study injections on the appropriate study CRFs and clinical notes. Photos of the injection 
site may be taken to supplement documentation of ISRs any time during the study. If necessary, 
a consultation with an appropriate clinical expert may be scheduled. All cases of injection site 
discoloration (hypopigmentation) will be photographed and consulted by a dermatologist.
5.1.2.
Injection Site Pain 
For the purpose of this protocol, injection site pain will include pain associated with insertion of 
the needle, injecting of the drug, and any pain or tenderness at/around the injection site. On the 
day of injection (Day 0) injection site pain will be evaluated twice: immediately after (ie, as soon 
as possible but no later than 10 minutes upon removing the needle) and 1 hour (±5 minutes) after 


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each injection (right before the next injection). Subjects will assess their injection site pain using 
an 11-point NRS by indicating a number between 0 (no pain) and 10 (worst pain). In addition, 
1 hour after the fourth (final) injection subjects will provide an overall ranking of all four 
administrations from least [1] to most [4] painful. Thereafter, injection site pain will be evaluated 
by self-reports on Days 1, 3, 7, and 14, Month 3 and 6, and at additional visits, if appropriate. If 
the subject reports injection site pain at any of these visits, she will be asked to use the NRS to 
evaluate the intensity of pain in order to determine if it meets the definition of an adverse event. 
5.2.
Safety Assessments
The following safety and tolerability measures will be implemented throughout the study at the 
time points listed in Table 1.

vital signs and weight will be measured at Day 0 and Month 6 and study exit 

adverse events and concomitant medications will be evaluated at Day 0, at Months 1 
through 6, and at study exit 

information about adverse events and concomitant medications will not be actively 
solicited but documented if reported on Days 1, 3, 7, and 14 and unscheduled visits
5.2.1.
Definition of an Adverse Event
An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical 
product, regardless of whether it has a causal relationship with the treatment. 
In this study, any adverse event occurring after the subject has signed the ICF through the end of 
the follow up period will 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, or 
significant worsening of any concurrent disease, whether or not considered related to TV-46046, 
diluted TV-46046, TV-46046 Placebo or Depo-subQ 104. A new condition or the worsening of a 
pre-existing condition will be considered an adverse event. 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

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] should be recorded as an adverse event if frequency of its 
occurrence increases during this study.)

drug interactions

laboratory or diagnostic test abnormalities, that result in the withdrawal of the subject 
from the study, are associated with clinical signs and symptoms or a serious adverse 


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event, or 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 subject from entering the study or receiving 
study treatment are not considered adverse events.)

Any physical examination, vital signs measurement, or other safety assessment 
finding that is judged by the investigator as a clinically significant change 
(worsening) compared with a baseline value will be considered an adverse event. For 
the purpose of this study, the following will be considered adverse events:

Irregular vaginal bleeding that requires medical intervention or meets the 
definition of “serious adverse event” (See Section 5.2.5)

Injection site pain with a NRS score of 7 to 10

Injection site pruritus/itching if itching localized to the injection site requiring ≥48 
hours treatment OR generalized itching causing inability to perform usual social 
and functional activities

Injection site erythema/redness of ≥5 cm in diameter (or ≥ 25 cm2 surface area) 
or greater than minimal interference with usual social and functional activities

Injection site induration/swelling of ≥5 cm in diameter (or ≥ 25 cm2 surface area) 
or greater than minimal interference with usual social and functional activities

Any ISR that meets the definition of “serious adverse event” 

Pre-existing diseases or conditions that worsen during the study.
5.2.2.
Recording and Reporting Adverse Events
For adverse event recording, the study period is defined for each subject as that time period from 
signature of the ICF through the end of the subject's follow-up period. 
All adverse events that occur during the defined study period must be recorded on the source 
documentation and transcribed onto the CRF, regardless of the severity of the event or judged 
relationship to the IMP. For serious adverse events, the Serious and Protocol Defined Adverse 
Event Form must also be completed and the event must be reported immediately (See 
Section 5.2.5.3). The investigator does not need to actively monitor subjects for adverse events 
once their follow-up period has ended. Serious adverse events occurring in a subject after study 
discontinuation will be reported to the sponsor if the investigator becomes aware of them, 
following the procedures described in Section 5.2.5.3.
At the Day 0, Months 1 through 6 and study exit, the investigator must question the subject 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.” At the scheduled Day 1, 3, 7, 
and 14 and unscheduled visits the information about adverse events will not be actively solicited 
but documented if spontaneously reported by the subject. All observed or reported signs and 
symptoms will be recorded individually, except when considered manifestations of a medical 
condition or disease state. A precise diagnosis will be recorded whenever possible. When such a 
diagnosis is made, all related signs, symptoms, and any test findings will be recorded collectively 


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as a single diagnosis on the CRF and, if it is a serious adverse event, on the Serious Adverse 
Event Form.
The clinical course of each adverse event will be monitored at suitable intervals until resolved or 
stabilized or returned to baseline, or until a determination of a cause unrelated to the treatment or 
study procedure is made.
The onset and end dates and times, action taken regarding IMP, treatment administered, and 
outcome for each adverse event must be recorded on the source documentation and transcribed 
onto the CRF. 
The relationship of each adverse event to IMP and study procedures, and the severity and 
seriousness of each adverse event, as judged by the investigator, must be recorded as described 
below.
5.2.3.
Severity of an Adverse Event
The severity of adverse events including ISRs must be recorded as one of the following:
Mild:
No limitation of usual activities
Moderate:
Some limitation of usual activities
Severe:
Inability to carry out usual activities 
5.2.4.
Relationship of an Adverse Event to the IMP
The relationship of an adverse event to the IMP will be characterized per the table below where 
possible, noting it may not be possible to assess relatedness of systemic adverse events due to the 
cross-over nature of the study. 
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 subject’s 
clinical state, environmental, or toxic factors, or other 
modes of therapy administered to the subject.

It does not follow a known pattern of response to the 
IMP. 

It does not reappear or worsen when the IMP is 
readministered. 


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Term
Definition
Clarification
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 IMP administration 
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 subject’s clinical state, 
environmental or toxic factors or other modes of therapy 
administered to the subject.

It disappears or decreases on cessation or reduction in 
dose. There are important exceptions when an adverse 
event does not disappear upon discontinuation of the IMP, 
yet an IMP relationship clearly exists.

It follows a known pattern of response to the IMP.
5.2.5.
Serious Adverse Events
5.2.5.1.
Definition of a Serious Adverse Event
A serious adverse event is an adverse event that results in any of the following outcomes or 
actions:

death

a life threatening adverse event (ie, the subject was at immediate risk of death from 
the event as it occurred); does not include an event that, had it occurred in a more 
severe form, might have caused death

inpatient hospitalization or prolongation of existing hospitalization, which means that 
hospital inpatient admission and/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 prior to study entry will not be considered serious adverse 
events, unless there was worsening of the preexisting condition during the subject’s 
participation in this study

persistent or significant disability or incapacity (refers to a substantial disruption of 
one’s ability to conduct normal life functions)

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 subject 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.
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event.


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5.2.5.2.
Expectedness
A serious adverse event that is not included in the Adverse Reaction Section of the relevant 
reference safety information (RSI) by its specificity, severity, outcome, or frequency is 
considered an unexpected adverse event. The RSI for this study is the current IB for TV-46046, 
and US prescribing information for Depo- SubQ 104, Depo-Provera CI and Depo Provera 400 
mg/mL (Depo-subQ 104 US prescribing information, Depo-Provera CI US prescribing 
information, and Depo-Provera Sterile Aqueous Suspension US prescribing information). 
The sponsor’s Pharmacovigilance Department will determine the expectedness for all serious 
adverse events. 
For the purpose of SUSAR reporting, the version of the IB at the time of occurrence of the 
SUSAR applies.
5.2.5.3.
Reporting a Serious Adverse Event
5.2.5.3.1. Investigator Responsibility
To satisfy regulatory requirements, all serious and protocol defined adverse events that occur 
during the study period (including the protocol defined follow-up period, regardless of judged 
relationship to treatment with the study drug), 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 and protocol defined adverse event form and reporting the event must not 
be delayed, even if not all the information is available. 
The serious adverse event form will be sent to FHI 360 (contact information can be found in 
Appendix A). FHI 360 will forward the report to the sponsor's Global Patient Safety & 
Pharmacovigilance Department.
The following information should be provided to record the event accurately and completely:

study number

investigator and investigational center identification

participant number

onset date and detailed description of adverse event

investigator's assessment of the relationship of the adverse event to the study drug (no 
reasonable possibility, reasonable possibility)
Additional information may include the following:

age and sex of subject

date of study drug injection

action taken

outcome, if known

severity

explanation of assessment of relatedness


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
concomitant therapy (including doses, routes and regimens) and treatment of the 
event

pertinent laboratory or other diagnostic test data

medical history 

for an adverse event resulting in death:
○
cause of death (whether or not the death was related to study drug)
○
autopsy findings (if available)
The investigator does not need to actively monitor subjects for adverse events once this study has 
ended. Serious adverse events occurring to a subject after the treatment of that subject has ended 
will be reported to the sponsor if the investigator becomes aware of them.
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 study drug, study 
procedures, and to underlying disease. 
If additional (follow-up) information about a serious adverse event becomes available, the 
investigator will forward it to the sponsor within 24 hours.
Blinding will be maintained for the people who are directly involved in the study except for 
authorized unblinded study staff and the unblinded study monitor. In the case of a SUSAR, only 
the sponsor and a designated unblinded FHI 360 staff will receive the unblinded report for 
regulatory submission; the others will receive a blinded report.
5.2.5.3.2. Sponsor Responsibility
If a serious unexpected adverse event is believed to be related to the study drug or study 
procedures, the sponsor will take appropriate steps to notify all investigators participating in 
sponsored clinical studies of TV-46046 and the appropriate health authorities and IRB/IEC, if 
appropriate. 
In addition to notifying the investigators and health authorities (and IRB/IEC, if appropriate), 
other measures may be required, including the following: 

amending the protocol

discontinuing or suspending the study

informing current study subjects of new findings by amending the existing ICF and 
re-consenting all subjects

modifying listings of expected toxicities to include adverse events newly identified as 
related to TV-46046
5.2.6.
Protocol Defined Adverse Events for Expedited Reporting
No protocol defined adverse events for expedited reporting to the sponsor were identified for this 
study.


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5.2.7.
Weight and Vital Signs
Weight and vital signs (BP [systolic/diastolic], temperature, pulse and respiration rate) will be 
measured at enrollment, Month 6, and study exit as detailed in Table 1.
Before pulse and BP are measured, the subject must be in a supine or semi-erect/seated position 
and resting for at least 5 minutes. (The same position and arm should be used each time vital 
signs are measured for a given subject.) For any abnormal vital sign finding, the measurement 
will be repeated. Any vital sign value that is judged by the investigator as a potentially clinically 
significant change (worsening) from a baseline value will be considered an adverse event. 
Weight gain or loss will be documented as an adverse event only if reported by the subject.
5.2.8.
Medication Error and Special Situations Related to the Investigational 
Medicinal Products
Any administration of IMP that is not in accordance with the study protocol will be recorded as a 
deviation. If it meets the important protocol deviation criteria, the incorrect IMP administration 
will be categorized as “Non-Compliance to Investigational Medicinal Product (IMP).”
The following are types of medication errors and special situations:

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.

Overdose: Administration of a quantity of a medicinal product given per administration 
or cumulatively which is above the maximum recommended dose according to the 
authorized product information. Clinical judgment should always be applied. Any dose of 
IMP (whether the test IMP, reference IMP, or placebo IMP), whether taken intentionally 
or unintentionally, in excess of that prescribed must be immediately reported to the 
sponsor. 

Misuse: Any intentional therapeutic use of a drug product in an inappropriate way or 
opioid use contrary to the directed or prescribed pattern of use, regardless of the presence 
or absence of harm or adverse effects. Examples: under usage, erratic or disorganized 
use, inappropriate use (for anxiety), in conjunction with alcohol or illegal substances, 
overuse.

Abuse: Any intentional, nontherapeutic use of a drug product or substance, even once, for 
the purpose of achieving a desirable psychological or physiological effect, or intentional 
use of the opioid for a nonmedical purpose, such as euphoria or altering one’s state of 
consciousness.

Off-label use: Situations where an IMP is intentionally used for a medical purpose not in 
accordance with the authorized product information.

Occupational exposure: Exposure to an IMP, as a result of one’s professional or 
non-professional occupation.


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5.2.9.
Protocol Deviations Because of an Adverse Event
If a subject experiences an adverse event or medical emergency, departures from the protocol 
may be allowed on a case-by-case basis. After stabilization and/or treatment has been 
administered to ensure subject safety, the investigator or other physician in attendance must 
contact the physician identified in Appendix A of this protocol as soon as possible to discuss the 
situation. The investigator, in consultation with the sponsor and FHI 360, will decide whether the 
subject should continue to participate in the study.
5.2.10.
Pregnancy 
The risk of pregnancy is minimal since only women who are at low risk of pregnancy will be 
enrolled in the study (see Section 3.2.1 for Inclusion Criteria). Only women who are not pregnant 
on the day of the study injection and do not want to become pregnant in the next 18 months will 
be enrolled in the study. During the study, a urine pregnancy test will be performed if the woman 
is experiencing any symptoms or signs of pregnancy, or thinks she may be pregnant. In the 
unlikely event of pregnancy during the study, the subject will be withdrawn and pregnancy will 
be recorded as the reason for discontinuation on the appropriate study CRFs, and the investigator 
must provide FHI360 with the pregnancy form. The process for reporting a pregnancy is the 
same as that for reporting a serious adverse event (see Section 5.2.5.3 for details). All subjects 
who become pregnant will be monitored to the completion or termination of the pregnancy. If the 
pregnancy continues to term, the outcome, including spontaneous or voluntary termination, 
details of birth and presence or absence of any birth defect, congenital abnormalities, or maternal 
and newborn complications, will be reported to the study sponsor.
The investigator is not required to report subjects who are found to be pregnant between 
screening and baseline.
If the pregnancy does not continue to term, one of the following actions will be taken:

For an elective abortion due to developmental anomalies, report as a serious adverse 
event and also fill in the pregnancy form. 

For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event.

For a spontaneous abortion, report as a serious adverse event and also fill in the 
pregnancy form.


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6.
PHARMACOKINETIC MEASUREMENTS AND ASSESSMENTS
Pharmacokinetics will not be evaluated in this study.


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7.
PHARMACODYNAMIC, PHARMACOGENOMIC,
IMMUNOGENICITY, AND BIOMARKER MEASUREMENTS 
AND ASSESSMENTS
7.1.
Pharmacodynamics
Pharmacodynamics will not be evaluated in this study.
7.2.
Pharmacogenomic Assessments
Pharmacogenomic sampling is not applicable in this study.
7.3.
Immunogenicity
Immunogenicity will not be assessed in this study.
7.4.
Assessment of Exploratory Biomarkers
Biomarkers will not be assessed in this study.


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8.
STATISTICS
This section describes statistical analyses of primary and secondary objectives as foreseen at the 
time the protocol was written. Further details will be described in a separate statistical analysis 
plan which will be approved prior to unblinding of study statisticians. Any additional analyses or 
changes to planned analyses will be fully disclosed in the clinical study report. All statistical 
analyses will be performed using SAS® software Version 9.4 or later. All tests and comparisons 
between treatment groups will be conducted at the two-sided 0.05 significance level, with no 
adjustment for multiple comparisons.
8.1.
Sample Size and Power Considerations
The study size of 24 subjects, each of whom will receive all four treatments (one per abdominal 
quadrant), will provide at least 80% power to detect differences in the rates of ISRs among 
groups of the magnitude (>40%) observed in recent non-comparative studies of TV-46046 and 
Depo-subQ 104 (see Table 3). Although not designed to obtain precise estimates of less frequent 
ISR rates (eg, injection site discoloration [hypopigmentation]), there is a high (>90%) probability 
of detecting one or more specific ISR types per treatment if the true rate of such events is at least 
10%. No randomized subjects will be replaced. However, if more than two subjects fail to 
receive all four injections or discontinue before Month 6, then additional subjects may be 
enrolled to help ensure that there are at least 22 subjects who complete the treatment sequence 
and are evaluable for at least 6 months. 
Table 3:
ISR Rates (per injection)
Injection 
Pain
Redness
Injection Site 
Discoloration 
(Hypopigmentation) 
Any Adverse 
Event
Reference
TV-46046 (Study 
#TV-46046-WH-
10075; IND 126249) 
8/12 
(66.7%)
9/12 
(75.0%)
2/12 
(16.7%)
9/12 
(75.0%)
Ongoing PK/PD
Depo-subQ 104
(Study #702179; 
IND 127097)
3 /18 
(16.7%)
1/18 
(5.5%)
0/18 
(0%)
2/18 
(11.1%)
Ongoing PK/PD
8.2.
Method of Randomization
Each eligible subject will be randomized to one of the 24 possible treatment sequences (one 
subject per sequence). The randomization scheme will result in each drug being injected first, 
second, third, fourth on 6 occasions; and each drug being injected in each quadrant of the 
abdomen on 6 occasions. 
Allocation assignments will be concealed using a centralized randomization application 
implemented within the OpenClinica data management system, with sequentially-numbered 
concealed envelopes available at the investigational center as a back-up method of assignment. 
The next available randomization sequence will be assigned to each subject only after she has 
been enrolled into the study. See Section 3.4.1 for how randomization will be performed and 
blinding maintained by the study staff. 


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8.3.
Analysis Sets
There will be a single analysis set defined for this study: the Treated Analysis Set, which will 
include all subjects who receive at least 1 of the 4 study injections. All analyses will be 
performed according to treatment group, even if the result of a randomization or allocation error. 
8.4.
Data Handling Conventions
Any decision to exclude potential outliers will be made in blinded review. No missing data will 
be imputed.
8.5.
Study Population
The set of randomized subjects who receive at least one injection will be used for all study 
population summaries, unless otherwise noted. 
8.5.1.
Subject Disposition
The number of screened and randomized subjects, number of subjects who fail to receive all four 
injections, total study visits completed and subject end of study status (eg, completed study, lost 
to follow-up, or discontinued before study completion) will be summarized using frequencies 
and percentages. Only women who are not enrolled will be considered screening failures. 
Reasons for early withdrawal will be listed.
8.5.2.
Demographic and Baseline Characteristics 
Subject demographic and baseline characteristics will be summarized for all subjects in the 
Treated Analysis Set. For continuous variables, descriptive statistics (number [n], mean, standard 
deviation, median, minimum, and maximum) will be provided. For categorical variables, subject 
counts and percentages will be provided. Categories of missing data will be presented if 
necessary.
8.6.
Analysis of Primary Endpoints
8.6.1.
Local Tolerability 
The primary ISR endpoint will be assessed at least twice on Day 0: immediately after [ie, as soon 
as possible but no later than 10 minutes upon removing the needle] and again 1 hour after each of 
the four injections), at Days 1, 3, 7 and 14, at Months 3 and 6, and at additional visits, if 
indicated. Prior to the interim and/or final analysis, FHI 360's clinician will conduct a blinded 
review of ISR outcome information (recorded on study CRFs and clinical notes, if necessary) to 
assess adherence to protocol definitions; proper ISR and/or adverse event documentation and 
reporting; and potential redundant endpoints. All documented ISRs will be summarized for each 
treatment group using frequencies and percentages. The frequency of ISRs as well as ISRs that 
meet the per-protocol definition of an adverse event, will be compared between the treatment 
groups. 
If there are sufficient numbers of ISRs to warrant the use of asymptotic methods, pair-wise 
treatment odds ratios for ISR (there are 6 possible comparisons among 4 treatment groups) will 
be assessed using logistic regression models with generalized estimating equations and robust 


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variance estimation to account for the correlated nature of the data. The primary model for such 
ISRs will only include effects of treatment group. An exchangeable working correlation structure 
will be used to estimate covariance parameters. Parameter estimates, standard errors, 95% 
confidence intervals, Z scores, and p-values for parameter estimates will also be produced. In 
addition, if the population is sufficiently heterogeneous with respect to these factors, exploratory 
analyses may be performed to assess effect of injection order, age and race. For less frequent ISR 
types, differences between groups will be assessed using exact McNemar’s tests (separately for 
each of the 6 possible treatment comparisons). A final determination of whether the asymptotic 
method is appropriate will be made by the lead statistician based on observed correlation 
structures and event rates, blinded to treatment group prior to database lock and will be 
documented in the final statistical analysis plan. Regardless of analysis method, all tests will be 
conducted at the nominal two-sided 0.05 significance level with no adjustment for multiple 
comparisons. 
8.7.
Analysis of Secondary Endpoints
8.7.1.
Injection Site Pain
NRS pain scores for assessments on the day of injection (Day 0) will be summarized by 
treatment group in frequency tables, separately for pain measured immediately after (ie, as soon 
as possible but no later than 10 minutes upon removing the needle) injection and at 1 hour after 
injection. If an appropriate distribution of pain scores can be identified in the blinded review 
(e.g., continuous, negative binomial or Poisson), then generalized linear models with 
exchangeable working correlation structure to account for correlated data will be used to 
compare treatment groups. The primary analysis model will only include effects of treatment, but 
exploratory analyses will be performed to assess effects of injection order, age, previous 
experience with injectable contraceptives, and race. If the dispersion of NRS scores is not 
amenable to parametric regression methods, then rank-order, permutation tests will be used to 
compare treatment groups (excluding any subjects who did not receive both injections being 
compared).
Approximately 1 hour after completing their sequence of the four treatments, each subject will 
also be asked to rank the injections according to overall pain from least [1] to most [4] painful. 
The ranking of treatments will be summarized in a frequency table, restricted to subjects who 
received all four injections. Differences in ranking of most painful injection will be assessed 
using an exact multinomial test for homogeneity across groups.
The proportion of subjects who self-report injection site pain during the follow-up will be 
compared between the treatment groups using exact, pair-wise McNemar tests
8.7.2.
Overall Safety
Adverse events will be summarized in listings and frequency tables by treatment group 
according to system organ class, preferred term, and relatedness (noting it may not be possible to 
assess relatedness of systemic adverse events when all subjects receive all treatments). Medical 
coding will be done using WHO Drug. Concomitant medication use will also be summarized in 
frequency tables and subject listings. Change in weight and vital signs compared to baseline will 


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be summarized descriptively (no comparisons between treatment groups will be possible given 
that all subjects receive all four treatments at enrollment). 
Additional details of all primary and secondary endpoint analyses (including table, figure, and 
listing shells), will be provided in the expanded statistical analysis plan.


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9.
INVESTIGATIONAL MEDICINAL PRODUCT INFORMATION
9.1.
Investigational Medicinal Product Storage and Security
All IMPs (TV-46046, diluted TV-46046, TV-46046 Placebo, and Depo-subQ 104) must be 
stored according to the manufacturer’s drug product stipulation, in a dry place, and in a securely 
locked, substantially constructed cabinet or enclosure. TV-46046 should be stored at controlled 
room temperature 20 to 25°C (68 to 77°F).
The investigator must confirm appropriate temperature conditions have been maintained for all 
IMPs received and any discrepancies are reported and resolved before use of the IMPs.
9.2.
Investigational Medicinal Product Accountability
Each IMP shipment will include a packing slip listing the contents of the shipment and any 
applicable forms. The investigator is responsible for ensuring that deliveries of IMP and other 
study materials from the sponsor are correctly received, recorded, handled and stored safely and 
properly in accordance with the CFR or local regulations, and used in accordance with this 
protocol. 
A record of IMP accountability (ie, IMP and other materials received, used, retained, returned, or 
destroyed) must be prepared and signed by the investigator, with an account given for any 
discrepancies. Empty and partially used containers of IMP will be destroyed at the 
investigational center in accordance with investigational center SOPs, with sponsor approval. In 
the event the investigational center is unable to destroy the empty and/or unused units of IMP, 
the IMP will be disposed of, retained, or returned to the sponsor or designee per FHI 360 
instructions.
IMP accountability includes maintaining accurate records of quantity of products received, date 
of receipt, condition at receipt, temperature noted during transit, lot number of clinical study 
products received and dispensed, description of damaged units if any, dispensation, and product 
disposition or destruction. Storage temperature continuity tracking will occur for clinical study 
products during storage and transit time. Study personnel are responsible for daily temperature 
monitoring and safe storage of the study products.


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10.
QUALITY CONTROL AND QUALITY ASSURANCE
10.1.
Protocol Amendments, Protocol Deviations, and Important Protocol 
Deviations
10.1.1.
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 IRB/IEC and local health 
authorities, as applicable, except when necessary to address immediate safety concerns to the 
subjects or when the change involves only nonsubstantial logistics or administration. The 
investigator, coordinating investigator and the sponsor will sign the protocol amendment. 
10.1.2.
Important Protocol Deviations 
Any deviation from the protocol that affects, to a significant degree, (a) the safety, physical, or 
mental integrity of the subjects 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 subject, the investigator, or the sponsor to protocol-specific 
inclusion and exclusion criteria, primary objective variable criteria, or GCP guidelines; or 
noncompliance to IMP administration. Important protocol deviations will be identified and 
recorded by study staff on a CRF and will be reported to the responsible IRB/IEC, as required.
When an important protocol deviation is reported, FHI 360 in consultation with the sponsor will 
determine whether to discontinue the subject from the study or permit the subject to continue in 
the study. The decision will be based on ensuring the safety of the subject and preserving the 
integrity of the study.
Changes in the inclusion and exclusion criteria of the protocol are not prospectively granted by 
the sponsor. If study staff learn that a subject who did not meet protocol inclusion and exclusion 
criteria was entered in a study, they must immediately inform FHI 360 of the important protocol 
deviation. If such a subject has already completed the study or has withdrawn early, no action 
will be taken but the important protocol deviation will be recorded.
FHI 360 will record lesser protocol deviations, ie those that do not significantly affect subject 
safety or scientific value of the data, on a Protocol Deviation Log. The cumulative log will be 
submitted to the responsible IRB/IEC at annual reviews, if/as required.
10.2.
Study Monitoring
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that subjects have signed the ICF and the study is conducted in accordance with 
applicable SOPs, the protocol, and other written instructions and regulatory guidelines. Details of 
the monitoring procedures are outlined in the study's clinical monitoring plan which is 
maintained by FHI 360.
The main responsibilities of the study monitor are 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 subjects before they participate in the study and when changes to the consent 


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form are warranted, in accordance with IRB/IEC approvals. The study monitor will be permitted 
to check and verify the various records (CRFs and other pertinent source data records), including 
specific electronic source documentation (see Section 12.1) 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 or FHI 360 personnel may, on 
request, accompany the study monitor on visits to the investigational center. The investigator and 
assisting staff must agree to cooperate with the study monitor to resolve any problems, errors, or 
possible misunderstandings concerning the findings detected during these monitoring visits 
and/or provided in follow-up written communication.
10.3.
Clinical Product Complaints
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical IMP supplies and/or clinical device supplies used in a 
sponsor’s clinical research study. Examples of a product complaint include but are not limited to 
the following: 

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

unexpected or unanticipated taste or odor, or both

device not working correctly or appears defective in some manner
Each investigational center will be responsible for reporting a possible clinical product complaint 
by completing the Product Complaint Form provided by the sponsor and emailing it to 
clinical.productcomplaints@tevapharm.com within 48 hours of becoming aware of the issue.
For complaints involving a device or other retrievable item, it is required that the device (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 subject’s IMP supply) should be 
sent back to the sponsor for investigative testing whenever possible. 
10.3.1.
Product Complaint Information Needed from the Investigational Center
In the event that the Product Complaint Form cannot be completed, the investigator will obtain 
the following information, as available:

investigational center number and investigator name

name, phone number, and address of the source of the complaint 

clinical protocol number


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
subject identifier (subject study number) and corresponding visit numbers, if 
applicable

product name and strength for open label studies

subject number, bottle, and kit numbers (if applicable) for double-blind or open label 
studies

product available for return Yes/No

product was taken or used in accordance with the protocol Yes/No

description or nature of complaint

associated serious adverse event Yes/No

clinical supplies unblinded (for blinded studies) Yes/No

date and name of person receiving the complaint 
Note: Reporting a complaint must not be delayed even if not all the required information can be 
immediately obtained. Known information must be immediately reported. The sponsor will 
collaborate with the investigator to obtain any outstanding information.
10.3.2.
Handling the Product Complaint IMP at the Investigational Center
The investigator is responsible for retaining the IMP related to the product complaint 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.
If it is determined that the investigational center must return all IMP, 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. 
10.3.3.
Documenting a Product Complaint
The investigator will record a description of the product complaint in the source documentation, 
along with any actions taken to resolve the complaint and to preserve the safety of the subject. 
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.
10.4.
Data Quality Control
The investigator is responsible for the accuracy, quality, completeness, and internal consistency 
of the data from this study. Data handling, including data quality control, will comply with 
international regulatory guidelines, including ICH GCP guidelines. Data management and 
control processes specific to this study, along with all steps and actions taken regarding data 
management and data quality control, will be described in a data management plan.


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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.
Case report forms will be processed and reviewed for completeness, consistency, and the 
presence of mandatory values. Applicable terms will be coded according to the coding 
conventions for this study. Logical checks will be implemented to ensure data quality and 
accuracy. 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 clinical data management system (CDMS). Discrepancies 
found will be queried.
Data corrections in the CDMS will be made using the CDMS update function. The system 
requires a reason for each change and keeps a complete audit trail of the data values, dates and 
times of modifications, and authorized electronic approvals of the changes.
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 acknowledgement that all data 
have been captured and confirmed as accurate. All data collected will be approved by the 
investigator at the investigational center. 
10.5.
Audit and Inspection
The sponsor or FHI 360 may audit the investigational center to evaluate study conduct and 
compliance with protocols, SOPs, GCPs, and applicable regulatory requirements. The sponsor’s 
Global Clinical Quality Assurance department, independent of the Global Clinical Development 
department, is responsible for determining the need for (and timing of) an investigational center 
audit.
The investigator must accept that health authorities and sponsor representatives may conduct 
inspections to verify compliance with GCP guidelines.


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11.
ETHICAL AND REGULATORY CONSIDERATIONS
11.1.
Investigator Responsibilities
This study will be conducted in full accordance with the International Council for Harmonisation 
(ICH) Harmonised Tripartite Guideline for Good Clinical Practice (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 studies on 
medicinal products for human use). Any episode of noncompliance will be documented.
The investigator has the overall responsibility for the conduct and administration of the clinical 
study and for contacts with study management, with the IRB/IEC, and with health authorities.
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 FHI 360 and other forms as required by national health authorities in the 
country where each investigational center is located.
The investigator is responsible for ensuring the privacy, health, and welfare of the subjects 
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 investigator is responsible for giving information about the study to all staff members 
involved in the study or in any element of subject management, both before starting the study 
and during the study (eg, when new staff become involved). The investigator must ensure that all 
study personnel are qualified by education, experience, and training to perform their specific 
responsibilities. These study personnel must be listed on the center’s staff delegation log, which 
includes a clear description of each staff member’s responsibilities and appropriately delegated 
significant study-related responsibilities. This list must be updated throughout the study, as 
necessary.
11.2.
Health Authorities and Independent Ethics Committees/Institutional 
Review Boards
Before this study starts, the protocol will be submitted to health authorities, if required, and to 
each IRB/IEC for review. As required, the study will not start at Profamilia before the 
IEIRB/IEC and health authority (as applicable) for the center give written approval or a 
favorable opinion.


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11.3.
Informed Consent
The investigator, or a qualified person designated by the investigator, will fully inform the 
subject of all pertinent aspects of the study, including the written information approved by the 
IRB/IEC. All written and oral information about the study will be provided in a language as 
nontechnical as practical and understood by the subject. The subject will be given ample time 
and opportunity to inquire about details of the study and to decide whether to participate in the 
study. The above will be detailed in the source documentation.
Written informed consent will be obtained from each subject before any study specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained, in accordance with applicable regulatory requirements. The 
subject’s willingness to participate in the study will be documented in an ICF, which will be 
signed and personally dated by the subject and by the person who conducted the informed 
consent discussion. The investigator will keep the original consent forms, and copies will be 
given to the subject. It will also be explained to the subject that the subject is free to refuse entry 
into the study and free to withdraw from the study at any time without prejudice to future 
treatment.
11.4.
Subject Confidentiality 
The investigator must ensure that the privacy of the subjects, including their identity and all 
personal medical information, will be maintained at all times. In CRFs and other documents or 
image material submitted to the sponsor, subjects will be identified not by their names, but by an 
identification code (ie, identification number).
Personal medical information may be reviewed for subject safety and for verifying data in the 
source and transcribed onto the CRF. This review may be conducted by the study monitor, 
properly authorized persons on behalf of the sponsor or FHI 360, Global Quality Assurance 
(GQA), or health authorities. Personal medical information will always be treated as 
confidential.
11.5.
Declaration of the End of the Clinical Study
Local regulations will be followed to determine the end of the study. 
11.6.
Registration of the Clinical Study
In compliance with local regulations and in accordance with the sponsor’s standard procedures, 
this clinical study will be registered on clinicaltrials.gov.


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12.
STUDY DOCUMENTATION
12.1.
Source Data and Case Report Forms
Data will be collected at the investigational center by appropriately designated and trained 
personnel. The investigator must maintain the original records (ie, source documents) of each 
subject’s data at all times. The investigator will maintain a confidential subject identification list 
that allows the unambiguous identification of each subject. Subject identity will not be 
discernible from the data provided on CRFs. 
Examples of source documents are hospital records, office visit records, examining physician’s 
finding or notes, laboratory reports, drug inventory, IMP label records, and worksheets that are 
used as the source.
Some data may be recorded directly onto the CRF, if instructed by FHI 360; the investigational 
center will complete a Source Data Guide document specifying which data are recorded directly 
onto CRFs. “Case report form” means any CRF, whether paper or electronic.
The medical experts, study monitors, auditors, IRB/IEC, and inspectors from health authorities 
(or their agents) will be given direct access to source data and documents (eg, medical 
charts/records, laboratory test results, printouts) for source data verification, provided that 
subject confidentiality is maintained in accordance with national and local requirements.
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. 
The data collected on CRFs will be entered in a clinical data management system (CDMS) that 
meets the technical requirements described in 21CFR Part 11 (USA) and documents of other 
concerned health authorities. The CDMS will be fully validated to ensure that it meets the 
scientific, regulatory, and logistical requirements of the study before it is used to capture data 
from this study. Before using the CDMS, 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.
For subjects who sign an ICF but do not meet eligibility criteria, at a minimum, data for screen 
failure reason, demography, and adverse events from the time of informed consent will be 
entered onto a CRF. 
12.2.
Archiving of Study Documentation
12.2.1.
FHI 360 Responsibilities
All data management tasks for this study are delegated to FHI 360; these functions will be 
carried out as described in FHI 360 SOPs. The original CRFs will be stored at the respective 
investigational centers until the end of the study. 


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12.2.2.
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 ICFs

subject identification lists

case report forms for each subject on a per-visit basis

data from other sources (eg, external laboratory)

safety reports

reports of receipt, use, and disposition of the IMPs

copies of all correspondence with FHI 360, the IRB/IEC, and any health 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 FHI 360 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 FHI 360 has not provided written notification of destruction, then the 
investigator may submit a written request to FHI 360 at least 60 days before any planned 
disposition of study records. After receipt of such request, FHI 360 may arrange for appropriate 
archival or disposition, including requiring that the investigator deliver such records to the 
sponsor or FHI 360. The investigator shall notify FHI 360 of any accidental loss or destruction of 
study records.


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13.
FINANCING AND INSURANCE
A separate clinical study agreement, including a study budget, will be entered into between each 
investigator and FHI 360 before the study drug is delivered.
This clinical study is insured in accordance with the corresponding local legal provisions. The 
policy coverage is subject to the full policy terms, conditions, extensions, and exclusions. 
Excluded from the insurance coverage are inter alia, damages to health, and worsening of 
previous existing disease that would have occurred or continued if the subject had not taken part 
in the clinical study.


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14.
REPORTING AND PUBLICATION OF RESULTS
The sponsor is responsible for ensuring that the public has access to the appropriate information 
about the study by conforming to local and regional requirements and regulations for registration 
and posting of results, and to requirements outlined in any current or future agreements between 
the sponsor and FHI 360.
FHI 360 will prepare the clinical study report, in cooperation with the sponsor. The final report is 
signed by the sponsor and FHI 360.
When the sponsor generates reports from the data collected in this study for presentation to 
health authorities, drafts will be circulated to FHI 360 for comments and suggestions. 
No unpublished information shall be published or disclosed to a third party without the prior 
written consent of the sponsor and FHI 360. The primary publication from this study will report 
the results of the study in accordance with the current “Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals” (www.ICMJE.org). 
Publication of the results will occur in a timely manner according to applicable regulations. 
Authorship will be based on meeting all the following 4 criteria:

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.
A joint publications committee will be established by the sponsor and FHI 360 to oversee this 
process. Additional publications may follow upon the agreement of the committee. Policies 
regarding the publication of the study results are further defined in a collaboration agreement 
between the sponsor and FHI 360. Any disputes or issues about publication will be referred to 
the Executive Committee, as described in that 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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15.
REFERENCES
Castle WM, Sapire KE, Howard KA. Efficacy and acceptability of injectable 
medroxyprogesterone. A comparison of 3-monthly and 6-monthly regimens. S Afr Med J. 
1978;53(21):842-5.
Curtis KM, Tepper NK, Jatlaoui TC. U.S. Medical Eligibility Criteria for Contraceptive Use, 
2016. MMWR Recomm Rep 2016; 65(No. RR-3):35-54. Appendices available at: 
https://www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6503.pdf. Accessed on 04 May 2018
Depo subQ Provera 104 [package insert]. New York, NY: Pfizer Inc; 2016.
Depo-Provera Sterile Aqueous Suspension US prescribing information [package insert]. New 
York, NY: Pfizer Inc; 2017.
Depo-Provera Contraceptive Injection [package insert]. New York, NY: Pfizer Inc; 2016.
Dias C, Abosaleem B, Crispino C, Gao B, Shaywitz A. Tolerability of High-Volume 
Subcutaneous Injections of a Viscous Placebo Buffer: A Randomized, Crossover Study in 
Healthy Subjects. AAPS PharmSciTech. 2015 Oct;16(5):1101-7. Epub 2015 Feb 19. Erratum in: 
AAPS PharmSciTech. 2015 Dec;16(6):1500
Jain J, Dutton C, Nicosia A, Wajszczuk C, Bode FR, Mishell DR Jr. Pharmacokinetics, ovulation 
suppression and return to ovulation following a lower dose subcutaneous formulation of Depo-
Provera. Contraception. 2004;70(1):11-8.
Kaunitz AM, Darney PD, Ross D, Wolter KD, Speroff L. Subcutaneous DMPA vs. 
intramuscular DMPA: a 2-year randomized study of contraceptive efficacy and bone mineral 
density. Contraception. 2009;80:7-17.
Kaunitz AM, Grimes DA. Removing the black box warning for depot medroxyprogesterone 
acetate. Contraception. 2011;84(3):212-3.
Lee NC, Rosero-Bixby L, Oberle MW, Grimaldo C, Whatley AS, Rovira EZ. A case-control 
study of breast cancer and hormonal contraception in Costa Rica. J Natl Cancer Inst. 
1987;79(6):1247-54.
Li CI, Beaber EF, Tang MTC, Porter PL, Daling JR, Malone KE. Effect of 
depo-medroxyprogesterone acetate on breast cancer risk among women 20 to 44 years of age. 
Cancer Res. 2012;72(8):2028-35.
Mackay EV, Khoo SK, Adam RR. Contraception with a six-monthly injection of progestogen. 
Part 1. Effects on blood pressure, body weight and uterine bleeding pattern, side-effects, 
efficacy, and acceptability. Aust and N Z J Obstet Gynaecol. 1971;11(3):148-55.
McDaniel EB, Pardthaisong T. Use-effectiveness of six-month injections of DMPA as a 
contraceptive. Am J of Obstet and Gynecol. 1974; 119(2):175-80.
Morrison CS, Chen P-L, Kwok C, Baeten JM, Brown J, Crook AM, et al. Hormonal 
contraception and the risk of HIV acquisition: An individual participant data meta-analysis. 
PLoS medicine. 2015;12(1):e1001778.


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Paul C, Skegg DCG, Spears GFS. Depot medroxyprogesterone (Depoi-Provera) and risk of 
breast cancer. Br Med J 1989:299(6702);759-62.
Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN, et al. An updated 
systematic review of epidemiological evidence on hormonal contraceptive methods and HIV 
acquisition in women. AIDS. 2016;30(17):2665-83.
PRDEPO-PROVERA and PRDEPO-PROVERA-SC [product monograph]. Kirkland, Quebec: 
Pfizer Canada, Inc; 2013.
Ralph LJ, McCoy SI, Shiu K, Padian NS. Hormonal contraceptive use and women's risk of HIV 
acquisition: a meta-analysis of observational studies. Lancet. 2015;15(2):181-9.
Schwallie PC, Assenzo JR. Contraceptive use--efficacy study utilizing Depo-Provera 
administered as an injection once every six months. Contraception. 1972;6(4):315-27.
Shapiro S, Rosenberg L, Hoffman M, Truter H, Cooper D, Rao S, et al. Risk of breast cancer in 
relation to the use of injectable progestogen contraceptives and combined estrogen/progestogen 
contraceptives. Am J Epidemiol 2000;151(4);396-403.
World Health Organization Department of Reproductive Health and Research. Hormonal 
contraceptive eligibility for women at high risk of HIV: 2017 guidance statement 
(WHO/RHR/17.04). Geneva: World Health Organization; 2017. Available at: 
http://www.who.int/reproductivehealth/publications/family_planning/HC-and-HIV-2017/en/. 
Accessed on 26 March 2018.
World Health Organization. Breast cancer and depot-medroxyprogesterone acetate: a 
multinational study. Lancet. 1991;338(8771):833-8.


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16.
SUMMARY OF CHANGES TO PROTOCOL
16.1.
Protocol Amendment 04 Dated 18 May 2020
The primary reason this protocol amendment are administrative updates and to update the 
procedures after the follow-up period and before the close out monitoring visit.
Original text with changes shown
New wording
Reason/Justification for 
change
COVER PAGE
Sponsor
Teva Branded Pharmaceutical
Products R&D, Inc.
41 Moores Road
Frazer, Pennsylvania 19355
United States
145 Brandywine Pkwy, 
West Chester, PA 19380
United States
Sponsor
Teva Branded Pharmaceutical
Products R&D, Inc.
145 Brandywine Pkwy, 
West Chester, PA 19380
United States
Address updated.
Authorized Representative
Vice President, Global Specialty R&D, 
Respiratory TA Head
Teva Branded Pharmaceutical Products 
R&D, Inc.
41 Moores Road
Frazer, Pennsylvania 19355
United States of America
+1-610-893-1145
145 Brandywine Pkwy, 
West Chester, PA 19380
United States
+
Authorized Representative
Vice President, Global Specialty R&D, 
Respiratory TA Head
Teva Branded Pharmaceutical Products 
R&D, Inc.
145 Brandywine Pkwy, 
West Chester, PA 19380
United States
Address updated.
Section 3.4.5.
Post-6 Month Follow-up
If the subject does not have any ISRs at this 
visit, it will be her final visit and the subject 
will be instructed to contact the clinic if any 
ISRs develop after her final visit. If any 
ISRs are identified or still ongoing at this 
additional visit between Months 9 and 12, 
monthly follow-up visits for ISR evaluation 
will be scheduled until the ISR is resolved 
or Month 18, whichever is earlier. In this 
case, ISR, adverse event, and concomitant 
medication evaluation, and vital sign and 
weight measurements will be repeated at 
her final visit.
If any ISRs are identified or still ongoing 
at this additional visit between Months 9 
and 12, monthly follow-up visits for ISR 
evaluation will be scheduled until the ISR 
is resolved or Month 18, whichever is 
earlier. In this case, ISR, adverse event, 
and concomitant medication evaluation, 
and vital sign and weight measurements 
will be repeated at her final visit.
Update.


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Original text with changes shown
New wording
Reason/Justification for 
change
If the subject reports injection site pain at 
any of these visits, she will be asked to use 
the NRS to evaluate the intensity of pain in 
order to determine if it meets the definition 
of an adverse event. If the subject does not 
have any ISRs at this visit, it will be her 
final visit. However, the subject will be 
instructed to return to the clinic if any ISRs 
develop after her final visit. In that case,
she will be consented, her status will 
change from completed the study to active 
and she will be followed until ISR 
resolution or Month 18, whichever is 
earlier, as described above.
If the subject reports injection site pain at 
any of these visits, she will be asked to 
use the NRS to evaluate the intensity of 
pain in order to determine if it meets the 
definition of an adverse event. If the 
subject does not have any ISRs at this 
visit, it will be her final visit. However, 
the subject will be instructed to return to 
the clinic if any ISRs develop after her 
final visit. In that case, she will be 
consented, her status will change from 
completed the study to active and she will 
be followed until ISR resolution or Month 
18, whichever is earlier, as described 
above.
Update.


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16.2.
Protocol Amendment 03 Dated 19 November 2019
The primary reasons for this amendment are updates, clarifications, and corrections. Changes 
made within the text of the protocol were also made within the synopsis.
Original text with changes shown
New wording
Reason/Justification for 
change
TITLE PAGE
Authorized Representative
Vice President, Global Specialty R&D, 
Respiratory TA Head
Teva Branded Pharmaceutical Products 
R&D, Inc.
2 West Liberty Blvd, Suite 300
Malvern41 Moores Road
Frazer, Pennsylvania 19355
United States of America
Authorized Representative
Vice President, Global Specialty R&D, 
Respiratory TA Head
Teva Branded Pharmaceutical Products 
R&D, Inc.
41 Moores Road
Frazer, Pennsylvania 19355
United States of America
Correction.
Sponsor’s Safety Representative 
Safety Physician, Medical Scientific Unit –
US
Teva Branded Pharmaceutical Products 
R&D, Inc.
400 Interpace Pkwy, Bldg. A, Suite 221367
Parsippany, NJ 07054
Sponsor’s Safety Representative 
Safety Physician, Medical Scientific Unit 
– US
Teva Branded Pharmaceutical Products 
R&D, Inc.
400 Interpace Pkwy, Bldg. A, Suite 367
Parsippany, NJ 07054
Correction.
CLINICAL STUDY PROTOCOL SYNOPSIS
All subjects will be followed for at least 6 
months after receiving their injections. 
Subjects with injection site reactions (ISRs) 
will be followed through the resolution of 
ISR(s) or 18 months after injection, 
whichever comes first.
All subjects will be followed for at least 6 
months after receiving their injections.
Correction. Duplicate 
sentence removed. 
Section 1.3
Known and Potential Benefits and Risks
Additional information regarding risks to 
subjects may be found in the current IB. In 
addition to the benefit and risk information 
described in this section, please refer to the 
current IB (Section 3, Section 6.3, and 
Section 7).
In addition to the benefit and risk 
information described in this section, 
please refer to the current IB (Section 3, 
Section 6.3, and Section 7).
Clarification.
Section 1.3.2.9
Other
Additional information regarding risks to 
subjects related to Depo-subQ 104 may be 
found in the Summary of Product 
Characteristics (SPC) Depo-subQ 104 
Prescribing Information (Depo-subQ 104 
US Prescribing Information 2016).
Additional information regarding risks to 
subjects related to Depo-subQ 104 may 
be found in the Depo-subQ 104 
Prescribing Information (Depo-subQ 104 
US Prescribing Information 2016).
Correction.


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Original text with changes shown
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Reason/Justification for 
change
Section 1.4.1 
General Study Design Rationale
In the ongoing TV46046-WH-10147 study, 
several cases of hypopigmentation had a 
later onset (ie, approximately 6 months 
post-injection) than observed in Study 
TV46046-WH-10075. In order to identify 
any late onset ISRs, subjects who have 
exited the study at Month 6 with no new or 
ongoing ISRs and who agree to return for a 
single follow-up visit between Months 9 
and 12, will undergo ISR, adverse event, 
and concomitant medication evaluation, and 
vital sign and weight measurements at that
time (see Section 3.4.5 for more detail).
In the ongoing TV46046-WH-10147 
study, several cases of hypopigmentation 
had a later onset (ie, approximately 6 
months post-injection) than observed in 
Study TV46046-WH-10075. In order to 
identify any late onset ISRs, subjects who 
have exited the study at Month 6 with no 
new or ongoing ISRs and who agree to 
return for a single follow-up visit between 
Months 9 and 12, will undergo ISR, 
adverse event, and concomitant 
medication evaluation, and vital sign and 
weight measurements at that time (see 
Section 3.4.5 for more detail).
Addition. Text added to 
explain why the duration of 
the follow-up period was 
extended. 
Section 3.1 General Study Design
Subjects with unresolved ISR(s) at Month 6
will be followed monthly through the 
resolution of ISR(s) or Month 18, 
whichever comes first.
Subjects with unresolved ISR(s) will be 
followed monthly through the resolution 
of ISR(s) or Month 18, whichever comes 
first.
Clarification. Text edited to 
reflect extension of follow-
up period.
Vital signs and weight will be measured at 
baseline, Month 6, and study exit. 
Vital signs and weight will be measured 
at baseline, Month 6, and study exit.
Clarification. Text added to 
match Study Procedures 
and Assessments table.
Table 1:Study Procedures and Assessments
Months 3 and 6 a
Months 3 and 6 a
Addition. Footnote added to 
describe subject’s visits if 
ISRs are reported at 6 
months. 
Months 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 
17, 18b
Months 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 
17, 18b
Addition. Footnote added to 
describe study visits for 
those who have exited the 
study with no new or 
ongoing ISRs at Month 6.
a If the subject does not have any ISRs at 
Month 6 and does not return for an 
additional post-6 month follow up visit, 
Month 6 will be her final visit. In addition 
to ISR, adverse event, and concomitant 
medication evaluation, her weight and vital 
signs will be measured at that time. 
Subjects who complete the study at Month 
6 will be instructed to contact the clinic if 
any ISRs develop after their final visit. If 
the subject is reported to have ISR(s) at 
Month 6, she will be instructed to return to 
the clinic monthly until ISR resolution or 
Month 18, whichever is earlier. In this case, 
the Month 6 procedures will be repeated at 
her final visit.
a If the subject does not have any ISRs at 
Month 6 and does not return for an 
additional post-6 month follow up visit, 
Month 6 will be her final visit. In addition 
to ISR, adverse event, and concomitant 
medication evaluation, her weight and 
vital signs will be measured at that time. 
Subjects who complete the study at 
Month 6 will be instructed to contact the 
clinic if any ISRs develop after their final 
visit. If the subject is reported to have 
ISR(s) at Month 6, she will be instructed 
to return to the clinic monthly until ISR 
resolution or Month 18, whichever is 
earlier. In this case, the Month 6 
procedures will be repeated at her final 
visit.
Addition. Text edited to 
reflect extension of follow-
up period.


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Original text with changes shown
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Reason/Justification for 
change
Subjects who have exited the study with no 
new or ongoing ISRs at Month 6 and who 
agree (providing written informed consent) 
to return for a single follow-up visit 
between Months 9 and 12, will undergo 
ISR, adverse event, and concomitant 
medication evaluation, and vital sign and 
weight measurements at that time. If the 
subject does not have any ISRs at this visit, 
it will be her final visit and the subject will 
be instructed to contact the clinic if any 
ISRs develop after their final visit. If the 
subject does have ISR(s) at this visit, she 
will be instructed to return to the clinic 
monthly until the ISR resolution or Month 
18, whichever is earlier. In this case, ISR, 
adverse event, and concomitant medication 
evaluation, and vital sign and weight 
measurements will be repeated at her final 
visit.
Subjects who have exited the study with 
no new or ongoing ISRs at Month 6 and 
who agree (providing written informed 
consent) to return for a single follow-up 
visit between Months 9 and 12, will 
undergo ISR, adverse event, and 
concomitant medication evaluation, and 
vital sign and weight measurements at 
that time. If the subject does not have any 
ISRs at this visit, it will be her final visit 
and the subject will be instructed to 
contact the clinic if any ISRs develop 
after their final visit. If the subject does 
have ISR(s) at this visit, she will be 
instructed to return to the clinic monthly 
until the ISR resolution or Month 18, 
whichever is earlier. In this case, ISR, 
adverse event, and concomitant 
medication evaluation, and vital sign and 
weight measurements will be repeated at 
her final visit.
Addition. Text added to 
detail the follow-up visit 
between Months 9 and 12.
c Vital signs and weight will be measured 
on Enrollment/Injection Day (Day 0) and 
Month 6, and at study exit (if different from 
Month 6).
c Vital signs and weight will be measured 
on Enrollment/Injection Day (Day 0) and 
Month 6, and at study exit.
Addition. Weight 
assessment added to Day 0.
eIf the subject does not have any ISRs at 
Month 6, Month 6 will be her final visit.
[Text removed]
Correction. Footnote 
removed.
g Study staff will inquire about adverse 
events and concomitant medications at 
Months 1, 2, 3, 4, 5 and 6 and at study exit, 
but will document adverse events and 
concomitant medications at any visit where 
the subject reports any new or changed 
adverse events or concomitant medications. 
For subjects who have previously exited the 
study at Month 6 and who agree to return 
for a single follow-up visit between Months 
9 and 12, study staff will inquire about 
adverse events and concomitant 
medications during this visit and at study 
exit.
g Study staff will inquire about adverse 
events and concomitant medications at 
Months 1, 2, 3, 4, 5 and 6 and at study 
exit, but will document adverse events 
and concomitant medications at any visit 
where the subject reports any new or 
changed adverse events or concomitant 
medications. For subjects who have 
previously exited the study at Month 6 
and who agree to return for a single 
follow-up visit between Months 9 and 12, 
study staff will inquire about adverse 
events and concomitant medications 
during this visit and at study exit.
Addition. Text added to 
describe adverse events 
inquires for subjects who 
have previously exited the 
study at Month 6 and who 
agree to return for a single 
follow-up visit between 
Months 9 and 12
Section 3.4.3 Follow-up/Final Visits
If the subject does not have any ISRs at 
Month 6, Month 6 will be her final visit., 
unless she agrees to return for additional 
follow up as detailed in Section 3.4.5.  
If the subject does not have any ISRs at 
Month 6, Month 6 will be her final visit, 
unless she agrees to return for additional 
follow up as detailed in Section 3.4.5.  
Addition. Text edited to 
reflect extension of follow-
up period.
•
injection sites evaluated for ongoing 
and/or new ISRs (Days 1, 3, 7, and 14 and 
Months 3 and 6 and at study exit)
•
injection sites evaluated for ongoing 
and/or new ISRs (Days 1, 3, 7, and 14 and 
Months 3 and 6 and at study exit)
Clarification. Text added to 
describe when injection 
sites will be assessed.
•
injection site pain assessed if self-
reported (Days 1, 3, 7, and 14 and Months 3 
and 6, and other visits if appropriate)
•
injection site pain assessed if self-
reported (Days 1, 3, 7, and 14 and Months 
3 and 6, and other visits if appropriate)
Clarification. Text added to 
describe when injection site 
pain will be assessed.


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Original text with changes shown
New wording
Reason/Justification for 
change
•
adverse event and concomitant 
medication inquiry conducted (at Months 1, 
2, 3, 4, 5 and 6 and at study exit)
•
adverse event and concomitant 
medication inquiry conducted (at Months 
1, 2, 3, 4, 5 and 6 and at study exit)
Clarification. Text added to 
describe when adverse 
event and concomitant 
medication inquiry will 
occur.
•
vital signs and weight measured 
(Month 6 and at study exit)
•
vital signs and weight measured 
(Month 6 and at study exit)
Clarification. Text added to 
describe when vital signs 
and weight will be 
measured.
Section 3.4.5 Post-6 Month Follow-up
In order to identify any late onset ISRs, 
subjects who have exited the study with no 
new or ongoing ISRs at Month 6 and who 
agree (providing written informed consent) 
to return for a single follow-up visit 
between Months 9 and 12, will undergo 
ISR, adverse event and concomitant 
medication evaluation, and vital sign and 
weight measurements at that time. If the 
subject does not have any ISRs at this visit, 
it will be her final visit and the subject will 
be instructed to contact the clinic if any 
ISRs develop after her final visit. If any 
ISRs are identified or still ongoing at 
Month 9, monthly follow-up visits for ISR 
evaluation will be scheduled until the ISR is 
resolved or Month 18, whichever is earlier. 
In this case, ISR, adverse event, and 
concomitant medication evaluation, and 
vital sign and weight measurements will be 
repeated at her final visit. If the subject 
reports injection site pain at any of these 
visits, she will be asked to use the NRS to 
evaluate the intensity of pain in order to 
determine if it meets the definition of an 
adverse event.
In order to identify any late onset ISRs, 
subjects who have exited the study with 
no new or ongoing ISRs at Month 6 and 
who agree (providing written informed 
consent) to return for a single follow-up 
visit between Months 9 and 12, will 
undergo ISR, adverse event and 
concomitant medication evaluation, and 
vital sign and weight measurements at 
that time. If the subject does not have any 
ISRs at this visit, it will be her final visit 
and the subject will be instructed to
contact the clinic if any ISRs develop 
after her final visit. If any ISRs are 
identified or still ongoing at Month 9, 
monthly follow-up visits for ISR 
evaluation will be scheduled until the ISR 
is resolved or Month 18, whichever is 
earlier. In this case, ISR, adverse event, 
and concomitant medication evaluation, 
and vital sign and weight measurements 
will be repeated at her final visit. If the 
subject reports injection site pain at any of 
these visits, she will be asked to use the 
NRS to evaluate the intensity of pain in 
order to determine if it meets the 
definition of an adverse event.
Addition. Section added to 
describe the post 6 month 
follow-up visits.
Section 4.3 Blinding/Unblinding
All FHI 360 staff (aside from the unblinded 
clinical monitor) and sponsor staff project 
team members involved in assessment of 
adverse events, data analysis, or results 
interpretation will be blinded to treatment 
sequence until at least the first interim 
analysis, at which time results may be 
reviewed by treatment to inform decisions 
whether to stop enrollment or modify the 
study.
FHI 360 and sponsor project team 
members involved in assessment of 
adverse events, data analysis, or results 
interpretation will be blinded to treatment 
sequence until at least the first interim 
analysis, at which time results may be 
reviewed by treatment to inform decisions 
whether to stop enrollment or modify the 
study.
Clarification. Details added 
to describe which study 
personnel will be blinded.
Section 5.1.1 Local Tolerability


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Original text with changes shown
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Reason/Justification for 
change
All ongoing ISRs will be examined during 
the next clinic visit, regardless of visit type, 
or more frequently at the discretion of the 
investigator, until ISR resolution, or 
outcome. Subjects with no ISRs at the 
Month 6 Subjects with no new or ongoing 
ISRs at their final visit will complete the 
study but be instructed to contact the clinic 
if new ISRs develop after their final visit.
(see Section 3.4.3 and Section 3.4.5).
Subjects with no new or ongoing ISRs at 
their final visit will complete the study 
but be instructed to contact the clinic if 
new ISRs develop after their final visit 
(see Section 3.4.3 and Section 3.4.5).
Addition. Text added to 
describe procedures if new 
ISRs develop during the 
follow-up period.
Subjects with ISRs at Month 6 their final 
visit will be followed monthly (or more 
frequently if indicated) until ISR resolution 
or Month 18, whichever comes first.
Subjects with ISRs at their final visit will 
be followed monthly until ISR resolution 
or Month 18, whichever comes first.
Addition. Text added to 
describe procedures if new 
ISRs develop during the 
follow-up period.
Section 5.2 Safety Assessments
•
vital signs and weight will be measured 
at Day 0 and Month 6 and study exit (if not 
Month 6)
•
vital signs and weight will be 
measured at Day 0 and Month 6 and study 
exit
Correction. Text removed.
•
adverse events and concomitant 
medications will be evaluated at Day 0, 
Month at Months 1, and then monthly
through Month 6, and at study exit
•
adverse events and concomitant 
medications will be evaluated at Day 0, at 
Months 1 through 6, and at study exit
Clarification. Text added to 
state that safety will be 
evaluated in the follow-up 
period.
Section 5.2.2 
Recording and Reporting Adverse Events
At the Month 3 Day 0, Months 1 through 6
and Month 6 follow up visits study exit, the 
investigator must question the subject 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.”
At the Day 0, Months 1 through 6 and 
study exit, the investigator must question 
the subject 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.”
Addition. Details added to 
describe how adverse event 
data will be collected in the 
follow-up period.
Section 5.2.7 
Weight and Vital Signs
Weight and vital signs (BP 
[systolic/diastolic], temperature, pulse and 
respiration rate) will be measured at 
enrollment, and Month 6, and study exit as 
detailed in Table 1.
Weight and vital signs (BP 
[systolic/diastolic], temperature, pulse and 
respiration rate) will be measured at 
enrollment, Month 6, and study exit as 
detailed in Table 1.
Addition. Text added to 
describe weight and vital 
sign collection in follow-up 
period. 
Section 8.7 Analysis of Secondary Endpoints
Section 8.7.2.
Overall Safety
Change from baseline to Month 6 visits in 
weight and vital signs compared to baseline
will be summarized descriptively (no 
comparisons between treatment groups will 
be possible given that all subjects receive 
all four treatments at enrollment).
Change in weight and vital signs 
compared to baseline will be summarized 
descriptively (no comparisons between 
treatment groups will be possible given 
that all subjects receive all four treatments 
at enrollment).
Clarification. Month 6 visits 
removed.
Appendix A.  STUDY RESPONSIBILITIES


Local Tolerability Study - Contraception
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Original text with changes shown
New wording
Reason/Justification for 
change
Safety Physician, Medical Scientific Unit –
US
Teva Branded Pharmaceutical Products 
R&D, Inc.
400 Interpace Pkwy, Bldg. A, Suite 221
367
Parsippany, NJ 07054
Safety Physician, Medical Scientific Unit 
– US
Teva Branded Pharmaceutical Products 
R&D, Inc.
400 Interpace Pkwy, Bldg. A, Suite 367
Parsippany, NJ 07054
Correction.


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78
16.3.
Protocol Amendment 02 Dated 11 April 2019
The primary reasons for this amendment are corrections. 
Original text with changes shown
New wording
Reason/Justification for 
change
Title Page
Claudio Pasquinelli MD, PhD
Sr Dir Clinical Development, Respiratory
Teva Branded Pharmaceutical Products 
R&D, Inc.
+1-610-893-1264
Correction. Updated staff 
information.
Haixiao Chen, MD
Global Patient Safety & Pharmacovigilance
Teva Branded Pharmaceutical Products 
R&D, Inc.
+1-610-893-1035
Safety Physician, Medical Scientific Unit –
US
Teva Branded Pharmaceutical Products 
R&D, Inc.
400 Interpace Pkwy, Bldg. A, Suite 221
Parsippany, NJ 07054
+
Safety Physician, Medical Scientific Unit 
– US
Teva Branded Pharmaceutical Products 
R&D, Inc.
400 Interpace Pkwy, Bldg. A, Suite 221
Parsippany, NJ 07054
Correction. Updated staff 
information.
Appendix A
Claudio Pasquinelli MD, PhD 
Sr Dir Clinical Development, Respiratory
+1-610-893-1264
Correction. Updated staff 
information.
Haixiao Chen, MD
Global Patient Safety & Pharmacovigilance
+1-610-893-1035
Safety Physician, Medical Scientific Unit –
US
Teva Branded Pharmaceutical Products 
R&D, Inc.
400 Interpace Pkwy, Bldg. A, Suite 221
Parsippany, NJ 07054
Safety Physician, Medical Scientific Unit 
– US
Teva Branded Pharmaceutical Products 
R&D, Inc.
400 Interpace Pkwy, Bldg. A, Suite 221
Parsippany, NJ 07054
Correction. Updated staff 
information.


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16.4.
Protocol Amendment 01 Dated 02 July 2018
The primary reasons for this amendment are corrections and clarifications. Changes made within 
the text of the protocol were also made within the synopsis.
Original text with changes shown
New wording
Reason/Justification for 
change
Clinical Study Protocol Synopsis
Study : TV-46046-WH-10147
Study : TV46046-WH-10147
Correction. Dash removed 
from the study number. 
Section 1.3.2.9
Other
Women 40 years or older must have normal 
mammogram results in the last year prior to 
enrollment to be eligible for this study. If a 
woman 40 years or older has not had a 
mammogram in the past year, one will be 
scheduled between screening and 
enrollment.Women with normal 
mammogram results in the last year prior to 
enrollment will be eligible for this study. If 
a woman has not had a mammogram in the 
past year, one will be scheduled between 
screening and enrollment.
Women 40 years or older must have 
normal mammogram results in the last 
year prior to enrollment to be eligible for 
this study. If a woman 40 years or older 
has not had a mammogram in the past 
year, one will be scheduled between 
screening and enrollment.
Clarification. Age 
requirement added for 
normal mammograms.
Section 3.1 General Study Design
This is a randomized, crossover, single-
center, Phase 1 study to evaluate and 
compare local tolerability following 
subcutaneous administration of TV-46046, 
diluted TV-46046, TV-46046 Placebo, and 
Depo-subQ 104, in 24 healthy female 
subjects 18 to 50 years of age55 years of 
age.
This is a randomized, crossover, single-
center, Phase 1 study to evaluate and 
compare local tolerability following 
subcutaneous administration of 
TV-46046, diluted TV-46046, TV-46046 
Placebo, and Depo-subQ 104, in 24 
healthy female subjects 18 to 50 years of 
age.
Correction. Age limit 
lowered to 50 years of age.
Section 3.2.1
Subject Inclusion Criteria
c.
is 18 to 55 50 years of age (inclusive)
c.
is 18 to 50 years of age (inclusive)
Correction. Age limit 
lowered to 50 years of age.
f.
had a normal mammogram within the 
last year, if 40 years or older
f.
had a normal mammogram within the 
last year, if 40 years or older
Clarification. Age 
requirement added for 
normal mammograms.
Table 1
Study Procedures and Assessments
Vital Sign (Blood pressure) a
Blood pressure
Correction. Text corrected 
to remove “Vital signs” 
and subscript and indicate 
that blood pressure will be 
assessed on Day -1. 
Vital Signs (Blood pressure, Ppulse, 
respiration rate, temperature) a
Vital Signs (Blood pressure, pulse, 
respiration rate, temperature)a
Correction. Text corrected 
to indicate that blood 
pressure will be assessed 
on Day 0.


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Reason/Justification for 
change
b Normal mammogram within 1 year prior 
to enrollment, if 40 years or older
b Normal mammogram within 1 year prior 
to enrollment, if 40 years or older
Clarification. Age 
requirement added for 
normal mammograms.
Section 3.4.1
Procedures for Screening Visit
If the participant has not had a 
mammogram in the past year and is 40 
years or older, one should will be scheduled 
prior to enrollment.
If the participant has not had a 
mammogram in the past year and is 40 
years or older, one will be scheduled prior 
to enrollment.
Clarification. Age 
requirement added for 
normal mammograms.
Section 3.4.2 
Procedures for Enrollment/Injections Visit
On the day of enrollment, a urine 
pregnancy test will be performed and 
weight and vital signs measured (ie, blood 
pressure, pulse rate, respiration rate and 
temperature). The 
enrollment/randomization procedures, 
including confirming eligibility, should be 
done after a normal mammogram result has 
been received.
On the day of enrollment, a urine 
pregnancy test will be performed; weight 
and vital signs will be measured (ie, blood 
pressure, pulse rate, respiration rate and 
temperature). Mammogram results from the 
prior year will be verified for women 40 
years and older. Subject eligibility will be 
confirmed and enrollment/randomization 
procedures will be performed.
On the day of enrollment, a urine 
pregnancy test will be performed; weight 
and vital signs will be measured (ie, blood 
pressure, pulse rate, respiration rate and 
temperature). Mammogram results from 
the prior year will be verified for women 
40 years and older. Subject eligibility will 
be confirmed and 
enrollment/randomization procedures will 
be performed.
Clarification. Text edited 
to improve clarity and 
include the age 
requirement for normal 
mammograms.
Section 4.6.1 
Subject Withdrawal Criteria and Procedures
The final visit procedures should will be 
followed for all subjects who withdraw, if 
possible (see Section 3.4.3
.(
The final visit procedures will be followed 
for all subjects who withdraw, if possible 
(see Section 3.4.3).
Correction. The word 
"will" replaced "should".
If the investigator determines that an 
adverse event is related to the test IMP, 
monitoring will should continue until the 
adverse event has resolved or stabilized, the 
subject exited the study or the subject has 
reached the end of the follow-up period.
If the investigator determines that an 
adverse event is related to the test IMP, 
monitoring will continue until the adverse 
event has resolved or stabilized, the 
subject exited the study or the subject has 
reached the end of the follow-up period.
Correction. The word 
"will" replaced "should".
Section 5.1.1
Local Tolerability
Photos of the injection site may be taken to 
supplement documentation of ISRs any 
time during the study.
Photos of the injection site may be taken 
to supplement documentation of ISRs any 
time during the study.
Clarification. Text added 
to state that photos of the 
injection site may be taken 
at any time during the 
study. 


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Original text with changes shown
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Reason/Justification for 
change
All cases of injection site discoloration 
(hypopigmentation) should will be 
photographed and consulted by a 
dermatologist.
All cases of injection site discoloration 
(hypopigmentation) will be photographed 
and consulted by a dermatologist.
Correction. The word 
"will" replaced "should".
Section 5.2.1
Definition of an Adverse Event
In this study, any adverse event occurring 
after the subject has signed the ICF through 
the end of the follow up period should will
be recorded and reported as an adverse 
event.
In this study, any adverse event occurring 
after the subject has signed the ICF 
through the end of the follow up period 
will be recorded and reported as an 
adverse event. 
Correction. The word 
"will" replaced "should".
Section 5.2.2
Recording and Reporting Adverse Events
Serious adverse events occurring in a 
subject after study discontinuation should
will be reported to the sponsor if the 
investigator becomes aware of them, 
following the procedures described in 
Section 5.2.5.3
.
Serious adverse events occurring in a 
subject after study discontinuation will be 
reported to the sponsor if the investigator 
becomes aware of them, following the 
procedures described in Section 5.2.5.3
.
Correction. The word 
"will" replaced "should".
5.2.5.3.1
Investigator Responsibility
The serious adverse event form should will
be sent to FHI 360 (contact information can 
be found in Appendix A).
The serious adverse event form will be 
sent to FHI 360 (contact information can 
be found in Appendix A).
Correction. The word 
"will" replaced "should".
Serious adverse events occurring to a 
subject after the treatment of that subject 
has ended should will be reported to the 
sponsor if the investigator becomes aware 
of them.
Serious adverse events occurring to a 
subject after the treatment of that subject 
has ended will be reported to the sponsor 
if the investigator becomes aware of them.
Correction. The word 
"will" replaced "should".
Section 5.2.7
Weight and Vital Signs
For any abnormal vital sign finding, the 
measurement should will be repeated
For any abnormal vital sign finding, the 
measurement will be repeated
Correction. The word 
"will" replaced "should".
Section 5.2.8
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
will be recorded as a deviation.
Any administration of IMP that is not in 
accordance with the study protocol will be 
recorded as a deviation.
Correction. The word 
"will" replaced "should".
If it meets the important protocol deviation 
criteria, the incorrect IMP administration 
should will be categorized as “Non-
Compliance to Investigational Medicinal 
Product (IMP).”
If it meets the important protocol 
deviation criteria, the incorrect IMP
administration will be categorized as 
“Non-Compliance to Investigational 
Medicinal Product (IMP).”
Correction. The word 
"will" replaced "should".


Local Tolerability Study - Contraception
Clinical Study Protocol with Amendment 04
TV46046-WH-10147
82
Original text with changes shown
New wording
Reason/Justification for 
change
Section 11.3
Informed Consent
The investigator, or a qualified person 
designated by the investigator, should will
fully inform the subject of all pertinent 
aspects of the study, including the written 
information approved by the IRB/IEC. All 
written and oral information about the study 
will be provided in a language as 
nontechnical as practical and understood by 
the subject. The subject should will be 
given ample time and opportunity to inquire 
about details of the study and to decide 
whether to participate in the study. The 
above should will be detailed in the source 
documentation.
The investigator, or a qualified person 
designated by the investigator, will fully 
inform the subject of all pertinent aspects 
of the study, including the written 
information approved by the IRB/IEC. All 
written and oral information about the 
study will be provided in a language as 
nontechnical as practical and understood 
by the subject. The subject will be given 
ample time and opportunity to inquire 
about details of the study and to decide 
whether to participate in the study. The 
above will be detailed in the source 
documentation.
Correction. The word 
"will" replaced "should".
Section 12.1
Source Data and Case Report Forms
Subject identity should will not be 
discernible from the data provided on 
CRFs.
Subject identity will not be discernible 
from the data provided on CRFs. 
Correction. The word 
"will" replaced "should".


Local Tolerability Study - Contraception
Clinical Study Protocol with Amendment 04
TV46046-WH-10147
83
APPENDIX A. STUDY RESPONSIBILITIES 
Sponsor’s Authorized Representative
Vice President, Global Specialty R&D, 
Respiratory TA Head
+1-610-893-1145 
Sponsor’s Medical Expert
Sponsor’s Safety Representative
Safety Physician, Medical Scientific Unit – US
Teva Branded Pharmaceutical Products R&D, Inc.
400 Interpace Pkwy, Bldg. A, Suite 367
Parsippany, NJ 07054
Investigator
 
 
Coordinating Investigator
 
 
Monitor
United States
Trial Supply Management (TSM) Vendor
 USA
Central Institutional Review Board
United States of America

SAP_001.pdf: 
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41 Moores Road 
Frazer, Pennsylvania 19355 
United States of America 
Study Implementation 
FHI 360 
359 Blackwell St, Suite 200 
Durham, NC 27701 
Unites States of America 
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