Clinical trial NCT02817464
Conditions: Pregnancy Contraception
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2016-10-26; Completion date: 2018-12-03
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this pharmacodynamic and pharmacokinetic study is to identify a dose of TV-46046 (within the range 80 to 300 mg) that is both safe and consistent with contraceptive effect when injected every 6 months.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: TV-46046 - 400 mg/mL intervention 2: TV-46046 - 200 mg/mL
Intervention descriptions: intervention 1: A single subcutaneous injection in the abdomen of undiluted TV-46046 - 400 mg/mL intervention 2: A single subcutaneous injection in the abdomen of saline-diluted TV-46046 - 200 mg/mL

Protocol documents:
Prot_000.pdf: 
 
 
 
Clinical Study Protocol 
 
 
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 
 
 
Study Number TV46046-WH-10075 
 
 
NCT02817464 
 
 
Protocol with Amendment 04 Approval Date: 09 August 2017 


Pharmacokinetic Study–Contraception
Clinical Study Protocol with Amendment 04
Study TV46046-WH-10075
1
Clinical Study Protocol with Amendment 04
Study Number TV46046-WH-10075
FHI 360 Study Number: 780861
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
Phase 1
IND number: 126249
Amendment 04 Approval Date: 09 August 2017
Amendment 03 Approval Date: 27 March 2017
Amendment 02 Approval Date: 04 November 2016
Amendment 01 Approval Date: 29 May 2016
Original Protocol Approval Date: 01 May 2016
Sponsor
Teva Branded Pharmaceutical Products R&D, Inc.
41 Moores Road
Frazer, Pennsylvania 19355
United States of America
Confidentiality Statement
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as directed 
by the provisions of the International Conference on Harmonisation (ICH); United States (US) Code of 
Federal Regulations (CFR) and European Union (EU) Directives (as applicable in the region of the 
study); local country regulations; and the sponsor’s Standard Operating Procedures (SOPs).
This document contains confidential and proprietary information (including confidential commercial 
information pursuant to 21CFR§20.61) and is a confidential communication of Teva. The recipient agrees 
that no information contained herein may be published or disclosed without written approval from the 
sponsor.
© 2016 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved.


Pharmacokinetic Study–Contraception
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AMENDMENT HISTORY
The protocol for Study TV46046-WH-10075 (original protocol dated 01 May 2016) has been 
amended and reissued as follows:
Amendment 01
29 May 2016
No subjects have been enrolled to date.
Amendment 02
04 November 2016
No subjects have been enrolled to date.
Amendment 03
27 March 2017
6 subjects have been enrolled to date
Amendment 04
09 August 2017
12 subjects have been enrolled to date
Details about the changes and reason/justification for each change are provided in Section 16.


Pharmacokinetic Study–Contraception
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INVESTIGATOR AGREEMENT


P har mac o ki netic St u d y – C o ntrace pti o n
Cli nical St u d y  Pr ot oc ol wit h A me n d me nt 04
St u d y  T V 4 6 0 4 6-W H -1 0 0 7 5
4
C O O R DI N A TI N G I N V E S TI G A T O R A G R E E M E N T
Cli nic al St u d y Pr ot oc ol wit h A me n d me nt 0 4


Pharmacokinetic Study–Contraception
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CLINICAL LABORATORY AND OTHER DEPARTMENTS AND 
INSTITUTIONS
Sponsor’s Authorized Representative
, Global Clinical Pharmacology & Pharmacometrics
Teva Pharmaceutical Industries, Ltd
Sponsor’s Medical Expert
, Women’s Health
Teva Pharmaceutical Industries, Ltd.
Monitor
FHI 360
Sponsor’s Representative of Global Patient Safety and Pharmacovigilance
Global Patient Safety & Pharmacovigilance
Teva Branded Pharmaceutical Products R&D, Inc.
Central Institutional Review Board
Protection of Human Subjects Committee
FHI 360


Pharmacokinetic Study–Contraception
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Study TV46046-WH-10075
6
Investigational Center Ethics Committees
University of Pennsylvania IRB
3624 Market Street, Suite 301S
Philadelphia, Pennsylvania 19104
United States of America
Chesapeake IRB
6940 Columbia Gateway Drive, Suite 110 
Columbia, Maryland 21046
United States of America
Comité Ético Científico del Servicio de Salud Metropolitano Central
Victoria Subercaseaux #381
Santiago, Chile
Comité de Ética de PROFAMILIA 
Clínica Abreu, Calle Beller #42 esq. Ave. Independencia
Santo Domingo, Dominican Republic
Central Bioanalytical Laboratory
Pharmaceutical Product Development, LLC (PPD)
2244 Dabney Road
Richmond, Virginia 23230
United States of America
Clinical Laboratories
University of Pennsylvania Endocrinology Laboratory
8th Floor
3701 Market Street
Philadelphia, Pennsylvania 19104
United States of America
Jones Institute for Reproductive Medicine Endocrinology Laboratory
601 Colley Avenue
Norfolk, VA 23507
United States of America
Laboratorios Clinicos PUC - Centro Medico San Joaquin 
Vicuna Mackenna 4686 Macul 
Santiago, Chile
Referencia Laboratorio Clínico
Avenida Independencia 202, 3er piso
Edificio Santa Ana
Santo Domingo, Dominican Republic
Data Management
, Data Management


Pharmacokinetic Study–Contraception
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FHI 360
Bioanalytical Pharmacokinetics
, Biostatistics Division
FHI 360
Investigational Centers
Women’s Health Clinical Research Center
University of Pennsylvania
3701 Market Street Suite 810
Philadelphia, Pennsylvania 19104
United States of America
Conrad Clinical Research Center
Eastern Virginia Medical School
601 Colley Avenue
Norfolk, VA 23507
Unites States of America
Instituto Chileno de Medicina Reproductiva 
Jose Victorino Lastarria 29 of 101
Santiago Centro, Santiago
Chile
Asociación Dominicana Pro Bienestar de la Familia, Inc.
(PROFAMILIA)
Nicolas de Ovando esq. Calle 16
Ens. Luperon
Santo Domingo, Dominican Republic


Pharmacokinetic Study–Contraception
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CLINICAL STUDY PERSONNEL CONTACT INFORMATION
For medical issues, contact the physician listed below: 
, Medical Research, FHI 360
Medical Monitor
Tel: 
Tel: 
Fax: 
For operational issues, contact the operational lead listed below:
, FHI 360
Tel: 
Email:
For protocol issues, contact the study leader listed below:
, FHI 360
Tel: 
Tel: 
Fax: 
For serious adverse events:
Send by e-mail to the local safety officer (LSO) and to the FHI 360 medical monitor. The email 
address will be provided in the serious adverse event report form. In the event of difficulty 
transmitting the form, contact the sponsor’s study personnel identified above for further 
instruction.


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CLINICAL STUDY PROTOCOL SYNOPSIS
Study Number: TV46046-WH-10075
Title of Study: 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
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
IND Number: 126249
EudraCT number: Not applicable
Name of Active Ingredient: Medroxyprogesterone acetate (MPA)
Name of Investigational Product or Device: Depot Medroxyprogesterone Acetate (DMPA [TV-46046])
Phase of the Study: 1
Number of Investigational Centers Planned: up to 5
Countries Planned: United States (US), Chile, and the Dominican Republic 
Planned Study Period: November 2016 (first subject screened) to November 2019 (last subject last visit).
Number of Participants Planned: 12 to 78 healthy female participants. In an initial exploratory pharmacokinetics 
component (Part 1), 12 women (6 per group) will be assigned sequentially to a single subcutaneous injection in the 
abdomen of 120 mg TV-46046 at 1 of 2 concentrations: 0.3 mL of undiluted (400 mg/mL) product (initial 
6 subjects) or 0.6 mL of 200 mg/mL saline-diluted product (next 6 subjects). If the undiluted formulation exhibits a 
promising pharmacokinetics profile, then up to 60 additional subjects (20 per treatment group) will be randomized to 
up to 3 additional recommended dose levels of undiluted TV-46046 within the range 80 to 300 mg (up to 20 subjects 
per treatment group) in a dose-range finding component of the study (Part 2). If undiluted TV-46046 does not 
exhibit an appropriate pharmacokinetic profile then Part 2 of the study will not be initiated.
If the results from Part 1 indicate that information on an intermediate concentration of TV-46046 is necessary to 
inform the TV-46046 development program, then 6 additional subjects will be enrolled in Part 1 as treatment 
group 3, to receive a subcutaneous injection of 120 mg TV-46046 at 0.4 mL of 300 mg/mL saline-diluted 
concentration.
Study Population: Healthy female subjects 18 to 40 years of age, inclusive, at low risk of pregnancy (ie, sterilized, 
in exclusively same-gender partnership, in monogamous relationship with vasectomized partner, or using 
non-hormonal intrauterine device [IUD]), and who are confirmed to have ovulated during the pretreatment phase of 
the study.
Primary Objectives
Part 1, Exploratory Pharmacokinetics: To assess the pharmacokinetics of medroxyprogesterone acetate (MPA) 
following a single subcutaneous injection of undiluted and saline-diluted 120 mg TV-46046. This information will 
be used to inform up to 3 dose levels of undiluted TV-46046 and the study size for the dose-range finding 
component (Part 2) of the study, or to select a drug concentration for further investigation if undiluted TV-46046
does not exhibit an appropriate pharmacokinetic profile.
Part 2, Dose-range Finding: If undiluted TV-46046 exhibits an appropriate pharmacokinetic profile in Part 1, then 
Part 2 will evaluate the pharmacodynamics of MPA after a single subcutaneous injection of undiluted TV-46046 at 


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up to 3 recommended dose levels (where pharmacodynamic response is defined as suppression of ovulation 
determined through serum progesterone concentrations). 
Secondary Objectives 

To characterize the pharmacokinetics of up to 3 dose levels of undiluted TV-46046

To evaluate the relationship between serum MPA concentration and return to ovulation

To evaluate the safety of a subcutaneous injection of TV-46046 over the range of different doses and 
concentrations

To evaluate the acceptability of a subcutaneous injection of TV-46046 over the range of different 
doses and concentrations
Study Endpoints: 
Part 1, Exploratory Pharmacokinetics: Individual and mean serum MPA concentration-time profiles, and 
estimated noncompartmental pharmacokinetics parameters, including but not limited to maximum observed serum 
drug concentration (Cmax), time to maximum observed serum drug concentration (tmax), observed serum drug 
concentration at day 182 (C182, week 26), area under the serum drug concentration by time curve from time 0 to 
day 182 (AUC0-182), area under the serum drug concentration by time curve from time 0 to infinity (AUC0-∞), and
apparent terminal half-life.
Part 2, Dose-range Finding: Time to ovulation, where ovulation is defined as a single-elevated serum progesterone
(P ≥4.7 ng/mL). Secondary endpoints include pharmacokinetics of MPA based on individual serum MPA 
concentration-time profiles and estimated noncompartmental pharmacokinetics parameters, including but not limited 
to Cmax, tmax, C182, observed serum drug concentration at day 210 (C210, week 30), AUC0-182, area under the serum 
drug concentration by time curve from time 0 to day 210 (AUC0-210), AUC0-∞, and apparent terminal half-life. In 
addition, release rates, relative bioavailability, and other pharmacokinetic parameters derived from non-linear mixed 
effects model compartmental analysis of MPA concentrations over time will be reported. Safety endpoints include
but are not limited to the occurrence of changes in vital signs and body weight; delayed return to ovulation
(>12 months [>52 weeks] post-study drug injection), adverse events, injection site reactions (ISRs), use of 
concomitant medications, and changes in mood, liver function tests, and menstrual bleeding patterns. Acceptability
endpoints include subjects’ responses to questions about injection pain, ISR complaints, and menstrual bleeding 
patterns; and the study staff’s assessment of the ease of the injection.
General Design and Methodology: This is a 2-part study to evaluate the pharmacokinetics and pharmacodynamics 
of MPA in healthy female subjects after a single subcutaneous injection of TV-46046. Prior to injection, ovulation 
will be confirmed by measuring serum progesterone twice a week during the 2 to 3 weeks preceding expected 
menses. Twelve subjects (6 per treatment group) with confirmed ovulation and who meet all other eligibility criteria 
will be admitted to Part 1 and assigned sequentially to receive a single subcutaneous injection in the abdomen of 
120 mg TV-46046 at 1 of 2 concentrations: 0.3 mL of undiluted 400 mg/mL (initial 6 subjects in treatment group 1) 
or 0.6 mL of saline-diluted 200 mg/mL (next 6 subjects forming treatment group 2). Depending on the results, a 3rd
treatment group may subsequently be enrolled to receive a single subcutaneous injection of 120 mg TV-46046 at a 
concentration of 300 mg/mL (0.4 mL) (saline-diluted).
The decision to move into Part 2 will be based on predicted pharmacokinetic parameters for a range of potential 
Part 2 doses, as informed by observed Part 1 pharmacokinetic data. Features of the undiluted drug may also enter the 
decision-making, including stability, re-suspendability, syringeability and safety. Part 2 will only be implemented if 
the administration of undiluted TV-46046 (400 mg/mL) in Part 1 demonstrates an appropriate pharmacokinetic 


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profile. Pharmacokinetic criteria considered before moving into Part 2 include: predicted mean Cmax less than 
3 ng/mL, predicted time to achieve 0.2 ng/mL no more than 24 hours after study drug administration for all subjects, 
predicted 6-month concentration greater than 0.1 ng/mL in 95% of subjects, and predicted concentration 24 months 
after the last injection below 0.1 ng/mL in 90% of subjects, for all treatment groups selected for Part 2. The interim
pharmacokinetic analysis to inform the decision to move into Part 2 will be performed after all 6 subjects in group 1 
receiving undiluted TV-46046 in Part 1 have had a chance to complete at least 4 months (17 weeks) of treatment. At 
that time, available pharmacokinetic data from women in treatment group 2 (ie, the next 6 women receiving diluted 
TV-46046) will also be analyzed. Additional assessments will be made if warranted. If the undiluted formulation 
exhibits a promising pharmacokinetic profile per the criteria described above, then a dose-range finding component 
of the study (Part 2) will be initiated and up to 60 additional subjects (up to 20 subjects per treatment group) will be 
randomized to receive a single subcutaneous injection of up to 3 recommended dose levels of undiluted TV-46046 
within the range of 80 to 300 mg. The selection of specific doses and number of subjects per TV-46046 dose in 
Part 2 will be informed by pharmacokinetics analysis and modeling of interim Part 1 data. If a diluted concentration 
of TV-46046 exhibits a more promising pharmacokinetic profile in Part 1, then Part 2 of the study will not be 
initiated. In that event, a clinical formulation of a diluted concentration may be developed and tested in a separate 
protocol under an amended Investigational New Drug (IND) application. If the results of Part 1 indicate that 
information on an intermediate concentration of TV-46046 is necessary to inform the TV-46046 development 
program, then 6 additional subjects will be enrolled in Part 1 as treatment group 3, to receive a subcutaneous 
injection of 120 mg TV-46046 at 0.4 mL of 300 mg/mL saline-diluted concentration. Study procedures for the 
6 subjects in treatment group 3 of Part 1 would be the same as for the other treatment groups. The data-driven 
decision to add a treatment group to Part 1 minimizes subject numbers and balances the need for more information 
on pharmacokinetics with an alternative dilution. If interim analysis of Part 1 data indicates that neither undiluted 
nor diluted TV-46046 is appropriate for further testing, then all subjects enrolled in Part 1 may be discontinued 
early, with only post-discontinuation follow-up visits for safety purposes.
Study participation will consist of a screening and pre-treatment phase (approximately 1 month, or 4 weeks), a 
treatment phase (6 months, or 26 weeks), and post-treatment follow-up (an additional 6 to 12 months). During the 
pre-treatment phase, ovulation will be confirmed in all subjects who are otherwise eligible for the study by 
measuring serum progesterone twice a week (preferably 3 days apart) during the 2 to 3 weeks preceding expected 
menses. Enrolled subjects will receive an injection of the study drug and then be followed for at least 12 months 
(52 weeks) to characterize pharmacodynamics and pharmacokinetics of MPA (ie, 6 months of treatment plus 
6 months of post-treatment follow-up), regardless of earlier return to ovulation. There will be three in-depth 
scheduled follow-up visits at day 7, week 13, and week 32 after injection, as well as frequent, brief laboratory visits 
that include collection of blood samples. 
Subjects in both parts of the study will be routinely evaluated for vital signs, body weight, and acceptability
(ie, responses to questions about injection pain, ISR complaints, and menstrual bleeding patterns), and will provide 
blood samples for serum progesterone, estradiol, and MPA at frequent predefined time points for 12 months 
(52 weeks) from start of study drug administration (regardless of earlier return to ovulation). Subjects who have not 
ovulated by month 12 (week 52) will be monitored by less frequent measurements of serum progesterone, estradiol, 
and MPA until ovulation returns for safety reasons for up to another 26 weeks (up to a total of 78 weeks from the 
injection of study drug). Injection sites will be observed for ISRs on the day of the study drug injection (day 0), 
post-injection at days 1, 2, 3, 5, and 7, week 13, week 32, at the final study visit, and other visits, if indicated. The 
subject’s menstrual bleeding pattern will be ascertained by interviewer-administered questionnaire at monthly 
intervals during scheduled laboratory visits (in Part 1 only), at two scheduled follow-up visits (weeks 13 and 32 
only), and at the final study visit. In addition, during Part 2 the subject’s menstrual bleeding patterns will be 
ascertained weekly using an on-line diary; and liver function testing and mood assessment will be done at screening, 


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the scheduled follow-up visits at week 13 and week 32, and the final study visit. Information on adverse events and 
concomitant medications will be collected throughout the study. The study staff will provide assessment on the ease 
of the injection.
Method of Blinding and Randomization: Part 1 is open-label and without random assignment: the 1st 6 enrolled 
subjects will be assigned 0.3 mL of 400 mg/mL TV-46046 (undiluted) and the next group of 6 subjects will be 
assigned 0.6 mL of 200 mg/mL TV-46046 (saline-diluted). If warranted to inform the TV-46046 development 
program, a 3rd group of 6 subjects will be assigned 0.4 mL of 300 mg/mL TV-46046 (saline-diluted). If 120 mg 
TV-46046 is selected as 1 of the treatment groups for Part 2, then up to 48 subjects will be randomized either to the 
120 mg treatment group or to 1 of 2 other selected treatment groups in a 2:3:3 ratio. If the 120 mg dose of TV-46046
is not selected as a dose for Part 2, then up to 54 subjects will be randomized in a 1:1:1 ratio to 1 of up to 3 selected 
treatment groups. In addition, 2 subjects with a body mass index (BMI) ≥ 40 will be randomized to each treatment 
group, for a maximum total of 60 subjects (up to 20 per treatment group) enrolled in Part 2.
Part 2 will be a subject-blinded study. Study staff will shield the syringe from view of the subject and any other 
study staff prior to and at the time of injection to ensure they remain blinded. The center investigator(s) staff
responsible for reviewing and grading adverse events and laboratory staff analyzing specimens will be fully blinded. 
Study Drug Dose, Mode of Administration, and Administration Rate:
Investigational Product: Part 1 of the study will evaluate a 120 mg dose of TV-46046 administered in up to 
3 different concentrations: 0.3 mL of 400 mg/mL undiluted TV-46046, 0.4 mL of 300 mg/mL saline-diluted 
TV-46046 (if warranted), and 0.6 mL of 200 mg/mL saline-diluted TV-46046. Saline-dilution of TV-46046 will be 
performed at the investigational centers by a pharmacist or other trained personnel before administering the study 
drug.
If undiluted TV-46046 is selected for further investigation, Part 2 of the study will evaluate undiluted TV-46046 at 
up to 3 additional dose levels within the range of 80 to 300 mg, which will be selected on the basis of the results in 
Part 1.
In both the exploratory pharmacokinetics and dose-range finding parts of the study, a single subcutaneous injection 
of TV-46046 will be administered in the abdomen during the first 5 days of the menstrual cycle using a 23-gauge 
3/8 inch needle.
Reference Treatment: Not applicable
Duration of Study Participation: The total duration of participation is up to approximately 78 weeks after the start 
of study drug administration.
Inclusion Criteria: Subjects may be included in the study if they meet all of the following criteria: 
a.
has regular menstrual cycle (24 to 35 days)
b.
has confirmed ovulatory cycle during the pretreatment phase (serum progesterone ≥ 4.7 ng/mL in 
2 consecutive samples)
c.
is at low risk of pregnancy (ie, sterilized, in exclusively same-sex partnership, in monogamous 
relationship with vasectomized partner, or using non-hormonal IUD)
d.
is in good general health as determined by a medical history 
e.
18 to 40 years of age, inclusive
f.
willing to provide informed consent and follow all study requirements


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g.
is not pregnant and does not have desire to become pregnant in the subsequent 36 months
h.
has a BMI of 18 to 35, inclusive (unless included in the subset of subjects with extreme obesity 
(BMI ≥40), 2 in each dose-range finding group from a single investigational center, in Part 2)
i.
has hemoglobin ≥10.5 g/L
j.
has had a normal mammogram within the last year (for Part 1 only).
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
○
vascular disease
b.
has current or history of ischemic heart disease
c.
has history of stroke
d.
has history of thromboembolic event 
e.
has systemic lupus erythematosus
○
positive (or unknown) antiphospholipid antibodies
○
severe thrombocytopenia
f.
has rheumatoid arthritis on immunosuppressive therapy
g.
has migraine with aura
h.
has unexplained vaginal bleeding
i.
has diabetes
j.
has 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 current or history of cervical cancer
l.
has severe cirrhosis (decompensated) or liver tumors
m. has one or more baseline liver function test(s) outside the local laboratory’s normal range (Part 2 only)
n.
has known significant renal disease 
o.
history of diagnosed clinical depression or bipolar disorder, with or without suicidal ideation, and/or 
history of suicide attempt
p.
in last two years, history of either hospitalization or medication management for 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
q.
used DMPA products (Depo-Provera CI or Depo-subQ Provera 104) in the past 12 months
r.
used any of the following medications within 1 month prior to enrollment:
○
any investigational drug


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○
prohibited drugs per protocol
○
oral contraceptives, contraceptive ring or patch 
○
levonorgestrel intrauterine system (LNG IUS) or contraceptive implant
s.
used a combined injectable contraceptive in the past 6 months
t.
less than 3 months since the end of last pregnancy
u.
currently lactating
v.
is using or plans to use prohibited drugs per protocol in the next 18 months
w.
has known sensitivity to MPA or inactive ingredients
x.
has a plan to move to another location in the next 24 months
y.
in the opinion of the investigator, potentially at elevated risk of HIV infection (eg, HIV-positive 
partner, IV drug use by self or by partner)
z.
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 complicate 
data interpretation.
Measures and Time Points:
Pharmacodynamic Measure and Time Points: The primary pharmacodynamics measure is serum 
progesterone concentration, evaluated as follows: on day 0 (baseline); then at day 7, and then weekly through 
week 32, regardless of ovulation status. If ovulation does not return by week 32, then weekly blood samples for 
serum progesterone will continue to be collected until ovulation or through week 52, whichever is earlier. If 
there is no ovulation by week 52, then blood samples for serum progesterone will be collected weekly between 
weeks 61 through 65 and between weeks 74 through 78, until ovulation is detected.
Pharmacokinetic Measures and Time Points: The primary pharmacokinetics measure is serum MPA 
concentration. Medroxyprogesterone acetate serum concentrations will be evaluated on days 0 (baseline), 1, 2, 
3, 5, 7, 10, 12, 14, 18, 21, 28, 35, and 42; then at weeks 8, 10, 12, 13, 15, 17, 19, 21, 23, 25, 26, 28, 30, and 32; 
and then every 28 days until week 52, regardless of ovulation status. In addition, subjects for whom ovulation 
does not return by month 12 (week 52), blood samples for MPA will be collected and tested up to 2 more times 
(at weeks 61 and 74), but not past return to ovulation. Blood samples will also be collected and stored for 
possible future MPA testing (if necessary) any time samples are collected for serum progesterone and estradiol, 
with the exception of pre-treatment visits and visits for confirmation of ovulation. The sampling schedule and 
duration of testing may be modified based on the interim results of Part 1 to ensure that primary and secondary 
outcomes are precisely measured in both parts of the study.
Efficacy: Efficacy will not be evaluated in this study.
Safety Measures and Time Points: Safety will be assessed throughout the study by monitoring adverse events, 
ISRs, concomitant medications, delayed return to ovulation (>12 months [>52 weeks] post-study drug 
injection), menstrual bleeding patterns, body weight, and vital signs (blood pressure [BP; systolic/diastolic], 
pulse, and respiration). Injection site reactions will be evaluated on the day of study drug injection (day 0) 
immediately after the injection (within 10 minutes) and within the 1st hour after injection; at days 1, 2, 3, 5, and 
7, week 13 and week 32 visits, at the final visit; and at other visits, if indicated. Vital signs and body weight will 
be assessed at scheduled follow-up visits at day 7, week 13, and week 32, and at the final study visit. Adverse 
events and use of concomitant medications will be measured throughout the study. If there is no ovulation by 
week 52, then blood samples for serum progesterone and estradiol will be collected weekly between weeks 61 
through 65 and between weeks 74 through 78, but not past return to ovulation. Acceptability of subcutaneous 
administration of TV-46046 will be evaluated on the day of study drug injection, at the three scheduled follow-


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up visits (day 7, week 13, and week 32), and at the final study visit. Menstrual bleeding patterns will be 
recorded during interviews at monthly intervals during scheduled laboratory visits (in Part 1 only), at 2
scheduled follow-up visits (weeks 13 and 32 only), and at the final study visit. In addition, in Part 2, menstrual 
bleeding data will be collected weekly using an on-line diary completed by the subjects; and change in liver 
function and mood will be assessed at screening, scheduled follow-up visits at week 13 and week 32, and at the 
final study visit.
Prohibited Medications Before and During the Study: Any drug(s) that may interfere with metabolism of MPA 
or affect ovarian function will be prohibited during the study.
Statistical Considerations:
Sample Size Rationale: Part 1 is not powered to definitively assess pharmacokinetics. Rather, if the 
pharmacokinetics profile of undiluted TV-46046 appears consistent with a safe and efficacious 6-month injectable 
contraceptive method, then up to 3 additional dose levels within the dose range of 80 to 300 mg will be 
recommended for Part 2. Likewise, the study size for Part 2 was not chosen to make definitive conclusions regarding 
the effectiveness of TV-46046 in the range of doses selected. However, up to 20 subjects per treatment group should 
be sufficient to provide meaningful insights into the distributions of pharmacokinetics and pharmacodynamics
outcomes, and to inform selection of a dose for further study.
Analysis of Primary Endpoints: The decision to move into Part 2 will be based on predicted pharmacokinetic 
parameters for a range of potential Part 2 doses, as informed by observed Part 1 pharmacokinetic data. Part 2 will 
only be implemented if the administration of undiluted TV-46046 (400 mg/mL) in Part 1 demonstrates an 
appropriate pharmacokinetic profile (eg, predicted mean Cmax less than 3 ng/mL, predicted time to achieve 
0.2 ng/mL no more than 24 hours after study drug administration for all subjects, predicted 6-month concentration 
greater than 0.1 ng/mL in 95% of subjects, and predicted concentration 24 months after the last injection below 
0.1 ng/mL in 90% of subjects for all treatment groups selected for Part 2).
The primary objective of Part 2 will be assessed by estimating the cumulative probability of return to ovulation 
through 52 weeks from start of study drug treatment using Kaplan-Meier methods. Time to ovulation will be 
estimated as the difference (in days) between enrollment and the date of first elevated serum progesterone 
concentration (≥4.7 ng/mL). Data from a subset of 6 subjects (2 per treatment group) with extreme obesity 
(BMI ≥40), and subjects with detectable MPA at baseline (more than 5% of their Cmax) or who used drugs known to 
interfere with pharmacokinetics or pharmacodynamics of MPA, will be excluded from the primary analysis but will 
be described separately.
Also in Part 2, individual and mean serum MPA concentration-time profiles, and estimated non-compartmental 
pharmacokinetics parameters including but not limited to Cmax, tmax, C182, C210, AUC0-182, AUC0-210, AUC0-∞, and
apparent terminal half-life will be summarized for each treatment group.
Nonlinear mixed effects pharmacokinetics/pharmacodynamics modeling and simulation will be used to explore the 
relationship between individual serum MPA concentrations and duration of ovulation suppression, with particular 
emphasis on characterizing the distribution of any apparent ovulatory suppression threshold, and the lowest dose, 
which may reliably inhibit ovulation for 6 months.
Multiple Comparisons and Multiplicity: No adjustments will be made for the planned or unplanned multiple 
comparisons of primary or secondary endpoints.
Acceptability Analysis: The responses to acceptability questions regarding menstrual patterns will be descriptively 
compared between treatment groups. Perceptions of pain at time of injection and responses on other acceptability 
questionnaire items will likewise be summarized and compared between treatment groups.


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Safety Analyses: Vital signs (BP [systolic/diastolic], pulse, and respiration) and body weight will be summarized 
graphically and using shift-tables. The number and percentage of subjects experiencing adverse events will be 
presented by treatment group: overall, by severity grade, and relatedness to treatment. Serious adverse events and 
adverse events leading to withdrawal from the study will be summarized separately. Summaries of ISR data will be 
provided by group in frequency tables and using subject-data listings. The percentage of women experiencing 
amenorrhea or other menstrual bleeding disturbances (irregular menstrual bleeding or spotting) will likewise be 
summarized descriptively and compared between treatment groups in Part 1 and Part 2 of the study. In Part 2 only:
liver function will be assessed by tabulating and graphing change in liver function tests including but not limited to 
ALT and AST, from screening to week 13 (month 3), week 32 (month 7.5), and final study visit. In Part 2 only: 
mood will be assessed in frequency tables at screening and at week 13 (month 3), week 32 (month 7.5), and final 
study visits. The probability of return to ovulation more than 12 months after treatment initiation with TV-46046 
will be estimated using Kaplan-Meier methods.


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TABLE OF CONTENTS
AMENDMENT HISTORY .............................................................................................................2
INVESTIGATOR AGREEMENT...................................................................................................3
COORDINATING INVESTIGATOR AGREEMENT...................................................................4
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS ..............5
CLINICAL STUDY PERSONNEL CONTACT INFORMATION ...............................................8
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................9
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................25
1.
BACKGROUND INFORMATION...........................................................................28
1.1.
Introduction.................................................................................................................28
1.2.
Name and Description of Investigational Product......................................................29
1.3.
Findings from Nonclinical and Clinical Studies.........................................................30
1.3.1.
Nonclinical Studies.....................................................................................................30
1.3.1.1.
Nonclinical Studies Conducted by Teva.....................................................................30
1.3.1.2.
Nonclinical Literature.................................................................................................31
1.3.2.
Clinical Studies...........................................................................................................32
1.3.2.1.
Clinical Pharmacology Studies...................................................................................32
1.3.2.2.
Clinical Safety Studies................................................................................................33
1.4.
Known and Potential Benefits and Risks to Human Subjects....................................33
1.4.1.
Benefits of TV-46046.................................................................................................33
1.4.2.
Risks of TV-46046 .....................................................................................................33
1.5.
Selection of Drugs and Doses.....................................................................................37
1.6.
Compliance Statement................................................................................................38
1.7.
Study Population and Justification .............................................................................38
1.8.
Location and Duration of Study .................................................................................39
2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES.....................................40
2.1.
Purpose of the Study...................................................................................................40
2.2.
Study Objectives.........................................................................................................40
2.2.1.
Primary Objectives .....................................................................................................40
2.2.2.
Secondary Objectives .................................................................................................40
2.3.
Study Endpoints..........................................................................................................40
2.3.1.
Primary Endpoints ......................................................................................................40


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2.3.2.
Secondary Endpoints ..................................................................................................41
2.3.3.
Safety Endpoints.........................................................................................................41
2.3.4.
Acceptability Endpoints..............................................................................................41
3.
STUDY DESIGN .......................................................................................................42
3.1.
General Design and Study Schematic Diagram..........................................................42
3.2.
Justification for Study Design ....................................................................................45
3.3.
Pharmacokinetic Measures and Time Points..............................................................46
3.4.
Pharmacodynamic Measures and Time Points...........................................................46
3.5.
Safety Measures and Time Points...............................................................................47
3.6.
Acceptability Measures and Time Points ...................................................................47
3.7.
Randomization............................................................................................................47
3.8.
Maintenance of Randomization and Blinding............................................................48
3.8.1.
Maintenance of Randomization..................................................................................48
3.8.2.
Blinding/Unblinding...................................................................................................48
3.8.3.
Data and Safety Monitoring Board.............................................................................49
3.9.
Drugs Used in the Study.............................................................................................50
3.10.
Drug Supply and Accountability ................................................................................50
3.10.1.
Drug Storage and Security..........................................................................................50
3.10.2.
Drug Accountability ...................................................................................................50
3.11.
Duration of Subject Participation and Justification....................................................51
3.12.
Stopping Rules and Discontinuation Criteria .............................................................51
3.13.
Source Data Recorded on the Case Report Form.......................................................52
3.14.
Study Procedures ........................................................................................................53
3.14.1.
Procedures Before Study Drug Treatment..................................................................55
3.14.2.
Pretreatment................................................................................................................56
3.14.3.
Procedures During Study Drug Treatment .................................................................57
3.14.3.1.
Enrollment (Injection) Visit (Day 0) ..........................................................................57
3.14.3.2.
Follow-up (Day 1 to Week 78)...................................................................................58
3.14.4.
Procedures After Study Drug Treatment and Lost to Follow-up ...............................60
3.14.4.1.
Final Visit ...................................................................................................................60
3.14.4.2.
Missed Visits ..............................................................................................................60
3.14.4.3.
Lost to Follow-up .......................................................................................................61
3.14.5.
Unscheduled Visits .....................................................................................................61


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4.
SELECTION AND WITHDRAWAL OF SUBJECTS..............................................62
4.1.
Subject Inclusion Criteria ...........................................................................................62
4.2.
Subject Exclusion Criteria..........................................................................................62
4.3.
Justification for Key Inclusion and Exclusion Criteria...............................................64
4.4.
Withdrawal Criteria and Procedures...........................................................................64
5.
TREATMENT OF SUBJECTS..................................................................................66
5.1.
Drugs Administered During the Study .......................................................................66
5.1.1.
Dilution Procedure of TV-46046................................................................................66
5.1.2.
Subcutaneous Administration of TV-46046...............................................................66
5.2.
Restrictions .................................................................................................................67
5.3.
Prior and Concomitant Medication or Treatment.......................................................67
5.4.
Procedures for Monitoring Subject Compliance ........................................................68
5.5.
Total Blood Volume ...................................................................................................68
6.
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS ........................................................................................69
6.1.
Pharmacokinetics........................................................................................................69
6.1.1.
Part 1: Exploratory Pharmacokinetic Variables .........................................................69
6.1.2.
Part 2: Dose-range Finding Variables.........................................................................69
6.1.3.
Blood Sampling and Handling....................................................................................70
6.1.4.
Shipment and Analysis of Samples ............................................................................70
6.2.
Pharmacodynamics.....................................................................................................70
7.
ASSESSMENT OF SAFETY.....................................................................................73
7.1.
Adverse Events ...........................................................................................................73
7.1.1.
Definition of an Adverse Event..................................................................................73
7.1.2.
Recording and Reporting Adverse Events..................................................................74
7.1.3.
Severity of an Adverse Event .....................................................................................74
7.1.4.
Relationship of an Adverse Event to the Study Drug.................................................75
7.1.5.
Serious Adverse Events..............................................................................................75
7.1.5.1.
Definition of a Serious Adverse Event .......................................................................75
7.1.5.2.
Expectedness...............................................................................................................76
7.1.5.3.
Reporting a Serious Adverse Event............................................................................76
7.1.6.
Protocol-Defined Adverse Events for Expedited Reporting ......................................78
7.1.7.
Withdrawal Due to an Adverse Event ........................................................................78


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7.1.8.
Overdose of Study Drug .............................................................................................79
7.1.9.
Protocol Deviations Because of an Adverse Event ....................................................79
7.2.
Pregnancy ...................................................................................................................79
7.3.
Medication Error and Special Situations....................................................................80
7.4.
Clinical Laboratory Tests ...........................................................................................80
7.5.
Vital Signs ..................................................................................................................81
7.6.
Body Weight...............................................................................................................81
7.7.
Injection Site Reactions..............................................................................................81
7.8.
Menstrual Bleeding Patterns.......................................................................................81
7.9.
Mood Changes............................................................................................................82
7.10.
Concomitant Therapy or Medication..........................................................................82
7.11.
Methods and Time Points of Assessing, Recording, and Analyzing Safety 
Data.............................................................................................................................82
7.12.
ASSESSMENT OF ACCEPTABILITY ....................................................................82
8.
STATISTICS ..............................................................................................................84
8.1.
Sample Size and Power Considerations .....................................................................84
8.2.
Analysis Sets...............................................................................................................84
8.2.1.
Screened Population ...................................................................................................84
8.2.2.
Treated Population......................................................................................................84
8.2.3.
Primary Evaluable Population ....................................................................................85
8.3.
Data Handling Conventions........................................................................................85
8.4.
Study Population.........................................................................................................85
8.4.1.
Subject Disposition.....................................................................................................85
8.4.2.
Demographic and Baseline Characteristics ................................................................86
8.5.
Pharmacokinetic Analysis ..........................................................................................86
8.5.1.
Primary Endpoints ......................................................................................................86
8.5.1.1.
Part 1 (Exploratory Pharmacokinetics).......................................................................86
8.5.1.2.
Part 2 (Dose-range Finding) .......................................................................................86
8.5.2.
Secondary Pharmacokinetic Endpoints ......................................................................86
8.5.3.
Planned Method of Analysis.......................................................................................86
8.5.3.1.
Sensitivity Analysis ....................................................................................................87
8.5.3.2.
Exploratory Analysis ..................................................................................................87
8.6.
Pharmacodynamic Analysis........................................................................................87


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8.7.
Multiple Comparisons and Multiplicity......................................................................88
8.8.
Safety Endpoints and Analysis ...................................................................................88
8.8.1.
Safety Endpoints.........................................................................................................88
8.8.2.
Safety Analysis ...........................................................................................................88
8.9.
Acceptability Variables and Analysis.........................................................................89
8.10.
Planned Interim Analyses...........................................................................................89
8.11.
Reporting Deviations from the Statistical Plan ..........................................................90
9.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................91
10.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................92
10.1.
Protocol Amendments and Protocol Deviations and Violations ................................92
10.1.1.
Protocol Amendments ................................................................................................92
10.1.2.
Protocol Violations.....................................................................................................92
10.2.
Information to Study Personnel..................................................................................92
10.3.
Study Monitoring........................................................................................................93
10.4.
Clinical Product Complaints.......................................................................................93
10.4.1.
Product Complaint Information Needed from the Investigational Center..................94
10.4.2.
Handling the Study Drug at the Investigational Center..............................................95
10.4.3.
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint ...................................................................................................................95
10.4.4.
Documenting a Product Complaint ............................................................................95
10.5.
Audit and Inspection...................................................................................................95
11.
ETHICS ......................................................................................................................96
11.1.
Informed Consent .......................................................................................................96
11.2.
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards.........................................................................................................................96
11.3.
Confidentiality Regarding Study Subjects..................................................................97
11.4.
Declaration of the End of the Clinical Study..............................................................97
11.5.
Registration of the Clinical Study...............................................................................97
12.
DATA HANDLING, DATA QUALITY CONTROL, AND RECORD 
KEEPING ...................................................................................................................98
12.1.
Data Collection...........................................................................................................98
12.2.
Data Quality Control...................................................................................................98
12.3.
Archiving of Case Report Forms and Source Documents..........................................99


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12.3.1.
Sponsor Responsibilities.............................................................................................99
12.3.2.
Investigator Responsibilities.......................................................................................99
13.
FINANCING AND INSURANCE...........................................................................101
14.
REPORTING AND PUBLICATION OF RESULTS..............................................102
15.
REFERENCES .........................................................................................................103
16.
SUMMARY OF CHANGES TO PROTOCOL .......................................................106
16.1.
Protocol Amendment 04 Dated 09 August 2017......................................................106
16.2.
Protocol Amendment 03 Dated 27 March 2017.......................................................122
16.3.
Protocol Amendment 02 Dated 04 November 2016.................................................142
16.4.
Protocol Amendment 01 Dated 29 May 2016 ..........................................................153
APPENDIX A.
DAIDS TABLE FOR GRADING ADULT AND PEDIATRIC 
ADVERSE EVENTS................................................................................................154
APPENDIX B.
INJECTION INSTRUCTIONS.......................................................................155


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LIST OF TABLES
Table 1:
Study Procedures and Assessments (Parts 1 and 2)....................................................54
Table 2:
Approximate Blood Volumes.....................................................................................68


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LIST OF FIGURES
Figure 1:
Pharmacokinetic Profiles of Depo-Provera CI and Depo-subQ 104..........................29
Figure 2:
Overall Study Schematic Diagram .............................................................................45


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
%CV
percent coefficient of variation
ALT
Alanine aminotransferase
API
active product ingredient
ARV
antiretroviral drug
AST
Aspartate aminotransferase
AUC
area under the serum drug concentration by time curve
AUC0-∞
area under the serum drug concentration by time curve from time 0 to infinity
AUC0-6
area under the serum drug concentration by time curve from time 0 to day 6
AUC0-89
area under the serum drug concentration by time curve from time 0 to day 89
AUC0-182
area under the serum drug concentration by time curve from time 0 to day 182
AUC0-210
area under the serum drug concentration by time curve from time 0 to day 210
BMD
bone mineral density
BMI
body mass index
BP
blood pressure
C182
observed serum drug concentration at day 182
CDC
Centers for Disease Control and Prevention
CDMS
clinical data management system
CFR
Code of Federal Regulations (US)
CIOMS
Council for International Organizations of Medical Sciences
COX-2
cyclooxygenase-2
Cmax
maximum observed serum drug concentration
CRF
case report form (refers to any media used to collect study data [ie, paper or 
electronic])
CRO
contract research organization
DAIDS
Division of Acquired Immune Deficiency Syndrome (AIDS)
Depo-Provera CI
Depo-Provera Contraceptive Injection
Depo-subQ 104
Depo subQ provera 104
DMPA
depot medroxyprogesterone acetate
DSMB
Data and Safety Monitoring Board


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Abbreviation
Term
DSS
docusate sodium sulfosuccinate
ePRO
electronic patient-reported outcome
EU
European Union
FDA
Food and Drug Administration (US)
FIH
first in human
FP
family planning
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HIV
human immunodeficiency virus
HSV-2
herpes simplex virus type 2
IB
Investigator’s Brochure 
ICH
International Conference on Harmonisation
ICMER
Instituto Chileno de Medicina Reproductiva
IEC
Independent Ethics Committee
Ig
immunoglobulin
IMP
investigational medicinal product
IND
Investigational New Drug
IRB
Institutional Review Board
ISR
injection site reaction
IUD
intrauterine device
LNG IUS
levonorgestrel intrauterine system
LOQ
limit of quantification
LSO
local safety officer 
MEC
Medical Eligibility Criteria
MedDRA
Medical Dictionary for Regulatory Activities 
MPA
medroxyprogesterone acetate
NDA
New Drug Application
OTC
over the counter
PHSC
Protection of Human Subjects Committee
PPD
Pharmaceutical Product Development, LLC
rpm
revolutions per minute
SD
standard deviation


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Abbreviation
Term
SOC
system organ class 
SOP
standard operating procedure
SSA
sodium sulfate anhydrous
STI
sexually transmitted infection
SUSAR
suspected unexpected serious adverse reaction
tmax
time to maximum observed serum drug concentration
US(A)
United States (of America)
USP
United States Pharmacopeia
WHO
World Health Organization
WY
women-years
XML
Extensible Markup Language


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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 
Injectable contraception has been a cornerstone of international family planning (FP) programs 
for decades. Currently, over 40 million women worldwide use injectable contraceptives 
(injectables) to prevent pregnancy (United Nations Department of Economic and Social Affairs 
2011). In sub-Saharan Africa, more than one-third of modern method contraceptive users rely on 
injectable contraceptives (Stanback et al 2010). Despite the broad and increasing use of 
injectables, discontinuation and late return rates for reinjection are high, frequently due to users’ 
difficulty complying with re-injection schedules (Baumgartner et al 2007). Depending on the 
formulation, currently available injectables are effective for 1 to 3 months, requiring women to 
return to their provider monthly, every other month or quarterly; this is recognized as a 
significant disadvantage of these methods compared to longer-acting reversible contraceptives 
(eg, intrauterine devices or implants) (Lakha et al 2005).
Depo-Provera®1 Contraceptive Injection (Depo-Provera CI) and its subcutaneous formulation
depo-subQ provera 104®1 (hereafter referred to as Depo-subQ 104), both also known as DMPA, 
provide contraceptive protection for 3 months and are the most popular injectable contraceptives 
worldwide. A longer-acting injectable contraceptive that lasts for 6 months would be a valuable 
addition to the method mix and ideal for women who are interested in spacing births, and/or are 
uncertain about their future reproductive plans. In addition to advantages for users, these 
methods would reduce the burden of participant load on clinical facilities and community-based 
programs. While efforts are under way to invest in novel sustained drug delivery technologies 
that hold promise for the development of a new longer-acting injectable contraceptive product 
(Halpern et al 2015), the adaptation of existing methods carries a distinct comparative advantage 
by shortening the time to market and reducing development costs.
Depo-Provera CI for intramuscular use provides contraceptive protection for 3 months and is the 
most popular injectable contraceptive worldwide. The subcutaneous route of administration is 
characterized by slower absorption and a more sustained release when compared to 
intramuscular injection. By changing the route of administration from intramuscular to 
subcutaneous and volume of injection, Pfizer developed a modified formulation for subcutaneous 
injection (ie, Depo-subQ 104) that is also effective for at least 3 months but uses approximately
31% less of the active ingredient MPA (Figure 1). When compared to Depo-Provera CI, Depo-
subQ 104 exhibited a lower average maximum observed serum drug concentration (Cmax)
                                                
1 Depo-Provera® CI and depo-subQ provera 104® are registered trademarks of Pfizer Inc.


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(1.56 ng/mL compared to 3.73 ng/mL), a longer mean half-life (43 days compared to 13 days), 
and lower overall drug exposure (area under the serum drug concentration by-time curve from 
time 0 to infinity [AUC0-∞] of 92.84 ng•day/mL compared to 134 ng•day/mL) (Jain et al 2004).
Teva and FHI 360 propose to evaluate the potential of TV-46046 to provide contraceptive 
protection when injected subcutaneously at a dose no higher than 300 mg every 6 months.
Figure 1:
Pharmacokinetic Profiles of Depo-Provera CI and Depo-subQ 104
Source: Adapted from Pfizer, Spieler, JM. New Contraceptive Technology and Unfinished Agenda. Presentation at 
the Johns Hopkins Bloomberg School of Public Health, 2012.
Depo-Provera CI=Depo-Provera Contraceptive Injection; Depo-subQ 104
Depo subQ provera 104; 
IM=intramuscular; SQ=subcutaneous; MPA= medroxyprogesterone acetate; DMPA= depot-medroxyprogesterone 
acetate.
1.2.
Name and Description of Investigational Product
TV-46046 (MPA injectable suspension, 400 mg/mL) for subcutaneous injection (TV-46046), the 
investigational product, is a sterile aqueous suspension of MPA, with the chemical name 
6α-methyl-3,20-dioxopregna-4-en-17-yl acetate.
TV-46046 is supplied in pre-filled vials each containing 400 mg of MPA per 1 mL. In Part 1, 
TV-46046 will be administered as a 120 mg fixed dose at up to 3 different concentrations 
(0.3 mL of 400 mg/mL, 0.4 mL of 300 mg/mL [if warranted], and 0.6 mL of 200 mg/mL) by the 
subcutaneous route. The 300 and 200 mg/mL concentrations will be achieved by diluting the 
original 400 mg/mL formulation with sterile saline by a pharmacist or other trained personnel
prior to injection.
If undiluted TV-46046 is selected for further testing, then the study will proceed to Part 2, 
wherein up to 3 additional doses of undiluted TV-46046 within the range of 80 to 300 mg will be 
administered as a single subcutaneous injection.
TV-46046 is manufactured by Teva. A more detailed description of the product is given in
Section 3.9 .


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1.3.
Findings from Nonclinical and Clinical Studies
The active ingredient, MPA is a synthetic analog of 17α-hydroxyprogesterone and it has been 
marketed globally for many years as oral (Provera® tablets), intramuscular injection formulations 
(Depo-Provera CI [150 mg/mL] and Depo-Provera® [400 mg/mL]) and, more recently, as a 
subcutaneous injection formulation (Depo-subQ 104 [104 mg/0.65 mL]). Depo-Provera CI is 
approved for use as an intramuscular contraceptive in the United States (US) (New Drug 
Application [NDA] 20-246). The first injectable formulation was approved in 1992 and is 
administered at a single dose of 150 mg every 3 months. Depo-subQ 104 was approved by the 
US Food and Drug Administration (FDA) in 2004 (NDA 21-583) to be administered 
subcutaneously in doses of 104 mg/0.65 mL every 3 months. Depo-subQ 104 was also approved 
for management of endometriosis-associated pain (NDA 21-584). Depo-Provera 400 mg/mL, 
administered intramuscularly, is indicated for the adjunctive and palliative treatment of advanced 
endometrial or renal carcinoma.
Although TV-46046 has not been tested clinically, both Depo-Provera CI and Depo-subQ 104 
have well-characterized safety profiles. They have been marketed in more than 80 countries 
worldwide, including the US. In addition to the successfully completed Investigational New 
Drug (IND) and NDA applications, a significant nonclinical and clinical safety database has been 
established with more than 800 published citations.
1.3.1.
Nonclinical Studies
Depot medroxyprogesterone acetate/medroxyprogesterone acetate (DMPA/MPA) has been 
extensively investigated in a number of animal species. Consequently, the nonclinical 
pharmacology and toxicology profiles of DMPA/MPA have been well established. Published 
nonclinical pharmacological and toxicological studies from literature, including nonclinical 
pharmacology and toxicology/toxicokinetic activities of DMPA/MPA support the contraception 
indication, nonclinical pharmacokinetics, and expected safety profile of TV-46046.
The nonclinical drug metabolism, pharmacokinetics, and toxicology profiles have been described 
within published literature using both in vitro and in vivo models. These data are briefly 
summarized below, along with the studies conducted by Teva.
Details may be found in the current Investigator’s Brochure (IB).
1.3.1.1.
Nonclinical Studies Conducted by Teva
Teva’s current nonclinical safety program consists of 4 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).
Subcutaneous administration of TV-46046 at a 2- or 3-fold higher dose compared to 
Depo-subQ 104 resulted in similar or slightly higher plasma concentrations in female rabbits
(Study DP-2014-135 and Study DS-2015-009). A significant burst was not observed. The 
duration of exposure after a single dose of 208 mg of TV-46046 appears to be at least similar to 
2 injections of Depo-subQ 104 given 3 months apart.


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No significant injection site reactions (ISRs) occurred following treatment with TV-46046 
containing 0.15% docusate sodium sulfosuccinate (DSS) and 1.1% sodium sulfate anhydrous 
(SSA) (Study DS-2015-009). Furthermore, there were no significant injection site differences in 
microscopic findings between TV-46046 and Depo-subQ 104 (a comparator) at day 7 and 
day 90. The expected pharmacologic effects of MPA were observed for TV-46046 and 
Depo-subQ 104, through day 90 of a single-dose subcutaneous injection study in rabbits. The 
magnitude of some effects (eg, higher triglycerides, liver and adrenal findings) observed in the 
TV-46046 group was slightly greater compared to the group given Depo-subQ 104. 
Subcutaneous injection of TV-46046 in rabbits results in no new toxicities, when compared to 
the group given Depo-subQ 104. However, the slight increase in the magnitude of effects in the 
TV-46046 group correlates with the higher MPA exposure levels observed on study, as measured 
by Cmax (8.6 ng/mL), area under the plasma drug concentration by time curve from time 0 to 
day 6 (AUC0-6) (42.6 ng•day/mL), and area under the plasma drug concentration by time curve 
from time 0 to day 89 (AUC0-89) (504.3 ng•day/mL). No toxic effects were associated with 
TV-46046 excipients.
Results of GLP and non-GLP murine local lymph node assays indicated that the TV-46046 
formulation was not a contact sensitizer (Studies DS-2015-017 and DS-2014-064, respectively). 
In the GLP mouse lymph node assay, DSS in vehicle did not elicit a contact sensitizing reaction 
at up to an 8-fold higher concentration than the concentration of DSS used to formulate 
TV-46046 (which contains 0.15% DSS).
1.3.1.2.
Nonclinical Literature
In in vitro genotoxicity studies, DMPA/MPA was negative in bacterial and mammalian somatic 
cell lines. Chromosomal aberrations were noted in germ cells of dogs and hamsters given single 
doses of DMPA (Williams et al 1971, 1972).
In earlier rabbit and monkey repeat-dose studies, the toxicology of DMPA/MPA was fairly 
unremarkable (Jordan 1994). At high doses, DMPA had an apparent glucocorticoid effect 
causing reduced adrenal weights. Another consistent finding was the expected uterine atrophy. 
Effects unique to dogs included drug-induced mortality at relatively low multiples of the human 
dose, due primarily to pyometra/metritis, malignant mammary tumors, thrombosis, and 
infarction. Additionally, DMPA decreased erythrocyte, hemoglobin, and hematocrit levels, 
produced acromegaly with increased plasma growth hormone levels, and impaired glucose 
metabolism.
In long-term studies, female beagle dogs developed mammary gland tumors when treated with 
DMPA, and 2 of 16 rhesus monkeys developed endometrial cancer with doses 50 times higher 
than the dose required for contraception. Subsequent studies found that the initial carcinogenicity 
findings in dogs could be explained by differences between dog and human pituitary responses to 
MPA (Jordan 1994). In dogs but not humans, MPA causes increased pituitary growth hormone 
secretion, with the increases in growth hormone causing hypertrophic mammary glands and 
development of acromegaly. Because of these differences, it was determined that the beagle dog 
is an unsuitable model for assessing the long-term effects of progestogens in women
(World Health Organization [WHO] 1993). Also, differences in dose and bioavailability may 
explain differences in carcinogenicity between animals and women.


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When administered during pregnancy, DMPA/MPA masculinized female fetuses and feminized 
male fetuses of rats, monkeys, and baboons and caused cleft palate in rabbits and possibly mice, 
probably due to its glucocorticoid-like effects.
More recent publications pertaining to the safety of MPA have focused on the new concerns 
raised about the possibility that the users of DMPA might be more susceptible to sexually 
transmitted diseases than non-DMPA-treated individuals. A number of studies in mice have 
shown that DMPA treatment changes susceptibility and local immune responses to genital herpes 
simplex virus type 2 (HSV-2) infection. Pretreatment with DMPA has been shown to induce a 
prolonged diestrus state in mice with significant increases in susceptibility to genital HSV-2 
infection as well as suppression of immune responses following immunization (Kaushic et al 
2003). Those immunized mice subsequently treated with DMPA have shown decreases in local 
HSV-2-specific immunoglobulin (Ig) G and IgA in vaginal washes. Both male and female rhesus 
monkeys treated with DMPA had decreased protective efficacy following immunization (Abel et 
al 2004, Genesca et al 2007), indicating that MPA may affect both local and systemic immune 
responses. Some investigators have attributed increased viral transmission in DMPA-treated 
female animals to atrophied vaginal epithelium, as the thin epithelium might allow the virus to 
more easily penetrate the epithelial layer and/or establish infection in susceptible target cells 
under the epithelium (Hild-Petito et al 1998).
Based on the published literature and results of Teva’s GLP-compliant nonclinical studies, 
subcutaneous administration of TV-46046 in humans should have a safety profile similar to that 
of the FDA-approved Depo-subQ 104.
1.3.2.
Clinical Studies
This is the first in human (FIH) clinical study for TV-46046. However, an extensive body of 
pharmacokinetic and safety data is available through peer-reviewed literature and product 
labeling for Depo-subQ 104 and for Depo-Provera CI.
1.3.2.1.
Clinical Pharmacology Studies
Information pertaining to the absorption, distribution, metabolism and excretion of MPA 
following intramuscular and subcutaneous administration is summarized in their respective 
prescribing information (Depo-Provera CI US Prescribing Information and Depo-subQ 104 US 
Prescribing Information).
Due to physical characteristics, MPA is slowly absorbed following either route of administration. 
Depo-Provera CI, when administered intramuscularly at the recommended dose to women every 
3 months, inhibits the secretion of gonadotropins which, in turn, prevents follicular maturation 
and ovulation and results in endometrial thinning. These actions are primarily responsible for its 
contraceptive effect. Following a single 150 mg intramuscular injection of Depo-Provera CI to 
women between 19 to 33 years of age, MPA concentrations increased for approximately 3 weeks 
to reach peak concentrations of 1 to 7 ng/mL and then decreased exponentially until they became 
undetectable (<100 pg/mL) between days 120 to 200 post-injection (Depo-Provera CI US 
Prescribing Information 2016).
Serum MPA concentrations following a single subcutaneous injection of Depo-subQ 104 
reached greater than or equal to 0.2 ng/mL (the threshold considered sufﬁcient to exert a 
consistent contraceptive effect) within 24 hours and the mean time to maximum observed 


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plasma/serum drug concentration (tmax) was attained approximately 1 week after injection 
(Depo-subQ 104 US Prescribing Information). Jain et al. (2004) compared the pharmacokinetic
profile of Depo-subQ 104 and Depo-Provera CI and reported average Cmax of 1.56 ng/mL and 
3.73 ng/mL, mean half-life of 43 and 13 days, and AUC0-∞of 92.84 and 134 ng•day/mL, 
respectively. These data provide additional evidence that the subcutaneous route of 
administration provides lower peak levels and more sustained blood levels than the intramuscular 
route. This pharmacokinetic/pharmacodynamics study will evaluate the potential of TV-46046 to 
provide contraceptive protection when injected subcutaneously every 6 months.
1.3.2.2.
Clinical Safety Studies
Depot medroxyprogesterone acetate has a well-characterized safety profile on the basis of 
numerous clinical trials, post-marketing research and real life use by millions of women globally,
although its use is associated with a number of side effects that include but are not limited to:
disruption of menstrual bleeding patterns; decrease in bone mineral density (BMD); weight gain; 
and delayed return to ovulation and fertility. The use of Depo-subQ 104 is associated slightly 
higher rate of ISRs compared to the intramuscular formulation.
Several worldwide clinical studies have indicated that higher doses of Depo-Provera, when 
administered by intramuscular injection, are also safe and well-tolerated. 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 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 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 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).
1.4.
Known and Potential Benefits and Risks to Human Subjects
Additional information regarding benefits and risks to subjects may be found in the current IB.
1.4.1.
Benefits of TV-46046
All potential subjects will be tested for anemia to meet inclusion criterion “i” before being 
enrolled in the study. There will be no other direct benefit to the subjects. The results of this 
study may facilitate the development of a new longer-acting injectable contraceptive.
1.4.2.
Risks of TV-46046
Pregnancy
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 


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among study participants. Only women who are not pregnant, not wanting to become pregnant in 
the next 36 months, and who are at low risk of pregnancy because they are sterilized, in a 
same-sex relationship, have vasectomized partner, or use non-hormonal intrauterine device 
(IUD) (see Section 4 for Inclusion Criteria) will be enrolled in this FIH 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.
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 breast-feeding should not have their first 
injection until the sixth postpartum week (Depo-Provera CI US Prescribing Information 2016).
However, 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 (CDC 2011).
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 women 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 group (8%) than in the Depo-Provera CI group (0.4%), an expected finding with a 
subcutaneous route of administration (Kaunitz et al 2009).
The potential for local irritation of TV-46046 has not yet been clinically tested. In order to assess 
the potential of TV-46046 for local irritation, a GLP-compliant 9-month local tolerance study in 
rabbits (Study DS-2015-009) has been carried out by Teva. Based on the nonclinical data 
obtained to date, Teva does 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. The risk of 
ISRs will be carefully evaluated in this FIH study. For details, see the Study Procedures and 
Assessments table (Table 1).
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 3 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). The effect on bleeding pattern of a single 
subcutaneous administration of TV-46046 has not been clinically tested. Women with 


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unexplained vaginal bleeding or anemia (hemoglobin <10.5 g/dL) will not be eligible for the 
study. Changes in menstrual bleeding patterns and its acceptability will be evaluated at specified 
study visits. For details, see the Study Procedures and Assessments table (Table 1).
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 3 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). While the effect on weight of a single 
subcutaneous administration of TV-46046 has not been tested clinically, it is anticipated that it 
will be less than the weight gain associated with the chronic use of the approved 3-month 
contraceptives. Body weight will be assessed periodically throughout the study.
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 increased risk of HIV 
acquisition (Morrison et al 2015; Ralph et al 2015; Polis 2016) the data are inconsistent and 
causality has not been established. In light of the inconclusive evidence, the 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 FIH 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 STIs will be 
provided to all subjects in this study.
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; 
earliest return to ovulation was 6 months after the last injection; and 12 women (80%) ovulated 
within 1 year of the last injection. Subcutaneous administration of DMPA is associated with a 
delayed return to ovulation compared to the intramuscular route. Median time to return of 
ovulation after a single intramuscular injection of Depo-Provera CI (150 mg) and a single 
injection of 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).


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Return to ovulation and fertility after a single subcutaneous injection of TV-46046 has not been 
tested but is also likely to be delayed. Therefore, only women who are at low risk of pregnancy 
and who do not desire pregnancy for a minimum of 36 months will be enrolled in the study. All 
women will be followed to assess return of ovulation. For details, see the Study Procedures and 
Assessments table (Table 1).
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 BMD (Depo-subQ 104 US
Prescribing Information 2016). Bone loss is greater with increasing duration of use and may not 
be completely reversible. It is unknown if use of depo-subQ provera 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. Similar boxed warning was added to the Depo-Provera CI 
prescribing information.
Existing evidence indicate 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 this FIH study, any permanent adverse impact on BMD of a single administration of 
TV-46046, even at a higher dose of 300 mg, is unlikely. 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 FIH study.
Other
The clinical performance of TV-46046 has not been tested but it is likely to cause similar side 
effects as Depo-Provera CI or Depo-subQ 104.
According to the US Depo-subQ 104 and Depo-Provera CI labels, women with a strong family 
history of breast cancer should be monitored with particular care 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); 2 studies demonstrated the statistically 
significant increased risk of breast cancer among recent DMPA users (Li et al 2012, Paul et al 
1989).
Infrequent reports of anaphylaxis and anaphylactoid reaction have been received associated with 
the use of Depo-Provera CI. Subjects in this FIH study will remain at the investigational center 
for observation for at least 15 minutes after the injection and receive counseling of possible signs 


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of anaphylactic reaction prior to leaving the investigational center. The investigational centers 
will have EpiPen®2 (epinephrine injection) on hand and easy access to emergency care of 
necessary in the unlikely event of an anaphylactic reaction with TV-46046.
Additional information regarding risks and benefits to human subjects may be found in the 
current IB.
1.5.
Selection of Drugs and Doses 
The proposed 2-part dose-range finding study will evaluate the potential of TV-46046 to provide 
contraceptive protection when injected subcutaneously every 6 months. The study will consist of 
2 parts. In Part 1, exploratory pharmacokinetics, the pharmacokinetics of MPA following a 
single subcutaneous injection of 120 mg TV-46046 at up to 3 different concentrations (0.3 mL of 
400 mg/mL, 0.4 mL of 300 mg/mL, and 0.6 mL of 200 mg/mL) will be evaluated. In Part 2, 
dose-range finding, the pharmacodynamics and pharmacokinetics of MPA after a single 
subcutaneous injection in the abdomen of undiluted TV-46046 at up to 3 additional dose levels 
within the range of 80 to 300 mg, which will be selected on the basis of the results in Part 1.
A detailed description of study drug administration is presented in Section 5.1.
Justification for Dose of Active Drug
The decision to move into Part 2 will be based on predicted pharmacokinetic parameters for a 
range of potential Part 2 doses, as informed by observed Part 1 pharmacokinetic data. Part 2 will 
only be implemented if the administration of undiluted TV-46046 (400 mg/mL) in Part 1 
demonstrates an appropriate pharmacokinetics profile (eg, predicted mean Cmax less than 
3 ng/mL, predicted time to achieve 0.2 ng/mL no more than 24 hours after study drug 
administration for all subjects, predicted 6-month concentration greater than 0.1 ng/mL in 95% 
of subjects, and predicted concentration 24 months after the last injection below 0.1 ng/mL in 
90% of subjects, for all treatment groups selected for Part 2). The 3 dose levels selected for 
Part 2 will depend on results of Part 1, and will be within the dose range of 80 to 300 mg.
A dose range of 80 to 300 mg is believed to be sufficiently broad to identify a safe dose of 
TV-46046 that will provide sustained blood levels of MPA sufficient for a contraceptive effect 
(ie, suppression of ovulation) when administered subcutaneously every 6 months. The maximum 
dose of 300 mg is defined by the goal of this project to develop a highly effective 6-month MPA 
contraceptive product administered subcutaneously at a dose not exceeding the highest total dose 
of 300 mg of an FDA-approved injectable DMPA product for intramuscular use when used for 
6 months (ie, two 3-month injection cycles of Depo-Provera CI, 150 mg/mL each).
The minimum dose of 80 mg is partially informed by the pharmacokinetic and 
pharmacodynamics data for MPA generated in the dose-range finding study for Depo-subQ 104 
(NDA 21-583; Study No. 265) that suggest the potential for contraceptive effectiveness of MPA 
for longer than 3 months at doses as low as 100 mg when given subcutaneously. In addition, the 
                                                
2 EpiPen is a registered trademark of Mylan Inc.


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use of Depo-subQ 104 was associated with complete suppression of ovulation between days 93 
and 150 following a single injection in 60 women (93%) in 1 study (see in MHRA Public 
Assessment Report 2015) and 90% suppression for 150 days among 39 women in another study 
(Jain et al 2004). On the basis of limited clinical data demonstrating a slower rate of 
intramuscular absorption with a higher concentration of MPA (Wright III et al 1983), MPA from 
the undiluted TV-46046 (400 mg/mL) may be absorbed more slowly than from Depo-subQ 104 
(160 mg/mL). This also has been suggested by animal data in rabbits showing that a 3-fold 
higher dose administered subcutaneously as TV-46046 resulted only in 50% higher MPA plasma 
exposure compared to Depo-subQ 104 through study day 90 (Study DS-2015-009). Hence, if the 
release pattern of MPA following the subcutaneous administration of TV-46046 in humans is 
similar to that observed in rabbits, it is possible that TV-46046 at a dose even lower than 100 mg 
will provide efficacious levels of MPA, and, therefore suppress ovulation for 6 months.
1.6.
Compliance Statement
This study will be conducted in full accordance with the International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (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, European Union [EU] Directive 2001/20/EC on the 
approximation of the laws, regulations and administrative provisions of the Member States 
relating to the implementation of GCP in the conduct of clinical trials on medicinal products for 
human use). Any episode of noncompliance will be documented.
The investigator is responsible for performing the 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 study in 
accordance with the protocol will be documented in separate study agreements with the sponsor 
and other forms as required by national 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 study and must ensure that trained personnel are immediately available in 
the event of a medical emergency. The investigator and the applicable study staff must be 
familiar with the background to, and requirements of, the study and with the properties of the 
study drug(s) as described in the IB or prescribing information.
The principal investigator at each investigational center has the overall responsibility for the 
conduct and administration of the study at that center and for contacts with study management, 
with the Independent Ethics Committee/Institutional Review Board (IEC/IRB), and with local 
authorities.
1.7.
Study Population and Justification
The study will enroll healthy women 18 to 40 years of age, inclusive, who are at low risk of 
pregnancy (ie, sterilized, in exclusively same-sex partnership, in monogamous relationship with 
vasectomized partner, using non-hormonal IUD), and who are confirmed to have ovulated during 
the pre-treatment phase of the study.


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1.8.
Location and Duration of Study 
This 2-part study is planned to be conducted in up to 5 investigational centers. For Part 1, the 
study is planned to be conducted at 1 to 2 investigational centers in the US. An additional 
US-based investigational center will only be considered if necessary to accomplish enrollment in 
a timely fashion. For Part 2, up to 3 more investigational centers will be added (at least two in 
Latin America). The expected duration of the 2-part study is from November 2016 (first subject 
screened) to November 2019 (last subject last visit). The number of investigational centers and 
expected duration of the study may be modified dependent on enrollment speed and other 
factors.


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2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES
2.1.
Purpose of the Study
The purpose of this pharmacodynamic and pharmacokinetic study is to identify a dose of 
TV-46046 (within the range 80 to 300 mg) that is both safe and consistent with a high degree of 
contraceptive efficacy when injected every 6 months.
2.2.
Study Objectives
2.2.1.
Primary Objectives
This Phase 1 study has a data-driven, 2-part design: an exploratory pharmacokinetics component 
(Part 1) and a dose-range finding component (Part 2). The primary objective of Part 1 is to assess 
the pharmacokinetics of MPA following a single subcutaneous injection of undiluted and 
saline-diluted 120 mg TV-46046. This information will be used to inform up to 3 dose levels of 
undiluted TV-46046 and the study size for the dose-range finding component (Part 2) of the 
study, or to select a drug concentration for further investigation, if undiluted TV-46046 does not 
exhibit an appropriate pharmacokinetic profile.
The primary objective of Part 2 is to evaluate the pharmacodynamics of MPA after a single 
subcutaneous injection in the abdomen of undiluted TV-46046 at up to 3 additional dose levels 
(where pharmacodynamics response is defined as suppression of ovulation determined through 
serum progesterone concentrations).
2.2.2.
Secondary Objectives
The secondary objectives of the study (relevant to both Part 1 and Part 2) are the following:

To characterize the pharmacokinetics of up to 3 dose levels of undiluted TV-46046

To evaluate the relationship between serum MPA concentration and return to 
ovulation

To evaluate the safety of a subcutaneous injection of TV-46046 over the range of 
different doses and concentrations

To evaluate the acceptability of a subcutaneous injection of TV-46046 over the range 
of different doses and concentrations
2.3.
Study Endpoints
2.3.1.
Primary Endpoints
In Part 1 (exploratory pharmacokinetics), the primary endpoints are individual and mean serum 
MPA concentration-time profiles measured during follow-up visits, and estimated 
noncompartmental pharmacokinetics parameters, including but not limited to Cmax, tmax, observed 
serum drug concentration at day 182 (C182), area under the serum drug concentration by time 
curve from time 0 to day 182 (AUC0-182), AUC0-∞, and apparent terminal half-life.


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In Part 2 (dose-range finding), the primary endpoint is time to ovulation, where ovulation is 
defined as a single elevated serum progesterone (P ≥4.7 ng/mL) measured during follow-up 
visits.
2.3.2.
Secondary Endpoints
In Part 2, secondary endpoints include pharmacokinetics of MPA based on individual and mean 
serum MPA concentration-time profiles and estimated noncompartmental pharmacokinetics 
parameters, including but not limited to Cmax, tmax, C182, observed serum drug concentration at 
day 210 (C210), AUC0-182, area under the serum drug concentration by time curve from time 0 to 
day 210 (AUC0-210), AUC0-∞, and apparent terminal half-life. In addition, release rates, relative 
bioavailability, and other pharmacokinetic parameters derived from non-linear mixed model 
compartmental analysis of MPA concentrations over time will be reported.
2.3.3.
Safety Endpoints
The safety endpoints for this study are as follows:

change in vital signs

change in body weight

delayed return to ovulation (ie, >52 weeks after start of study drug treatment)

occurrence of adverse events

change in menstrual bleeding patterns

change in mood (Part 2 only)

change in liver function tests (Part 2 only)

use of concomitant medications

occurrence of ISRs
2.3.4.
Acceptability Endpoints
Acceptability will be evaluated based on subject’s responses to acceptability questions including 
but not limited to, questions about injection pain, ISRs, and menstrual bleeding patterns; and on 
the study staff’s assessment of the ease of the injection.


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3.
STUDY DESIGN
3.1.
General Design and Study Schematic Diagram
This is a 2-part study to evaluate the pharmacokinetics and pharmacodynamics of MPA in 
healthy female subjects after a single subcutaneous injection of TV-46046. Prior to injection, 
ovulation will be confirmed in all subjects by measuring serum progesterone approximately 
twice a week during the approximately 2 to 3 weeks preceding expected menses. Twelve 
subjects (6 per treatment group) with confirmed ovulation and who meet all other eligibility 
criteria will be admitted to Part 1 and will be assigned sequentially to receive a single 
subcutaneous injection in the abdomen of 120 mg TV-46046 at 1 of the 2 concentrations: 0.3 mL 
of undiluted 400 mg/mL (initial 6 women forming treatment group 1) or 0.6 mL of saline-diluted 
200 mg/mL (next 6 women forming treatment group 2). Depending on the results, a 3rd treatment 
group may subsequently be enrolled to receive a single subcutaneous injection of 120 mg TV-
46046 at a concentration of 300 mg/mL (0.4 mL) (saline-diluted).
An interim pharmacokinetic analysis is planned to inform the decision to move into Part 2 and 
will be performed after all subjects in treatment group 1 (ie, the first 6 women receiving 
undiluted TV-46046) in Part 1 have had a chance to complete at least 4 months (17 weeks) of 
treatment. At that time, available pharmacokinetic data from women in treatment group 2 (ie, the 
next 6 women receiving diluted TV-46046) will also be analyzed. Additional assessments will be 
made if warranted (eg, when 12 women [in both the undiluted and diluted groups] complete 
4 months [17 weeks]). The decision to move into Part 2 will be based on predicted 
pharmacokinetic parameters for a range of potential Part 2 doses, as informed by observed Part 1 
pharmacokinetic data. Part 2 will only be implemented if the administration of undiluted 
TV-46046 (400 mg/mL) in Part 1 demonstrates an appropriate pharmacokinetic profile. Other 
features of the undiluted drug may also enter the decision-making, including stability, 
re-suspendability, syringeability and safety.
Pharmacokinetic criteria considered before moving into Part 2 include: predicted mean Cmax less 
than 3 ng/mL, predicted time to achieve 0.2 ng/mL no more than 24 hours after study drug 
administration for all subjects, predicted 6-month concentration greater than 0.1 ng/mL in 95% 
of subjects, and predicted concentration 24 months after the last injection below 0.1 ng/mL in 
90% of subjects, for all treatment groups selected for Part 2.
If the undiluted formulation exhibits a promising pharmacokinetic profile per the criteria 
described above, then a dose-range finding component of the study (Part 2) will be initiated and 
up to 60 additional subjects (up to 20 subjects per treatment group) will be randomized to receive 
a single subcutaneous injection of up to 3 recommended doses of undiluted TV-46046 within the 
range of 80 to 300 mg. The selection of specific doses and number of subjects per TV-46046 
dose in Part 2 will be informed by pharmacokinetic analysis and modeling of interim Part 1 data. 
If a diluted concentration of 200 mg/mL of TV-46046 exhibits a more promising 
pharmacokinetics profile, then Part 2 of the study will not be initiated. In that event, a clinical 
formulation of a diluted concentration may be developed and tested in a separate protocol under 
an amended IND.


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If the results of Part 1 indicate that information on an intermediate concentration of TV-46046 is 
necessary to inform the TV-46046 development program, then 6 additional subjects will be 
enrolled in Part 1 as treatment group 3, to receive a subcutaneous injection of 120 mg TV-46046 
at 0.4 mL of 300 mg/mL saline-diluted concentration. Study procedures for the 6 subjects in 
treatment group 3 of Part 1 would be the same as for the other treatment groups. The data-driven 
decision to add a treatment group to Part 1 minimizes subject numbers and balances the need for 
more information on pharmacokinetics with an alternative dilution.
If interim analysis of Part 1 data indicates that neither undiluted nor diluted TV-46046 is 
appropriate for further testing, then all subjects enrolled in Part 1 may be discontinued early, 
with only post-discontinuation follow-up visits for safety purposes.
Study participation will consist of a screening and pre-treatment phase (approximately 1 month, 
or 4 weeks), a treatment phase (6 months, or 26 weeks), and post-treatment follow-up (an 
additional 6 to 12 months). During the pre-treatment phase ovulation will be confirmed in all 
subjects who are otherwise eligible for the study by measuring serum progesterone
approximately twice a week (preferably 3 days apart) during the approximately 2 to 3 weeks 
preceding expected menses. Enrolled subjects will receive an injection of the study drug and then
be followed for at least 12 months (52 weeks) to characterize pharmacodynamics and 
pharmacokinetics of MPA (ie, 6 months of treatment plus 6 months of post-treatment follow-up), 
regardless of earlier return to ovulation. 
During the study, subjects will provide blood samples for serum progesterone, estradiol, and 
MPA at frequent pre-defined time points (see Table 1 for the study procedures and assessments).
In addition to frequent laboratory visits to collect blood samples, there will be 3 scheduled 
follow-up visits: at day 7, month 3 (13 weeks), and month 7.5 (32 weeks) after start of study 
drug treatment, during which subjects will be weighed and evaluated for ISRs, vital signs, and 
acceptability. Injection sites will be observed for ISRs on days 0 (within 10 minutes and within 
the 1st hour after injection), 1, 2, 3, and 5; at 3 scheduled follow-up visits (at day 7, week 13, 
week 32); at the final study visit, and at other visits, if indicated. The subject’s menstrual 
bleeding patterns will be obtained by an interview questionnaire at monthly intervals (in Part 1 
only), by weekly diary completed by the subjects on-line (in Part 2 only), and at follow-up visits 
(month 3 and month 7.5 only), and the final study visit. In Part 2 only, liver function will be 
assessed by tabulating and graphing change in liver function tests including but not limited to 
ALT and AST, from screening to week 13 (month 3), week 32 (month 7.5), and final study visit. 
In Part 2 only, mood will be assessed in frequency tables at screening and at week 13 (month 3), 
week 32 (month 7.5), and final study visits. Information on adverse events and concomitant 
medicines will be collected throughout the study. The study staff will provide assessment on the 
ease of the injection.
Subjects in whom ovulation does not return by month 12 (week 52) after initiation of treatment 
will be monitored by less frequent measurements of serum progesterone, estradiol, and MPA 
until ovulation returns for safety reasons for up to another 26 weeks (up to a total of 78 weeks 
from the injection of study drug).
The assessments and procedures performed during each study visit are detailed in Table 1 and
Section 3.14.


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Part 1 is planned to be conducted at a single investigational center: Women’s Health Clinical 
Research Center, University of Pennsylvania. An additional US-based center may be considered 
if necessary to accomplish enrollment in a timely manner. Up to 4 additional investigational 
centers will be added for Part 2 including Eastern Virginia Medical School in the US, Instituto 
Chileno de Medicina Reproductiva (ICMER) in Chile and the Biomedical Research Department 
with Profamilia in the Dominican Republic (Profamilia).
An independent Data and Safety Monitoring Board (DSMB) will oversee both parts of the study
(see Section 3.8.3).
The study schematic diagram is presented in Figure 2.


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Figure 2:
Overall Study Schematic Diagram
PART 1
Screening and 
pre-treatment phase
↓
Treatment phase
12 subjects (total)
↓
Treatment group1 (6 subjects) 
120 mg undiluted TV-46046 
(0.3 mL of 400 mg/mL)
↓
Treatment group 2 (6 subjects) 
120 mg saline-diluted TV-46046 
(0.6 mL of 200 mg/mL)
↓
Treatment group 3 (if warranted) 
(6 subjects) 
120 mg saline-diluted TV-46046 
(0.4 mL of 300 mg/mL)
↓
Follow-up
↓
PART 2
(dependent on Part 1 results and up 
to 60 additional subjects)
Treatment group 4 
(up to 20 subjects) 
low dose TV-46046 
(X.X mL of 400 mg/mL)
Treatment group 5 
(up to 20 subjects) 
mid-dose TV-46046 
(X.X mL of 400 mg/mL)
Treatment group 6 
(up to 20 subjects) 
high-dose TV-46046 
(X.X mL of 400 mg/mL)
X.X=will be determined on the basis of Part 1 results. Part 2 will include up to 3 additional groups, depending on 
Part 1 results.
3.2.
Justification for Study Design
The pharmacokinetic profile of MPA following subcutaneous injection of TV-46046 in humans 
is not known. The exploratory pharmacokinetics component (Part 1) will allow assessment of the 
pharmacokinetics profile of TV-46046 at 2 different concentrations (400 mg/mL and 
200 mg/mL) in humans because injection volume may be a covariate in the release rate as 
characterized by the pharmacokinetics profile. If undiluted TV-46046 has an acceptable 
pharmacokinetics profile (based on predicted mean Cmax less than 3 ng/mL, predicted time to 
achieve 0.2 ng/mL no more than 24 hours after study drug administration for all subjects, 
predicted 6-month concentration greater than 0.1 ng/mL in 95% of subjects, and predicted 
concentration 24 months after the last injection below 0.1 ng/mL in 90% of subjects, for all 


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treatment groups selected for Part 2), then the data will be used to select up to 3 additional dose 
levels of TV-46046 for the dose-range finding component (Part 2) of the study. This 
conservative, staged approach provides an assessment of the formulation following a TV-46046 
dose of 120 mg before exploring a full range of doses of TV-46046 of up to 300 mg.
If undiluted TV-46046 does not exhibit an appropriate pharmacokinetic profile for dose-range 
finding, then Part 2 of the study will not be initiated. In that case, treatment group 3 of Part 1 
may be enrolled to inform the TV-46046 development program further. If saline-diluted 
TV-46046 is associated with a more promising pharmacokinetics profile, then a less 
concentrated product formulation may be developed and tested in a separate protocol under an 
amended IND.
3.3.
Pharmacokinetic Measures and Time Points
The primary pharmacokinetics measure is serum MPA concentration. For Part 1, blood samples 
for measurement of serum concentrations will be obtained on days 0 (baseline), 1, 2, 3, 5, 7, 10, 
12, 14, 18, 21, 28, 35, and 42; weeks 8, 10, 12, 13, 15, 17, 19, 21, 23, 25, 26, 28, 30, and 32; and 
then every 28 days until week 52, regardless of ovulation status.
Among subjects in whom ovulation has not returned by month 12 (week 52), blood samples for 
MPA will be tested up to 2 more times (once at week 61 and once at week 74), but not past 
return to ovulation. The sampling schedule and duration of MPA testing may be modified based 
on accumulating data for a more accurate characterization of the pharmacokinetic profile of 
TV-46046. In addition, blood samples will also be collected and stored for possible future MPA 
testing (if necessary) at all weekly visits when samples are collected for serum progesterone and 
estradiol, except for pre-treatment visits and visits for confirmation of ovulation.
3.4.
Pharmacodynamic Measures and Time Points
The primary pharmacodynamics measure is serum progesterone concentration. Blood samples 
for measurement of progesterone and estradiol will be obtained as follows: on day 0 (baseline); 
then at day 7 and then weekly through week 32, regardless of ovulation status. If ovulation does 
not return by week 32, then weekly blood samples for serum progesterone and estradiol will 
continue to be collected until ovulation or through week 52, whichever is earlier. If there is no 
ovulation by week 52, then blood samples for serum progesterone and estradiol will be collected 
weekly between weeks 61 through 65 and between weeks 74 through 78, but not past return to 
ovulation.
At any time point during follow-up, a subject with progesterone ≥3.0 ng/mL will be asked to 
return within 5 days for repeated progesterone measurement to ensure close monitoring of the 
potential post-ovulatory rise of progesterone. If the repeated measurement within 5 days is at or 
below 3.0 ng/mL, the subject will continue follow-up per her visit schedule. At any time point
during follow-up, a subject with initial progesterone ≥4.7 ng/mL will be asked to return within 
5 days for repeated progesterone measurement for more accurate ascertainment of ovarian 
function.
Estradiol will be measured at the same time points as progesterone as a supporting 
pharmacodynamics measure.


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3.5.
Safety Measures and Time Points
The following safety measures will be implemented throughout the study:

vital signs (blood pressure [BP; systolic/diastolic], pulse, and respiration) on the 
day 7, and week 13 (month 3), and week 32 (month 7.5) visits, and at the final study 
visit

data on menstrual bleeding pattern by interview monthly interval during scheduled 
laboratory visits (in Part 1 only), as well as at the week 13 (month 3), week 32 
(month 7.5), and final visits

in Part 2 only: 

in addition to the scheduled and final visits, menstrual bleeding data weekly via 
an on-line diary

data on mood at the week 13 (month 3), week 32 (month 7.5), and final study 
visits

liver function testing at the week 13 (month 3), week 32 (month 7.5), and final 
study visits

body weight on day 7, and the week 13 (month 3) and week 32 (month 7.5) visits;
and at the final study visit

delayed return to ovulation (ie, >12 months [>52 weeks] after start of study drug 
treatment)

occurrence of adverse events throughout the study

use of concomitant medications throughout the study

ISRs immediately after the injection (within 10 minutes), within the 1st hour, at 
days 1, 2, 3, 5, and 7, at the week 13 (month 3) and week 32 (month 7.5) visits; and at 
the final study visit; and at other visits, if indicated.
3.6.
Acceptability Measures and Time Points
Acceptability of subcutaneous administration of different dose/volumes of TV-46046 will be 
assessed through acceptability interview questionnaire on the day of injection during the 
enrollment/injection visit, at the scheduled follow-up visits (day 7, month 3, and month 7.5) and 
at the final study visit. In addition, the ease of performing the injection will be assessed through 
responses provided by the study staff performing the injection during the enrollment/injection 
visit. Acceptability of the menstrual bleeding patterns will be assessed through responses by 
subjects obtained by an interview questionnaire at monthly intervals during scheduled laboratory 
visits (in Part 1 only); at scheduled follow-up visits (except day 7); and at the final study visit.
3.7.
Randomization 
In Part 1 (exploratory pharmacokinetics), 12 subjects (6 subjects per concentration of TV-46046) 
will be sequentially enrolled. Random assignment will not be performed.


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If the results from Part 1 indicate that information on an intermediate concentration of TV-46046 
is necessary to inform the TV-46046 development program, then 6 additional subjects will be 
enrolled in Part 1 as treatment group 3, to receive a subcutaneous injection of 120 mg TV-46046 
at 0.4 mL of 300 mg/mL saline-diluted concentration.
In Part 2 (dose-range finding), from up to 3 additional doses will be studied, depending on the 
interim results of Part 1. The treatment allocation ratio will depend on the number of doses 
selected for study, and whether or not the 120 mg dose of undiluted TV-46046 is selected for 
inclusion. If only 1 dose is selected for Part 2, no randomization will be done. If more than 
1 dose is selected, including the 120 mg dose, then up to 12 subjects will be randomized to that 
group, and up to 18 subjects will be randomized to each of the other selected treatment groups
(2:3:3 ratio). If the 120 mg dose is not selected for inclusion in Part 2 then the allocation ratio 
will be balanced (1:1 or 1:1:1) at each investigational center, with up to 18 subjects randomized 
to each treatment group. In addition, 2 subjects with a body mass index (BMI) ≥40 will be 
separately randomized into each treatment group (equaling a total of 20 subjects in each 
treatment group in Part 2) for exploratory analyses of the effect of extreme obesity on 
pharmacokinetics of MPA. Randomization will be stratified on investigational center, using 
appropriate random block sizes to minimize imbalance with respect to the overall target 
allocation ratio at each planned interim and final analysis. The randomization sequence will be 
developed by a qualified FHI 360 Randomization Statistician not otherwise involved in the study 
using a validated program written in SAS®.
No enrolled subjects who have received a study drug injection will be replaced in either part of 
the study. However, enrollment may be expanded if more than 10% of subjects discontinue (or 
are predicted to discontinue) before week 52 from start of study drug treatment, have detectable 
levels of MPA at enrollment, or have protocol violations identified that may adversely affect 
assessment of pharmacokinetics or pharmacodynamics. Any decision to expand enrollment will 
be informed by recommendations from the DSMB, and will be implemented so as to preserve the 
validity of randomization-based inferences using the same allocation ratio.
Part 1 is not blinded. Part 2 is subject-blinded, with some but not all study staff blinded to the 
study drug assignment.
3.8.
Maintenance of Randomization and Blinding
3.8.1.
Maintenance of Randomization
In Part 2 of the study, sequentially-numbered opaque randomization envelopes matching the 
randomization sequence will be provided to the investigational centers. Each envelope will have 
the randomization number printed on the outside, with the corresponding treatment group 
assignment concealed within the envelope. The randomization envelopes will be maintained in a 
secure office, with access limited to designated investigational center staff. The next available 
randomization number will be assigned to each subject only after she has been enrolled into the 
study. Randomization in Part 2 will be stratified on investigational center.
3.8.2.
Blinding/Unblinding
Investigational center-specific details of how randomization and allocation concealment are 
maintained in Part 2 of the study will be documented in the Study Manual. Briefly, study staff 


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who retrieve and open randomization envelopes may also administer the study drug injection but 
will not have any additional role on the study. Study staff will document treatment assignments 
in a log, securely store the log and randomization envelopes, and restrict access to this 
information to necessary study staff and clinical monitors.
Part 2 will be a subject-blinded study. The clinical staff who administers injections will not be 
blinded due to differences in preparation of the dose and volume of the study drug. However, in 
order to minimize potential bias with regard to the assessment of subjective outcomes (eg, pain at 
injection, ISR) all efforts will be made to keep the subjects and study staff conducting follow-up 
interviews and completing case report forms (CRFs), unaware of treatment assignments. The 
clinical staff providing the injections will be trained to shield the syringe from view of the 
subject or any other study staff prior to and at the time of injection. Ideally, clinical staff 
providing the injection should not be involved in any other study procedures.
The medical monitors responsible for reviewing and grading adverse events, and laboratory staff 
analyzing specimens will be fully blinded. The Coordinating Investigator, pharmacologists, 
study clinician, statisticians, and other essential study staff will be un-blinded at the group level 
following formal interim analyses of Part 2 data to inform project development. These reviews of 
unblinded data will take place independently of the DSMB reviews described in the section
below. Individual treatment assignments will also be made available to study medical monitor 
should it be necessary to inform medical treatment of the subjects. The number of personnel who 
are un-blinded while the study is ongoing will be kept as small as feasible, and the potential 
implications of un-blinding on study conduct and interpretation of study data will be described in 
the clinical report. Further details of blinding and un-blinding procedures are provided in the 
separate statistical analysis and DSMB operational plans.
3.8.3.
Data and Safety Monitoring Board
During the conduct of this study, an independent DSMB will review accumulating 
pharmacodynamics, pharmacokinetic, and safety data to ensure the continuing safety of the study 
subjects and the integrity of the study.
The DSMB will consist of 3 members, including at least 1 clinician with expertise in hormonal 
contraception. The DSMB will meet once before the study begins and at 2 or more scheduled 
points during the study (Section 8.10). There will be both an open and closed session at each 
DSMB meeting where study data are reviewed. During open sessions, representatives of the 
sponsor (Teva) and the Study Monitor (FHI 360) may be present and information is provided and 
discussed in a blinded fashion. During closed sessions, only the DSMB members, the DSMB 
Executive Secretary (to take notes only), and an independent analyst (possibly a clinical 
pharmacologist or statistician) will be present to discuss results by treatment group. Details of 
the DSMB procedure and responsibilities are documented in a separate DSMB Operational Plan.
If there is a request to unblind any treatment assignment, a written request from the DSMB (as a 
committee), signed by the DSMB chairperson, should be made to the unblinded statistician. The 
appropriate medical and operational personnel will be notified but will not receive the unblinded 
treatment information. Any use of unblinded treatment assignments should be clearly 
documented and reported to the sponsor at study termination.


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The DSMB chairperson will communicate with the sponsor in regard to issues resulting from the 
conduct and clinical aspects of the study. The sponsor will work closely with the committee to 
provide the necessary data for review.
The conduct and specific details regarding the DSMB sessions and requests to unblind any 
treatment assignment are outlined in the DSMB charter.
3.9.
Drugs Used in the Study
TV-46046 (MPA injectable suspension, 400 mg/mL) for subcutaneous injection (TV-46046) will 
be provided by the sponsor as a sterile suspension at concentration of 400 mg per 1 mL. In Part 1 
of the study, TV-46046 will be used at up to 3 different concentrations: 0.3 mL of 400 mg/mL 
(undiluted), 0.4 mL of 300 mg/mL (saline-diluted) (if warranted), and 0.6 mL of 200 mg/mL
(saline-diluted). To obtain lower concentrations the 400 mg/mL TV-46046 will be diluted with 
sterile saline by the investigational center pharmacist following the sponsor’s recommendations. 
In Part 2 of the study, only undiluted TV-46046 will be administered at up to 3 additional doses
between 80 to 300 mg.
Each TV-46046 dose will be presented in a 3 mL United States Pharmacopeia (USP) Type 1 
clear glass vial, 13-mm rubber stopper, and 13-mm aluminum seal covered with a green cap 
(STERI-TAMP®3 single-use tamper evident sticker). The study drug product is to be 
administered with a 23 gauge, 3/8 inch safety needle. Additional details may also be found in the 
current IB for TV-46046.
A brief description of dilution and administration procedures is provided in Section 5.1.
This is an uncontrolled study with no other study drug.
3.10.
Drug Supply and Accountability
3.10.1.
Drug Storage and Security
The study drug consists of TV-46046 vials, saline vials, and 23 gauge 3/8” syringes. TV-46046 
should be stored at controlled room temperature 20 to 25°C (68 to 77°F). All components 
including the saline vials and syringes 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.
3.10.2.
Drug Accountability
Each study drug shipment will include a packing slip listing the contents of the shipment, drug 
return instructions, and any applicable forms. The center investigator or designee will 
acknowledge receipt of clinical study products indicating shipment content and condition and 
follow drug accountability procedures throughout the study.
                                                
3 STERI-TAMP is a registered trademark of STERI-TAMP, LLC.


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Drug accountability includes maintaining accurate records, including 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 also responsible for 
daily temperature monitoring and safe storage of the study products. Empty and partially used 
containers of study drug 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 study drug, the study drug will be disposed 
of, retained, or returned to the sponsor or designee per FHI 360 instructions.
Only authorized investigational center personnel will administer study product and only to 
participants enrolled into this study.
The center investigator is responsible for ensuring that deliveries of study drug and other study 
materials from the sponsor are correctly received, recorded, handled, and stored safely and 
properly in accordance with the CFR or national and local regulations, and used in accordance 
with this protocol.
3.11.
Duration of Subject Participation and Justification
This study will consist of a pre-treatment period of approximately 1 month, a treatment period of 
6 months (26 weeks), and a post-treatment follow-up period of up to 12 months (up to 
52 weeks). If subjects have not ovulated by 12 months (week 52) they may be followed-up until 
return to ovulation or week 78. If Part 2 of the study is not initiated, participation in Part 1 of the 
study may be as short as approximately 7 months, or 30 weeks (approximately 1 month of 
pretreatment and 6 months of treatment). If Part 2 is initiated, minimal participation in the study 
for each subject is approximately 13 months, or 56 weeks (1 month of pre-treatment, 6 months of 
treatment plus 6 months of post-treatment follow-up); maximum participation in the study should 
not exceed 19 months, or approximately 82 weeks (1 month of pre-treatment, 6 months of 
treatment plus a maximum of 12 months of post-treatment follow-up). See Section 11.4 for the 
end of study definition.
3.12.
Stopping Rules and Discontinuation Criteria
There are no formal rules for early termination of the study due to apparent effectiveness or lack 
of effectiveness of TV-46046. However, Part 2 will not be initiated if undiluted TV-46046 does 
not exhibit an appropriate pharmacokinetic profile for moving into dose-range finding. This 
determination is intended to be made after all subjects enrolled in treatment group 1 of Part 1 (ie, 
6 subjects receiving undiluted TV-46046) have had a chance to complete at least 4 months
(17 weeks) of follow-up, but the timing may be modified based on accumulating data (eg,
additional review of the data for all 12 women [in both undiluted and diluted groups] when they 
complete 4 months [17 weeks] may be needed). Criteria for initiating Part 2 include a predicted 
mean Cmax less than 3 ng/mL, predicted time to achieve 0.2 ng/mL no more than 24 hours after 
study drug administration for all subjects, predicted 6-month concentration greater than 
0.1 ng/mL in 95% of subjects, and predicted concentration 24 months after last injection below 
0.1 ng/mL in 90% of subjects, for all treatment groups selected for Part 2.


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The study may also pause enrollment or stop early due to concerns for safety of subjects. In 
particular, the investigational center will be advised to pause enrollment if at any time 2 or more
subjects in Part 1 are diagnosed with severe ISR (ie, graded as Grade 3 or higher using the 
Division of Acquired Immune Deficiency Syndrome (Division of AIDS; DAIDS) Table for 
Grading Adult and Pediatric Adverse Events; see Appendix A), if severe ISRs are reported for 
2 injections in a particular treatment group among all investigational centers in Part 2, or if 5 or 
more severe ISRs have occurred at any time across all treatment groups and investigational 
centers in Part 2. Such occurrences will trigger an unplanned review of interim data by the 
DSMB, at which time a recommendation to halt the study, to reinitiate enrollment with continued 
careful monitoring of ISRs, or to drop one or more groups for safety (including the occurrence of 
dose-limiting toxicities in Part 2) will be made. Other planned data reviews will likewise take 
place at regular intervals (see Section 8.10), at which time the DSMB could advise that the study 
stop or be modified based on concerns for safety of subjects.
Since TV-46046 is 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 at least until safety
assessments are completed (including delayed return to ovulation). 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. The final 
follow-up visit procedures should be completed in all subjects who discontinue early, if possible. 
Reasons for discontinuation from the study will be recorded on the appropriate CRF.
Others reasons the study may be stopped include:
•
The sponsor decides to reduce the scope (eg, reduce sample size, drop one or more study 
groups) or discontinue the study (eg, due to noncompliance with protocol or regulatory 
requirements, feasibility, etc.). 
•
FHI 360’s Protection of Human Subjects Committee (PHSC) recommends to terminate 
the study
•
Local IRB(s) recommend to terminate the study
•
The FDA requests that the study be discontinued or placed on hold.
3.13.
Source Data Recorded on the Case Report Form
Subject data should have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed to the CRF; data will not be recorded directly on the case 
report form (CRF) and considered as source data unless FHI 360 provides written instructions 
specifying which data are permitted to be recorded directly to the CRF (eg, subject’s responses to 
interview questions about menstrual bleeding patterns and acceptability).
If data are processed from other institutions or means (eg, clinical laboratory, central image 
center, or on-line diary data), the results will be sent to the investigational center, where they will 
be retained but not transcribed to the CRF, unless otherwise noted in the protocol. These data 
may also be sent electronically to FHI 360 for direct entry into the clinical database (see 
Section 12.1). All data from other institutions will be available to the investigator.


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The CRFs are filed in the clinical sites’ files and CRFs will be shipped to the sponsor at the end 
of the trial.
Some CRFs data fields used in this study will have data directly recorded into them and will be 
considered source. Other source documents will include but will not be limited to, staff journals, 
medical notes, screening and enrollment logs, laboratory results, and implant dispensing records 
and consent forms. Source for all key study data will be defined and documented in site-specific 
source documentation guides.
The MPA testing will be conducted by Pharmaceutical Product Development, LLC (PPD)
(Richmond, Virginia, United States of America) who will maintain source documentation for the 
MPA data; MPA results will not be entered into CRFs but transferred electronically to the FHI 
360 data management group.
Hemoglobin, liver function testing, progesterone, and estradiol testing will be conducted at the 
local laboratories and made available to source verify.
3.14.
Study Procedures
Before implementation, the protocol and all relevant study documents including recruiting 
materials will be approved by the local IRB selected by the clinical site(s) and by the PHSC of 
FHI 360.
Participants will come to the study clinic for 1 screening visit, up to 6 pre-treatment visits, 
1 enrollment/injection visit, 3 scheduled follow-up visits, a final visit, and frequent laboratory 
visits to draw blood samples for progesterone, estradiol, and/or MPA. The number of laboratory 
visits will be in the range of 22 to 72 depending on whether Part 2 is initiated, and when 
ovulation returns in each individual subject. The sampling schedule and duration of testing may 
be modified based on the interim results of Part 1 to ensure that primary and secondary outcomes 
are precisely measured in both parts of the study.
Study procedures and assessments for Parts 1 and 2 with their timing are summarized in Table 1. 
Detailed visit-specific information is provided in this section. Detailed descriptions of each 
assessment are provided in Section 6 (pharmacokinetic and pharmacodynamic assessments) and 
Section 7 (safety assessments).


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Table 1:
Study Procedures and Assessments (Parts 1 and 2)
Procedures and assessments
Screening
Pretreatment
Enrollment
Follow-up
Day 0
Day 1 to week 78
Scheduled 
Follow-up 
(day 7, week 13, 
and week 32)
Lab 
visits
Final 
visit a
Informed consent
X
Medical history
X
X
Inclusion and exclusion 
criteria
X
X
Demographics and baseline 
characteristics
X
Height
X
X
Vital signs measurement
X
X
X
X
Body weight
X
X
X
X
Breast exam
X
X
Urine pregnancy test b
X
Randomization (Part 2)
X
Study drug administration 
(injection) c
X
Study staff assessment for ease 
of performing the injection
X
Serum progesterone e, f, g
X d
X
X
X
X
Estradiol e , f, g
X d
X
X
X
X
Serum MPA h
X
X
X
X
Injection site reactions i
X
X
X
Adverse event inquiry
X
X
X j
X
Concomitant medication 
inquiry
X
X
X j
X
Hemoglobin
X
Liver function testing (Part 2 
only)
X
X k
X
Mood evaluation (Part 2 only)
X
X k
X
Acceptability
X
X
X
Menstrual bleeding pattern l
X
X
X
Mammogram m
X


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a For subjects in whom ovulation returns before month 12 post-injection, the final study visit will be scheduled at 
month 12. If ovulation occurs between months 12 and 18 (between weeks 52 and 78), at the time when the 
defining serum progesterone result becomes available, the study staff will inform the subject that she needs to 
return within 5 days to the investigational center for the final study visit. For subjects in whom ovulation does not 
return by month 18, the laboratory visit at week 78 will be considered the final study visit
b A urine pregnancy test will be performed at enrollment; and during the study, if indicated.
c Day 0; within the 1st 5 days of the start of subject's menstrual cycle.
d Blood samples for serum progesterone and estradiol will be collected approximately twice weekly during the 
approximately 2 to 3 weeks preceding the subject's expected menses for confirmation of ovulation (ideally at least 
4 measurements).
e Blood samples for serum progesterone and estradiol will be collected on day 0 (baseline); then at day 7 and then 
weekly through week 32, regardless of ovulation status.  If ovulation does not return by week 32, then weekly 
blood samples for serum progesterone and estradiol will continue to be collected until ovulation or through week 
52, whichever is earlier. If there is no ovulation by week 52, then blood samples for progesterone and estradiol 
will be collected at weeks 61, 62, 63, 64, and 65; and at weeks 74, 75, 76, 77, and 78, if ovulation has not returned 
by week 65. During these additional laboratory visits, blood samples will be collected and tested for serum 
progesterone and estradiol at all visits, but not past return to ovulation.
f At any time during follow-up, subjects with initial serum progesterone ≥3.0 ng/mL will be asked to return within 5 
days for repeated progesterone and estradiol measurement. If repeated progesterone is at 3 ng/mL or below, the 
subject will continue follow-up per their visit schedule.
g At any time during follow-up, if the serum progesterone level is ≥4.7 ng/mL, subjects will be asked to return 
within 5 days for repeated progesterone and estradiol measurement.
h Blood samples for MPA will be collected on day 0; then on days 1, 2, 3, 5, 7, 10, 12, 14, 18, 21, 28, 35, and 42; 
then at weeks 8, 10, 12, 13, 15, 17, 19, 21, 23, 25, 26, 28, 30, and 32; and then every 28 days until week 52, 
regardless of ovulation status. Among subjects in whom ovulation does not return by week 52, blood samples for 
MPA will be collected up to 2 more times (at weeks 61 and 74), but not past return to ovulation. Blood samples 
will also be collected and stored for possible future MPA testing (if necessary) any time samples are collected for 
serum progesterone and estradiol, except for pre-treatment visits and visits for confirmation of ovulation.
i Injection site reactions will be recorded on day 0 immediately after the injection (within 10 minutes) and within 
the 1st hour after injection; at days 1, 2, 3, 5, and 7; week 13 and week 32 visits; at the final visit; and at other 
visits, if indicated.
j During laboratory visits, information on adverse events and concomitant medications will not be solicited, but will 
be documented if reported by the subject.
k Liver function testing and mood evaluation will be evaluated at the week 13 and week 32 follow-up visits.
l Menstrual bleeding patterns will be obtained by an interview questionnaire approximately monthly; at scheduled 
follow up visits (weeks 13 and 32 only); and the final study visit. In addition, in Part 2 menstrual data will be 
collected weekly via an on-line diary.
m Part 1 only, prior to enrollment.
Lab=laboratory, MPA=medroxyprogesterone acetate.
3.14.1.
Procedures Before Study Drug Treatment
Screening Visit
Women will be referred to the investigational center through various recruitment channels which 
may include, but not limited to internal participant databases, advertising via internet and radio. 
Women who express interest to participate in the clinical study will undergo the informed 
consent process administered by a trained investigational center staff member including 
information about the study objectives, design and procedures, and potential risks and benefits of 
study participation.
A signed and dated informed consent form will be obtained before screening procedures 
commence (see Section 11.1). Women who sign the informed consent form will be assigned a 


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participant number and have a screening interview to obtain the following: medical history and 
demographic information, breast examination, blood sample for hemoglobin and liver function, 
height, weight, and vital signs measurements (BP, pulse, and respiration), and an interview about 
mood. To be eligible for Part 1 of the study all participants must have had a normal mammogram 
within the last year. Participants without a normal mammogram in the last year or who have an 
undiagnosed mass detected by breast exam during the screening visit, will have to have 
mammography performed to rule out breast cancer. During the screening visit, the 
investigational center may conduct clinical procedures per site-specific standard of care that are 
not required by the study protocol (eg, cervical cytology, STI testing). A subject who is screened 
and does not meet study entry criteria may be rescreened 1 additional time if there is a change in 
the subject’s medical background or there is a modification to study entry criteria. If the re-
screening visit occurs more than 2 months apart from the original screening visit, all screening 
procedures including informed consent will be repeated and a new participant number assigned.
Eligible subjects will be scheduled to return to the clinic up to 6 times for serum progesterone 
and estradiol measurements to confirm their ovulatory cycle (approximately twice a week 
preferably 3 days apart during approximately the 2 to 3 weeks preceding their next expected 
menses). Subjects who present for screening approximately 2 weeks prior to their next expected 
menses, may have their first blood sample for serum progesterone and estradiol taken on the 
same day.
In summary, the following procedures will be performed at screening:

explain study purpose and procedures

obtain written informed consent before any other study-related procedures are 
performed

perform screening interview to determine eligibility and collect demographics and 
baseline data, including medical history

assign participant number

measure vital signs (BP [systolic/diastolic], pulse, and respiration)

measure body weight and height to estimate BMI

perform breast examination

refer for mammography, if necessary

interview about mood (Part 2 only)

obtain a blood sample for liver function testing (approximately 5 mL; Part 2 only)

obtain a blood sample for hemoglobin measurement (approximately 4 mL)
3.14.2.
Pretreatment
Subjects who meet the inclusion/exclusion criteria at screening visit will return to the clinic 
approximately twice a week (preferably 3 days apart) during the approximately 2 to 3 weeks 
preceding their next expected menses (ideally at least 4 times) for serum progesterone and 
estradiol measurements to confirm ovulation. They will also have a mammogram scheduled 


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during this time if they have not had a mammogram within the last 12 months during Part 1 only. 
During these visits, blood samples will be obtained for serum progesterone and estradiol 
evaluation. If progesterone is at or above 4.7 ng/mL in at least 2 consecutive samples, ovulation 
will be considered confirmed and the subject eligible for the study. Eligible subjects will be 
scheduled to return to the clinic for the enrollment/injection visit during the first 5 days of her 
next menstrual cycle.
3.14.3.
Procedures During Study Drug Treatment
3.14.3.1.
Enrollment (Injection) Visit (Day 0)
The enrollment visit should take place during the first 5 days of menses. During this visit, a urine 
pregnancy test will be performed. Participants with hemoglobin ≥10.5 g/dL measured at 
screening, confirmed ovulation and negative pregnancy test will be enrolled in the study. 
Medications that the subjects used over the last 30 days will be documented as concomitant 
medications; vital signs (BP [systolic/diastolic], pulse, and respiration), and body weight will be 
measured and blood samples will be collected for serum MPA, serum progesterone, and estradiol 
before the study drug injection.
Part 1 is open-label; therefore, subjects will be assigned without randomization. The study staff 
allocating the study drug assignments in Part 2 will open the next sequential randomization 
envelope, document treatment assignment in a secure log, store the opened envelope, and 
communicate the assigned treatment arm to the pharmacy and/or study staff preparing and 
administering the injection (unless s/he is the one administering the injection).
The Part 2 investigational center staff who assigns the study drug treatment, and study staff
providing the injection, will not be blinded but they will keep the subject and the rest of the 
investigational center staff unaware of the study drug treatment assignment. The study staff 
member will prepare the assigned study drug for injection according to the dilution procedures,
and, unless s/he is the one administering the injection, pass it to the study staff who will inject 
the study drug subcutaneously in the fatty tissue over the abdomen while shielding the study 
drug injection from the subject’s sight, as described in Section 5.1. After the injection the 
unblinded study staff will provide feedback on the ease of the injection administration. On the 
injection day the injection site will be examined for ISRs twice: within 10 minutes after the 
injection (by the un-blinded provider) who performed the injection; and within 1st hour after the 
injection (between 10 and 60 minutes) (by the blinded investigational center staff). The subject 
will be interviewed for acceptability of the study injection by the blinded investigational center 
staff. Before leaving the investigational center during the injection visit, each subject will receive 
the schedule of their follow-up visits.
The following procedures/assessments will be performed during enrollment/injection:

perform urine pregnancy test (and during the study, if indicated)

confirm eligibility

measure vital signs (BP [systolic/diastolic], pulse, and respiration)

measure body weight and height and estimate BMI


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
(prior to injection) obtain a blood sample (approximately 15 mL) for serum MPA, 
serum progesterone, and estradiol

open next opaque envelope to reveal the treatment allocation, have the pharmacist 
prepare the indicated dose, and deliver the syringe to the study staff (Part 2 only)

administer study drug injection

evaluate site of injection for an ISR after the injection twice (within 10 minutes and 
within 1st hour)

document concomitant medication in the last 30 days

document adverse events reported after the injection

assess subject’s acceptability of the injection

assess ease of study drug injection by the study staff
The subject will remain in the clinic for at least 15 minutes after the study drug injection for 
observation of possible anaphylactic reactions.
For logistical reasons, study drug injection may be administered the day after other enrollment 
procedures are completed. When the visit is split, the blood draw and injection will occur the day 
after other enrollment visit procedures are conducted. The date of injection is considered 
“day 0.”
3.14.3.2.
Follow-up (Day 1 to Week 78)
Regardless of ovulation status, all subjects should remain in follow-up for at least 52 weeks post-
injection.
There are 2 types of follow-up visits in this study: scheduled follow-up visits and laboratory 
visits.
3.14.3.2.1. Scheduled Follow-up Visits (Day 7, Month 3, and Month 7.5)
Scheduled follow-up visits will occur on day 7, month 3 (week 13), and month 7.5 (week 32) 
from start of study drug treatment. During these visits, in addition to collection of blood samples 
for serum MPA, progesterone, and estradiol, the site of study drug injection will be examined for 
ISR and subjects will be asked about pain, itching, and sensitivity disturbances, or other 
complaints at the site of injection. Measurement of vital signs and body weight will be 
performed. Subjects will be asked if they experienced any medical problems or took any 
medications since the previous report. Menstrual bleeding patterns, mood (for Part 2 only) and 
acceptability will be evaluated through an interview questionnaire. For Part 2, in addition to the 
scheduled follow-up visits menstrual bleeding patterns will be evaluated weekly through on-line 
diaries. For the laboratory measurement schedule, see Table 1.
The following procedures/assessments will be performed during the 3 scheduled follow-up 
visits:

measure vital signs (BP [systolic/diastolic], pulse, and respiration)

measure body weight


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
obtain blood sample (approximately 15 mL) for serum MPA, serum progesterone,
and estradiol

obtain blood sample (approximately 5 mL) for liver function tests (month 3 and 
month 7.5, Part 2 only)

evaluate site of injection for ISRs

inquire about adverse events

inquire about concomitant medication(s)

interview about mood (month 3 and month 7.5; Part 2 only)

interview about menstrual bleeding pattern (month 3 and month 7.5)

interview about acceptability
3.14.3.2.2. Laboratory Visits
During the laboratory visits, blood samples will be obtained for serum MPA, serum 
progesterone, and estradiol per the sampling schedule (see Sections 3.3 and 3.4, and Table 1). In 
addition, the injection site will be observed for ISRs on days 1, 2, 3, and 5; and thereafter, if 
indicated. Information on adverse events and concomitant medications will not be solicited but 
documented if reported by the subject.
The following procedures/assessments will be performed during laboratory visits:

obtain blood sample (up to approximately 15 mL) for serum MPA, serum
progesterone, and estradiol per the sampling schedule 

evaluate site of injection for ISRs (on days 1, 2, 3, and 5; and thereafter, if indicated)

interview about menstrual bleeding pattern once monthly (Part 1 only)

document adverse event (if reported)

document concomitant medication (if reported)
Blood samples for MPA will be collected and stored for possible future MPA testing (if 
necessary) any time when samples are collected for serum progesterone and estradiol, except for 
pre-treatment visits and visits for confirmation of ovulation.
3.14.3.2.3. Laboratory Visits after Week 52
Additional laboratory visits will be scheduled at weeks 61, 62, 63, 64, and 65 for all subjects in 
whom ovulation did not return by week 52; and at weeks 74, 75, 76, 77, and 78 if ovulation has 
not returned by week 65. During these additional laboratory visits, blood samples will be 
collected and tested for serum progesterone and estradiol (all visits) and serum MPA (weeks 61
and 74), but not past ovulation. Blood samples for MPA will be collected at all weekly visits 
after Week 52 and stored for possible future MPA testing (if necessary).


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3.14.4.
Procedures After Study Drug Treatment and Lost to Follow-up
3.14.4.1.
Final Visit
Subjects will complete the study at 12 months after administration of TV-46046, or after 
ovulation returns (if after month 12) or at the week 78 laboratory visit (if ovulation does not 
return before then). If Part 2 is not initiated, subjects in Part 1 may be discontinued from the 
study as early as 26 weeks following study drug injection. If Part 2 is initiated, subjects will stay 
in the study for a minimum of 12 months (52 weeks) from start of TV-46046 treatment even if 
ovulation returns before then. All subjects will complete the study by 18 months (78 weeks) from 
the start of TV-46046 treatment even if ovulation does not return by then. Additional post-
discontinuation follow-up may be considered for safety purposes until ovulation returns and/or 
MPA levels become undetectable.
For subjects in whom ovulation returns before month 12 post-injection, the final study visit will 
be scheduled at month 12. If ovulation occurs between months 12 and 18 (between weeks 52 and 
78), at the time when the defining serum progesterone result becomes available, the study staff 
will inform the subject that she needs to return within 5 days to the investigational center for the 
final study visit. For subjects in whom ovulation does not return by month 18, the laboratory visit 
at week 78 will be considered the final study visit.
The following procedures/assessments will be performed during the final visit:

obtain blood sample for serum MPA (approximately 5 mL) 

obtain blood sample for serum progesterone, estradiol (approximately 10 mL), if 
indicated; and liver function tests (Part 2 only, approximately 5 mL)

measure body weight

measure vital signs (BP [systolic/diastolic], pulse, and respiration)

perform breast exam

interview about acceptability

evaluate site of injection for ISRs

inquire about adverse events

inquire about concomitant medications

interviews about mood (Part 2 only) and menstrual bleeding pattern
If the subject cannot return to the investigational center in person, the final evaluation may be 
completed by telephone (to the extent possible) and documented in the CRF.
For subjects who withdraw prematurely from the study, the final visit will be performed at the 
time of discontinuation, if known.
3.14.4.2.
Missed Visits
Visits will be scheduled using target visit windows, as detailed in the Study Manual. When a 
subject cannot return to the clinic within her visit window, missed procedures will be performed 
at her next clinic visit.


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3.14.4.3.
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. One additional attempt to contact the subject will be made after each subsequent missed 
study visit. These attempts will be documented in the subject’s study file. If the subject does not 
return for the scheduled appointment, the subject will be considered “presumed lost to 
follow-up”. The subject’s file will remain open until study closeout. If the subject does not return 
to the study before the study is closed, the Final form will be completed at the end of the study 
(see Section 11.4 for definition). The form will indicate that the subject was lost to follow-up. 
The final “lost to follow-up” designation cannot be made for any subject until the closing date of 
the study.
3.14.5.
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, adverse events, 
concomitant medications and treatments, and results from procedures or tests).
Procedures performed during unscheduled visits include the following:

concomitant medication inquiry

vital signs measurements (BP [systolic/diastolic], pulse, and respiration)

adverse event inquiry
Other procedures may be performed at the discretion of the investigator.


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4.
SELECTION AND WITHDRAWAL OF SUBJECTS
Prospective waivers (exceptions) from study eligibility criteria to allow subjects to enter a study 
are not granted by Teva (see Section 10.1.2).
4.1.
Subject Inclusion Criteria
Subjects may be included in the study if they meet all of the following criteria:
a.
has regular menstrual cycle (24 to 35 days)
b. has confirmed ovulatory cycle during the pretreatment phase (serum 
progesterone ≥4.7 ng/mL in 2 consecutive samples)
c.
is at low risk of pregnancy (ie, sterilized, in exclusively same-sex partnership, in 
monogamous relationship with vasectomized partner, or using non-hormonal IUD)
d. is in good general health as determined by a medical history 
e.
18 to 40 years of age, inclusive
f.
willing to provide informed consent and follow all study requirements
g. is not pregnant and does not have desire to become pregnant in the subsequent 
36 months
h. has a BMI of 18 to 35, inclusive (unless included in subset of subjects with extreme 
obesity (BMI ≥40), 2 in each dose-range finding group from a single investigational 
center, in Part 2)
i.
has hemoglobin ≥10.5 g/L
j.
has had a normal mammogram within the last year (for Part 1 only)
4.2.
Subject Exclusion Criteria
Subjects will be excluded from participating in this study if they meet any of the following 
criteria:
a.
has hypertension:
○
systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg
○
vascular disease
b. has current or history of ischemic heart disease 
c.
has history of stroke
d. has history of thromboembolic event
e.
has systemic lupus erythematosus
○
positive (or unknown) antiphospholipid antibodies
○
severe thrombocytopenia


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f.
has rheumatoid arthritis on immunosuppressive therapy
g. has migraine with aura
h. has unexplained vaginal bleeding
i.
has diabetes
j.
has 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, and any male family member with breast cancer), 
or current or history of breast cancer, or undiagnosed mass detected by breast exam 
k. has current or history of cervical cancer
l.
has severe cirrhosis (decompensated) or liver tumors
m. has one or more baseline liver function test(s) outside the local laboratory’s normal 
range (Part 2 only)
n. has known significant renal disease
o. history of diagnosed clinical depression or bipolar disorder, with or without suicidal 
ideation, and/or history of suicide attempt
p. in last 2 years, history of either hospitalization or medication management for 
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
q. used DMPA products (Depo-Provera CI or Depo-subQ Provera 104) in the past 
12 months
r.
used any of the following medications within 1 month prior to enrollment:
○
any investigational drug
○
prohibited drugs per protocol
○
oral contraceptives, contraceptive ring or patch
○
levonorgestrel intrauterine system (LNG IUS) or contraceptive implant
s.
used a combined injectable contraceptive in the past 6 months
t.
less than 3 months since the end of last pregnancy
u. currently lactating
v. is using or plans to use prohibited drugs per protocol in the next 18 months
w. has known sensitivity to MPA or inactive ingredient
x. has a plan to move to another location in the next 24 months
y. in the opinion of the investigator, potentially at elevated risk of HIV infection (eg, 
HIV-positive partner, IV drug use by self or by partner)


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z. 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 complicate data interpretation
4.3.
Justification for Key Inclusion and Exclusion Criteria
Due to uncertain risk of pregnancy, all necessary precautions will be taken to minimize the risk 
of pregnancy among study subjects. Therefore, only women who are not pregnant, not wanting 
to become pregnant in the next 36 months, and who are at low risk of pregnancy will be enrolled 
in the study. The study will recruit women of reproductive age with regulatory menstrual cycle 
and with confirmed ovulation to ensure that the lack of ovulation during the treatment can be 
attributed to the treatment effect rather than the preexisting ovulatory dysfunction.
The study will not enroll female subjects who have medical contraindications to DMPA nor
medical or social conditions that may make study participation unsafe, interfere with drug 
absorption and metabolism, have 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 and any male family member with breast cancer or 
complicate data interpretation.
4.4.
Withdrawal Criteria and Procedures
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), 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 7.2), or other reasons concerning the health or well-being of the 
subject, or in the event of lack of cooperation. In addition, a subject may be withdrawn from the 
study as described in Sections 3.12 and 7.1.7 .
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. This may include but may not be limited to 
progesterone and MPA testing, pregnancy testing and assessment of ISRs, and/or acceptability. 
The final visit procedures should be followed for all subjects who withdraw, if possible (see 
Section 3.14.4.1).
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 reason for withdrawal is an adverse event, monitoring 
will be continued at the discretion of the investigator (eg, until the event has resolved or 
stabilized, until the subject is referred to the care of a healthcare professional, or until a 
determination of a cause unrelated to the study drug or study procedure is made). The specific 
event or test result must be recorded on the source documentation and transcribed onto the CRF.
In addition, a blood sample will be obtained for the measurement of study drug concentration. 
The sample date and time will be recorded on the source documentation and transcribed to the 
CRF.
All assessments should be performed according to the protocol as soon as possible.


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Since this is a single-dose study and the study product remains in the body months after 
injection, 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 at least until safety assessments are completed 
(including delayed return to ovulation [>12 months post-study drug injection]).


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5.
TREATMENT OF SUBJECTS
5.1.
Drugs Administered During the Study 
In Part 1 of the study after enrollment, 12 enrolled subjects will be sequentially assigned to a 
treatment group as presented below.
The first 6 subjects will be assigned to:

Treatment group 1: 0.3 mL of 400 mg/mL of undiluted TV-46046 (120 mg)
The next 6 subjects will be assigned to:

Treatment group 2: 0.6 mL of 200 mg/mL of saline-diluted TV-46046 (120 mg)
If warranted, an additional 6 subjects in Part 1 will be assigned to:

Treatment group 3: 0.4 mL of 300 mg/mL of saline-diluted TV-46046 (120 mg)
In Part 2 of the study, subjects will be randomly assigned to 1 of up to 3 treatment groups (up to 
3 additional dose levels of undiluted TV-46046 within the range of 80 to 300 mg).
5.1.1.
Dilution Procedure of TV-46046
Diluted TV-46046 will be prepared by the investigational center pharmacist or other trained 
personnel. Dilution procedures for TV-46046 treatment group 2 in Part 1 and, potentially, 
treatment group 3 in Part 1, are provided in the Pharmacy Manual.
5.1.2.
Subcutaneous Administration of TV-46046
In both parts of the study TV-46046 will be administered by a study staff member as a single 
subcutaneous injection in the abdomen during the first 5 days of the menstrual cycle using a 
23 gauge 3/8 inch needle following the sponsor’s instructions for administering a subcutaneous 
injection (see Appendix B).
Part 2 will be a subject-blinded study. The clinical staff providing the injections will be trained to 
shield the syringe from view of the subject or any other study staff prior to and at the time of 
injection. For additional details, see Section 3.8.2.
Briefly, the provider will follow these steps:
1. Use alcohol pad to wipe the skin in the abdominal injection area and allow the skin to dry
2. Gently grasp and squeeze a large area of skin in the chosen injection area between the 
thumb and forefinger, pulling it away from the body
3. Insert the 23 gauge 3/8 inch needle at a 45° angle so that most of the needle is in the fatty 
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4. Inject the medication slowly (over 5 to 7 seconds) until the syringe is completely empty
5. After withdrawing the needle, press a cotton pad lightly on the injection area (do not use 
Band-Aid®4 taking care of not rubbing the site of injection
5.2.
Restrictions
Medications prohibited before and/or during the study are described in Section 5.3. Subjects will 
remain at the investigational center for at least 15 minutes after the study drug injection for 
observation. The investigational center will have an EpiPen (epinephrine injection) available and 
easy access to emergency care necessary in the unlikely event of anaphylaxis or anaphylactoid 
reaction.
5.3.
Prior and Concomitant Medication or Treatment
Any prior or concomitant therapy, medication, or procedure a subject has had within 30 days 
before study drug administration and up to the final visit will be recorded on the CRF. During the 
scheduled follow-up visits, the investigator will ask subjects whether they have taken any 
medications (other than study drug), including over the counter (OTC) medications, vitamins, or 
herbal or nutritional supplements, since the previous visit. During laboratory visits information 
of the use of concomitant medications will be documented only if reported by the subject. 
Generic or trade name, indication, route of study drug administration, dosage, and start and end 
dates will be recorded.
Any drugs that may interfere with metabolism of MPA or affect ovarian function will be 
prohibited during the study. The following medications should not be used during this study
(unless medically indicated):

rifampicin

griseofulvin

anticonvulsants

barbiturates

antiretroviral drugs (ARVs): non-nucleoside reverse transcriptase inhibitors 
(efavirenz, nevirapine) and ritonavir-boosted protease inhibitors

aminoglutethimide

St. John’s wort

selective cyclooxygenase-2 (COX-2) inhibitors (eg, meloxicam, celecoxib) for 5 or 
more consecutive days

steroids (synthetic estrogens, progestins, androgens)
                                                
4 Band-Aid is a registered trademark of Johnson & Johnson Corporation.


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5.4.
Procedures for Monitoring Subject Compliance
Given that a single injection of the study drug will be provided by the investigational center 
personnel in the clinic, monitoring of subject compliance will not be necessary.
5.5.
Total Blood Volume
The total volume of blood to be collected for each subject in this study is approximately 909 mL, 
as provided in Table 2.
Table 2:
Approximate Blood Volumes
Type of samples
Volume 
per sample (mL)
Total number of 
samples
Total volume
(mL)
Pharmacodynamics (serum P and E2)
-before study drug injection
-if ovulation by week 52
-if no ovulation by week 52
about 10
(for both P and E2)
up to 7
up to 48
up to 58
~70
~480
~580
Pharmacokinetics (serum MPA)
-before study drug injection
-if ovulation by week 52
-if no ovulation by week 52
about 5
1
up to 48
up to 50
5
~240
~250
Hemoglobin
about 4
1
~4
Liver Function 
about 5
4
~20
Totala
~121
~924
a These are maximum figures, assuming a subject does not ovulate before week 78. The sampling schedule for Part 2 
may be reduced further based on assessment of Part 1 data.
~=approximately, P=progesterone, E2=estradiol.


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6.
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS
6.1.
Pharmacokinetics
Pharmacokinetics of MPA will be evaluated based on individual and mean serum MPA 
concentration-time profiles and estimated noncompartmental pharmacokinetic parameters (see 
Section 8.5). All subjects will be assessed for nonzero MPA levels at baseline. The MPA results 
will not be known until later in the study and, therefore, will not be used as exclusion criteria. 
Subjects with nonzero MPA levels at baseline (ie, more than 5% of their individual Cmax) will be 
excluded from the primary pharmacokinetic analyses (see Section 8.5.3). During the study MPA 
concentrations will be measured at pre-defined time points (see Table 1). In addition, subjects for 
whom ovulation has not returned by month 12 (week 52), blood samples for MPA will be 
collected and tested up to 2 more times (at week 61 and week 74), but not past return to 
ovulation. Based on accumulating data, additional sampling and testing for MPA in one or more 
study groups in Part 1 and/or Part 2 may be conducted for a more accurate characterization of the 
pharmacokinetic profile of TV-46046.
6.1.1.
Part 1: Exploratory Pharmacokinetic Variables
The following non-exhaustive list of non-compartmental pharmacokinetic parameters will be 
calculated for MPA for each treatment group:

Cmax

tmax

C182 (week 26)

AUC0-182

AUC0-∞

apparent terminal half-life
6.1.2.
Part 2: Dose-range Finding Variables
The following pharmacokinetic parameters will be calculated for MPA for each treatment and 
population:

Cmax

tmax

C182 (week 26)

C210 (week 30)

AUC0-182

AUC0-210


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
AUC0-∞

apparent terminal half-life
6.1.3.
Blood Sampling and Handling
Blood samples (~5 mL) for pharmacokinetic analysis will be obtained from all subjects via 
venipuncture at the time points detailed in Table 1.
The date and time of study drug administration and the date and time of each pharmacokinetic 
sample will be recorded on the source documentation and transcribed onto the CRF.
Blood specimen will be collected into one Vacutainer tube containing no anticoagulant and 
allowed to set at room temperature for at least 20 minutes, but no more than 40 minutes, to 
permit clot formation. Samples will be centrifuged at room temperature at 2500 to 
3000 revolutions per minute (rpm) (approximately 650 to 1450 ×g) for 10 to 15 minutes to 
achieve a clear serum layer over the clotted red cells. Approximately equal portions of the 
sample will then be immediately transferred into 2 properly labeled polypropylene sample 
storage tubes. The prepared serum samples will be immediately frozen at -20ºC and stored in an 
upright position until shipment.
6.1.4.
Shipment and Analysis of Samples
One aliquot will remain frozen on site, and another will be sent on dry ice in batches with other 
samples to PPD (Richmond, Virginia, United States of America) where MPA levels will be 
measured via a proprietary validated method utilizing sensitive and selective high-performance 
liquid chromatography coupled with mass spectrometry. This method is applicable to the 
quantitation of MPA within a nominal range between 0.02 to 5.00 ng/mL and requires a 250-μL 
aliquot of human serum. Timing of the initiation of sample analysis will be determined by the 
study monitor. The PPD staff performing the analysis will be blinded to the treatment 
assignment.
Source documentation for MPA will be maintained at PPD. The MPA results will be transferred 
electronically from PPD to FHI 360 for data management and analysis. The MPA results will not 
be documented on study CRFs or communicated to the study participants. No further testing of 
any remaining blood samples is planned; however, any remaining serum will be stored by PPD at 
least until the end of the study in the event of needed repeat testing or analysis of long-term 
stored sample stability. The PPD laboratory will discard remaining blood samples per PPD
standard operating procedures (SOPs) upon receiving written approval from FHI 360. Any 
remaining aliquots stored on site will also be maintained until the end of the study, and only 
discarded after receiving written FHI 360 approval.
More detailed instructions on how to take, prepare, store, and send the serum samples for 
analysis in the central laboratory will be provided in the Study Manual.
6.2.
Pharmacodynamics
Potential for contraceptive effect of TV-46046 when injected subcutaneously will be evaluated 
primarily based on its ability to suppress ovulation. While postovulatory maximum progesterone 
levels are usually greater than 16 nmol/L, progesterone levels used as a criterion of ovulation in 
contraceptive research usually range from 10 nmol/L to 16 nmol/L (approximately 3 to 5 ng/mL) 


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(Rahimy et al 1999, Brache et al 2012, Westhoff et al 2010, Jesam et al 2014). In addition, any 
rise in progesterone levels has to be sustained for at least 5 days to be consistent with ovulation. 
However, given the long-acting nature of TV-46046, anticipated irregular menstrual cycles, as 
well as the schedule of laboratory visits generally more than 5 days apart, it will not be possible 
to precisely define the timing within the luteal phase when elevated progesterone is detected. 
Therefore, measurement of sustained levels of progesterone for a presumption of ovulation will 
not be required in this study. The primary pharmacodynamics variable for this study will be 
ovulation defined as a single elevated serum progesterone ≥4.7 ng/mL. The same approach was 
used previously in pharmacokinetic/pharmacodynamic studies of Depo subQ 104 (Jain et al 
2004, Toh et al 2004).
During the pre-treatment phase ovulation will be confirmed in all women by measuring 
progesterone approximately twice a week during the approximately 2 to 3 weeks preceding their 
expected menses. Only women with confirmed ovulation will be enrolled in the study. During 
the pre-treatment phase of the study, if progesterone is at or above 4.7 ng/mL in at least 
2 consecutive samples, ovulation will be considered confirmed for the purposes of the study 
eligibility.
All enrolled subjects will provide blood for progesterone measurement before the injection to 
document the baseline level of progesterone. During the study, all subjects will return for serum 
progesterone testing according to the pre-defined schedule (see Table 1). Serum progesterone 
results will be available within approximately 24 to 48 hours of specimen collection. Any time 
during the study, all women with initial serum progesterone ≥3.0 ng/mL will be asked to return 
within 5 days for repeated progesterone measurement to ensure close monitoring of the potential 
post-ovulatory rise of progesterone. If the repeated measurement within 5 days is at or below 
3.0 ng/mL, the subject will continue follow-up per her visit schedule.
During the treatment phase of the study if progesterone is at or above 4.7 ng/mL in a single 
sample, ovulation will be considered confirmed for the purpose of the primary analysis. At any 
time during the study, any subject with initial progesterone ≥4.7 ng/mL will be asked to return 
within 5 days for repeated progesterone measurement. Although repeated elevated progesterone 
is not needed for the primary definition of ovulation, this information will be used for more 
accurate ascertainment of ovarian function. Subjects with a single elevated progesterone 
measurement of ≥4.7 ng/mL will be considered to have their ovulation restored.
Estradiol, an additional pharmacodynamic indicator, will be measured every time progesterone is 
measured. It will be used to more accurately characterize ovarian function. 
At the discretion of the center investigator and/or based on accumulating data, additional 
sampling and testing for progesterone and estradiol may be conducted to ensure accurate 
ascertainment of the primary pharmacodynamic endpoint.


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Blood Sampling and Handling
Detailed instructions on how to draw and prepare serum samples for progesterone and estradiol 
analysis, and liver function analysis (Part 2 only) will be investigational center-specific and 
provided in the laboratory SOPs and/or Study Manual. Briefly, blood samples for progesterone 
and estradiol (up to 10 mL) will be collected via venipuncture, centrifuged, and then transferred 
into 2 aliquots. One aliquot will be sent to the investigational center laboratory for the same day 
testing; and the other one stored as a back-up sample at -20°C. Collection and movement of 
progesterone and estradiol samples will be recorded on appropriate study CRFs and/or tracking 
tools. In Part 2 blood samples for liver function analysis (up to 5 mL) will be collected via 
venipuncture, centrifuged and then transferred to one aliquot for analysis.


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7.
ASSESSMENT OF SAFETY
In this study, safety will be assessed by qualified study personnel by evaluating the following: 
vital signs (BP [systolic/diastolic], pulse, and respiration), body weight, adverse events, 
concomitant medication usage, changes in menstrual bleeding patterns, mood, liver function 
tests, occurrence of ISRs, and return to ovulation after 12 months after the study drug injection.
7.1.
Adverse Events
7.1.1.
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 this treatment.
In this study, any adverse event occurring after signing the informed consent form should be 
recorded and reported as an adverse event.
An adverse event can, therefore, be any unfavorable and unintended medical condition 
(eg, physical sign, symptom, disease, or laboratory parameter) that develops or worsens in 
severity during the course of this study, whether or not considered related to the study drug. 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. Irregular vaginal bleeding will not be recorded on 
the Adverse Event Form unless it requires medical intervention or meets the definition of a 
serious adverse event.
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 the disease under 
study or other pre-existing conditions (Note: A condition recorded as pre-existing that 
is intermittently symptomatic [eg, headache] and that occurs during this study should 
be recorded as an adverse event.)

drug interactions

events occurring during diagnostic procedures or during any washout phase of this
study

laboratory or diagnostic test abnormalities that result in the withdrawal of the subject 
from the study, are associated with clinical signs and symptoms or a serious adverse 
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.)


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7.1.2.
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 informed consent form to the end of the 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 study drug. For serious adverse events, the Serious Adverse Event Form must 
also be completed and the serious adverse event must be reported immediately (see
Section 7.1.5.3.1). The investigator does not need to actively monitor subjects for adverse events 
once the study has ended. Serious adverse events occurring to a subject after study 
discontinuation should be reported to the sponsor if the investigator becomes aware of them, 
following the procedures described in Section 7.1.5.3.1.
At each of the 3 scheduled follow-up visits, the investigator or designee 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.” All reported 
or observed 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 as a single diagnosis on the CRF and, if it is a serious 
adverse event, on the Serious Adverse Event Form. During frequent laboratory visits adverse 
events will not be actively solicited but will be documented if reported by the subject.
The clinical course of each adverse event will be monitored at suitable intervals until resolved or 
stabilized or returned to baseline, or until the subject is referred for continued care to a another 
healthcare professional, or until a determination of a cause unrelated to the study drug or study 
procedure is made.
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding study drug, 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 study drug treatment and study procedures, and the 
severity and seriousness of each adverse event, as judged by the investigator, must be recorded 
as described below.
7.1.3.
Severity of an Adverse Event
The severity of adverse events including ISRs and abnormal laboratory tests will be graded per 
the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 2.0, November 2014 
(see Appendix A).


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7.1.4.
Relationship of an Adverse Event to the Study Drug
The relationship of an adverse event to the study drug is characterized as follows and will be 
determined by Teva:
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 study drug.
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 study drug.

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 
study drug. 

It does not reappear or worsen when the study drug is 
re-administered. 
Reasonable 
possibility
(related)
This category applies to adverse 
events for which, after careful 
medical consideration at the time 
they are evaluated, a connection with 
the study drug 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 study drug.

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 study drug, yet a drug
relationship clearly exists.

It follows a known pattern of response to the study 
drug.
7.1.5.
Serious Adverse Events
7.1.5.1.
Definition of a Serious Adverse Event
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions:

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.


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
Hospitalizations scheduled prior to study entry or hospitalization for elective surgery 
of pre-existing condition will not be considered serious adverse events, unless there 
was worsening of the preexisting condition during the subject’s participation in this 
study.

a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions

a congenital anomaly/birth defect

important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.

Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or the development of drug dependency or drug abuse. Note: Any 
suspected transmission of an infectious agent via a medicinal product is considered an 
important medical event.
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event, although it may nonetheless be severe (see Appendix A).
7.1.5.2.
Expectedness
A serious adverse event that is not included in the Adverse Reaction section of the relevant 
reference safety information by its specificity, severity, outcome, or frequency is considered an 
unexpected adverse event. The reference safety information (RSI) for this study is the current IB
for TV-46046.
This is a Phase 1 clinical study; to date, expected adverse reactions have not been identified for 
the study drug. However, the composition of TV -46046 including the active product ingredient 
(API) is similar to the approved contraceptive injectables Depo-Provera CI and Depo-subQ 104. 
A serious adverse event that is not included in the Appendix A - Reference Safety Information 
for Expedited Reporting Purposes in the IB is considered an unexpected adverse event.
Teva’s Pharmacovigilance Department will determine the expectedness for all serious adverse 
events.
For the purpose of suspected unexpected serious adverse reaction (SUSAR) reporting, the 
version of the IB at the time of occurrence of the SUSAR applies.
7.1.5.3.
Reporting a Serious Adverse Event
7.1.5.3.1. Investigator Responsibility
To satisfy regulatory requirements, all serious adverse events (as described in Section 7.1.5.1) 
that occur during the study period (including the protocol-defined follow-up period, described in 
Section 7.1.2), 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 adverse event form and reporting the 


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event must not be delayed, even if not all the information is 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 should 
be reported to the sponsor if the investigator becomes aware of them.
The serious adverse event form should be sent to the local safety officer (LSO) and FHI 360 
(contact information is in the Clinical Study Personnel Contact Information section); the LSO 
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

date and amount of last administered dose of study drug

action taken

outcome, if known

severity

explanation of assessment of relatedness

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)
Each report of a serious adverse event will be reviewed and evaluated by the investigator, the 
study medical monitor at FHI 360, 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.
Additional information (follow-up) about any serious adverse event unavailable at the initial 
reporting should be forwarded by the investigational center within 24 hours of when it becomes 
known to the same address as the initial report.


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For all countries, the sponsor’s Global Patient Safety & Pharmacovigilance Department will 
distribute the Council for International Organizations of Medical Sciences (CIOMS) 
form/Extensible Markup Language (XML) file to the LSO and FHI 360 for local submission to 
the regulatory authorities, IEC/IRBs, and investigators, according to regulations. The investigator 
is responsible for ensuring that the IEC/IRB is also informed of the event, in accordance with
national and local regulations.
Blinding will be maintained for the people who are involved directly in the study except for the 
pharmacist or other trained personnel administering the study drug injection. Therefore, in case 
of a SUSAR, only the LSO and FHI 360 medical monitor will receive the unblinded report for 
regulatory submission; the others will receive a blinded report.
Note: Although pregnancy is not a serious adverse event, the process for reporting a pregnancy is 
the same as that for reporting a serious adverse event, but using the pregnancy form
(see Section 7.2).
7.1.5.3.2. 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 regulatory authorities (and IEC/IRB, 
if appropriate).
In addition to notifying the investigators and regulatory authorities (and IEC/IRB, if appropriate), 
other measures may be required, including the following:

altering existing research by modifying the protocol

discontinuing or suspending the study

altering the process of informed consent by modifying the existing consent form and 
informing current study participants of new findings

modifying listings of expected toxicities to include adverse events newly identified as 
related to TV-46046
7.1.6.
Protocol-Defined Adverse Events for Expedited Reporting
No protocol-defined adverse events for expedited reporting were identified for this study.
7.1.7.
Withdrawal Due to an Adverse Event
Any subject who experiences an adverse event may be withdrawn from the study at any time at 
the discretion of the investigator. If a subject is withdrawn wholly or in part because of an 
adverse event, the adverse event CRF and the final status CRF will be completed at that time.
Given a single dose design and sustained nature of the study drug, withdrawal from the study is 
possible but withdrawal from treatment is not possible. Study staff will explain to participants 
who wish to discontinue the study early due to adverse event that the study product will remain 
in the body months after injection and the importance of staying in the study at least until 
resolution of an adverse event. Should the subject decide to withdraw from the study, every 
reasonable effort will be made to assess information relevant to the endpoints at the time of 


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discontinuation. This may include but may be not limited to progesterone and MPA testing, 
pregnancy testing and assessment of ISRs, and/or acceptability. The final visit procedures should 
be followed for all subjects who withdraw, if possible (see Section 3.14.4.1).
In addition, a blood sample will be obtained for the measurement of study drug concentrations. 
The subject will be monitored at the discretion of the investigator (eg, until the event has 
resolved or stabilized, until the subject is referred to the care of a health care professional, or 
until a determination of a cause unrelated to the study drug or study procedure is made). The 
investigator must inform the Clinical Project Physician/Clinical Lead as soon as possible of each 
subject who is being considered for withdrawal due to adverse events. Additional reports must be 
provided when requested.
If a subject is withdrawn from the study for multiple reasons that include adverse events, the 
termination page of the CRF should indicate that the withdrawal was related to an adverse event.
7.1.8.
Overdose of Study Drug
Given the single-dose study design and provision of the study drug by a medical provider, 
overdose of study drug is not anticipated. In the unlikely event of administration error, relevant 
information will be documented and reported to the study medical monitor and sponsor 
promptly.
7.1.9.
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 individual identified in the Clinical Study Personnel Contact Information section of 
this protocol as soon as possible to discuss the situation. The investigator, in consultation with 
the sponsor, will decide whether the subject should continue to participate in the study with 
understanding that the study drug will remain in the body for an extended period of time.
7.2.
Pregnancy 
The risk of pregnancy is minimal due to the fact that only women who are at low risk of 
pregnancy will be enrolled in the study (see Section 4.1 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 
36 months will be enrolled in the study. During the study 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, any participant becoming pregnant during the study will be 
withdrawn and pregnancy recorded as reason for discontinuation on appropriate study CRFs. 
Pregnancy will be reported immediately to the individual identified in the clinical study 
personnel contact information section of this protocol, and the investigator must provide the LSO
and FHI 360 medical monitor with the pregnancy form. The process for reporting a pregnancy is 
the same as that for reporting a serious adverse event (see Section 7.1.5.3 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.


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If the pregnancy does not continue to term, 1 of the following actions will be taken:

For an elective abortion due to developmental anomalies, report as a serious adverse 
event.

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.
7.3.
Medication Error and Special Situations
Any administration of medication that is not in accordance with the study protocol should be 
reported on the CRF either as a violation, if it meets the violation criteria specified in the 
protocol (Section 10.1.2), or as a deviation, in the subject’s source documents, regardless of 
whether an adverse event occurs as a result. All instances of incorrect medication administration 
should be categorized on the CRF as “Non-Compliance to investigational medicinal product 
(IMP)”.
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, subject, 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.

Misuse: Situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the authorized product information.

Abuse: Persistent or sporadic, intentional excessive use of medicinal products which 
is accompanied by harmful physical or psychological effects.

Off-label use: Situations where a medicinal product is intentionally used for a medical 
purpose not in accordance with the authorized product information.

Occupational exposure: Exposure to a medicinal product, as a result of one’s 
professional or non-professional occupation.
7.4.
Clinical Laboratory Tests
A clinical laboratory test for hemoglobin will be performed at the screening visit using the 
investigational center laboratory within 24 hours of blood collection. Liver function testing 
including, but not limited to, ALT and AST will be performed in Part 2 only by the 
investigational center laboratory at the screening visit, as well as at the month 3, month 7.5 and 
final visits. Detailed instructions on how to draw and prepare samples for liver function testing 
will be investigational center-specific and provided in the laboratory SOPs and/or Study Manual.


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7.5.
Vital Signs
Vital signs (BP [systolic/diastolic], pulse, and respiration) will be measured at the time points 
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 
should be repeated as soon as possible. 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, recorded on the source documentation, transcribed onto the CRF, and 
monitored as described in Section 7.1.2.
7.6.
Body Weight
Body weight will be measured at the time points detailed in Table 1 and documented on 
appropriate study CRF. A standardized protocol for weight measurement will be provided in the 
study manual.
Weight gain or loss will be documented as an adverse event only if reported by the subject.
7.7.
Injection Site Reactions
The tolerability of subcutaneous injection of different doses and volumes of TV-46046 will be 
assessed by evaluating ISRs after the injection during the enrollment/injection visit twice (within 
10 minutes and within the 1st hour of post-injection), at days 1, 2, 3, and 5; during the scheduled 
follow-up visits at day 7, month 3, and month 7.5; at the final visit; and at other visits, if 
indicated. All ongoing ISRs will be examined during the next clinic visit, regardless of visit type, 
or more frequently at the discretion of the center investigator, until ISR resolution, or outcome. 
Subjects will be asked about pain, itching, and other problems at the site of injection. The site of 
injection will be examined for signs of redness, swelling, induration, etc. Most ISRs will be 
reported as adverse events and graded for severity similar to adverse events using the DAIDS 
Table for Grading Adult and Pediatric Adverse Events, Version 2.0, November 2014 (see 
Appendix A). Injection site reactions that do not meet the definition of site reaction or Grade 1 
severity per the DAIDS table, “Adverse Event Severity Grading Table: Site Reactions to 
Injections and Infusions” will be considered minor and not reported adverse events. All other 
ISRs will be reported as adverse events. All findings will be recorded on the appropriate study 
CRFs. When feasible and with written consent from the study participant, photographs may be 
taken of the injection site to supplement documentation of ISRs.
7.8.
Menstrual Bleeding Patterns
Study subjects will be asked about changes in their menstrual bleeding patterns, including no 
bleeding since last assessment, at monthly intervals (in Part 1 only) and during the scheduled
follow-up visits in both Part 1 and Part 2 at week 13 (month 3) and week 32 (month 7.5), and at 
the final study visit. Interview items will include date of last bleeding, description of bleeding 
pattern since last visit, as well as frequency of bleeding, duration of episodes, pain/cramps, and 
volume, all compared with the pre-study period. The acceptability and tolerability of the 
bleeding pattern will be queried.


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In addition, in Part 2, subjects will be trained to use and prompted to complete weekly menstrual 
diaries on-line. On these diaries, subjects will record daily occurrence of no flow, spotting
(pantyliner or no protection needed), bleeding (tampons or sanitary pads needed), and pain 
(none/mild or moderate/severe) for the last seven days. These data will be automatically 
uploaded into the clinical data base using the OpenClinica Participate module.
7.9.
Mood Changes
In Part 2, subjects will be interviewed about aspects of and changes in mood at screening and at 
the scheduled follow-up visits at month 3 and month 7.5, and at the final study visit. To measure 
depression or psychological distress, a selected validated scale, such as the 10-item Patient 
Health Questionnaire (PHQ-9) that screens for depression, will ascertain the frequency of a 
variety of somatic and emotional indicators of well-being and produce an overall score that can 
be compared at different time points in the study. The PHQ-9 includes items on pleasure in doing 
things, having little energy, feeling bad about yourself, and having trouble concentrating, among 
others. The frequency of each indicator is then summed to produce a single overall score for the 
severity of depression.
7.10.
Concomitant Therapy or Medication
Concomitant therapy or medication usage will be monitored throughout the study. Details of 
prohibited medications are found in Section 5.3.
7.11.
Methods and Time Points of Assessing, Recording, and Analyzing 
Safety Data
All adverse events will be reviewed on a periodic basis by the medical monitor according to the 
medical monitoring plan (eg, scheduled safety reviews for study drug) as interim/preliminary 
safety databases become available. Safety data will be reviewed at the time of the study interim 
analyses by the DSMB. Information about the DSMB used for this study is provided in 
Section 3.8.3. In addition, safety data will additionally be evaluated periodically and ad hoc 
(if necessary) in the Teva’s Product Safety Group.
Methods and timing of assessing safety data are discussed in Section 3.14. Procedures for 
recording safety data are discussed in Section 12.1 and methods of analyses are discussed in 
Section 8.8.2.
7.12.
ASSESSMENT OF ACCEPTABILITY
The acceptability of the different injection doses and volumes will be assessed and recorded on 
appropriate study CRFs at the end of the enrollment/injection visit, at the scheduled follow-up 
visits at day 7, month 3 (week 13), and month 7.5 (week 32), and at the final visit by blinded 
staff. During the enrollment/injection visit the subject will be asked about her perception of pain 
at injection. Other acceptability questions will include but not be limited to questions about 
acceptability of the bleeding patterns (only during month 3 and month 7.5 follow-up visits, and 
final visit) and other side effects, what she likes and dislikes most about this method, whether she 
would use this method in the future and/or recommend it to a friend, and whether the schedule of 
re-injections was acceptable. In addition, the study staff performing the injection during the 


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enrollment/injection visit will be asked about the ease of resuspension and performing the study 
drug injection.


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8.
STATISTICS
This section describes the statistical and pharmacokinetic analyses of primary and secondary 
objectives as foreseen at the time of planning the study. Changes, additions, and further details 
about the analyses will be described in a separate statistical analysis plan written and approved 
prior to study initiation. Any substantive changes made to the statistical analysis plan after study 
initiation, including changes made to address revisions to the protocol, will be documented in 
subsequent approved versions of the statistical analysis plan and fully disclosed in the clinical 
study report.
8.1.
Sample Size and Power Considerations
Sample size for the exploratory pharmacokinetics component of the study (Part 1), 6 subjects in 
each of up to 3 additional treatment groups, is not intended to make definitive conclusions 
regarding the pharmacokinetics of TV-46046. Rather, it is intended to provide assurance that the 
half-life and other key pharmacokinetic properties of undiluted TV-46046 are consistent with a 
6-month duration of use before moving into the dose-range finding component of the study 
(Part 2). It will also allow assessment of whether a diluted formulation may have a more 
favorable pharmacokinetic profile, in the event undiluted drug is not moved into Part 2. 
Likewise, the sample size for Part 2 (up to 20 subjects in each of up to 3 additional treatment
groups) was not chosen to make definitive conclusions regarding the efficacy of TV-46046. 
However, on the basis of historical data of MPA delivered subcutaneously (eg, the variability of 
pharmacokinetic parameter estimates; Jain et al, 2004; Toh et al, 2004), the sample size should 
be sufficient to inform the selection of a dose of undiluted TV-46046 for further study as a 
6-month contraceptive method, if warranted. Scientific judgment will be used to determine if the 
sample size in Part 2 can be reduced from 20 subjects per group, depending on the variability of 
population pharmacokinetic parameter estimates and rates of return to ovulation observed in 
Part 1 or interim Part 2 data.
8.2.
Analysis Sets 
In the definitions that follow, an Analysis Population refers to a particular set of study subjects
and an Analysis Set refers to the time contributed to analyses by subjects in a given population. 
Each analysis population and analysis set will be derived and analyzed separately for each 
component (Part 1 and Part 2) of the study unless otherwise noted. However, the definitions are 
assumed to be the same for both components.
8.2.1.
Screened Population
All subjects who consent to be screened for a given part of the study, regardless of enrollment 
status.
8.2.2.
Treated Population
All subjects who consent to participate in a given part of the study, are enrolled, and receive an 
injection of study drug. Analyses of this population will be based on the treatment received. In 
the event of Part 2 randomization errors, failure to follow the intention-to-treat principle will be 
justified on the grounds that the study will not be used to make definitive conclusions regarding 


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the efficacy of TV-46046. The corresponding Treated Analysis Set includes all baseline and 
follow-up data contributed by subjects in the Treated Population, up to and including applicable 
censoring times described elsewhere in this section.
8.2.3.
Primary Evaluable Population
The Primary Evaluable Population is a subset of the Treated Population, excluding subjects who 
have detectable MPA in their baseline specimen (more than 5% of their individual Cmax) or for 
whom a major protocol violation occurred at enrollment, including: the absence of a confirmed 
ovulation in the pre-treatment period; BMI outside the eligible range (including the 6 subjects 
purposefully enrolled with BMI ≥40); or use of drugs known to impact ovulation or the 
pharmacokinetics of MPA. The Primary Evaluable Analysis Set includes all time contributed by 
participants in the Primary Evaluable Population during which a pharmacokinetic or 
pharmacodynamic outcome is assessed, up to the initiation of any concomitant medication 
known to impact ovulatory function or the pharmacokinetics of MPA.
8.3.
Data Handling Conventions
The primary pharmacodynamic outcome, time to serum progesterone ≥4.7 ng/mL, will be 
censored 12 months following initiation of treatment; no imputation of missing 
pharmacodynamic outcomes prior to month 12 will take place. Missing MPA concentrations at 
key time points (eg, start- and end-times of partial areas under the concentration-time curve) will 
be imputed, as appropriate, using methods specified in the detailed statistical analysis plan. 
Incomplete adverse event onset or concomitant medication use dates may also be imputed or 
adjudicated by the Medical Monitor (blinded to treatment group assignment and incorporated 
into the clinical database per FHI 360 SOPs) to assess safety or when censoring subjects from 
analyses due to excluded medication use. No other missing data will be imputed unless otherwise 
specified in the detailed statistical analysis plan.
8.4.
Study Population
8.4.1.
Subject Disposition
The numbers of subjects screened and enrolled to each treatment group in each part of the study 
will be tabulated by investigational center and pooled across sites. A flow diagram will be 
provided which presents the numbers and percentages of participants contributing to the 
Screened, Treated, and Primary Evaluable Populations; reasons for exclusion from analysis 
populations; total women-years (WY) of follow-up contributed to each analysis set (by treatment 
group and overall); and the numbers and percentages of subjects who complete the study, 
discontinue early (overall and by reason), or are lost to follow-up. Protocol deviations will be 
summarized in frequency tables, by investigational center and treatment group. Categories of 
deviations will include violations of study entry criteria (eg, age, BMI, or use of excluded 
medications), randomization errors, violation of study withdraw criteria, and other violations 
captured on CRFs.


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8.4.2.
Demographic and Baseline Characteristics
Summary statistics (frequencies, percentages, means, medians, inter-quartile range, minima, and 
maxima) appropriate to the measurement scale will be used to describe baseline demographic, 
behavioral, medical, and contraceptive use history data. Continuous variables may be described 
using categorical levels chosen based on previous experience with similar studies. Baseline data 
will be presented for the Screened Population, the Treated Population, and the Primary Evaluable 
Population. Summaries will be provided by treatment group, investigational center, and pooled 
across sites and regimens. No formal statistical testing will be performed to compare 
distributions of baseline characteristics between randomized method groups.
8.5.
Pharmacokinetic Analysis
8.5.1.
Primary Endpoints
8.5.1.1.
Part 1 (Exploratory Pharmacokinetics)
Individual and mean serum MPA concentration-time profiles, and estimated noncompartmental 
pharmacokinetics parameters, including but not limited to Cmax, tmax, C182 (week 26), AUC0-182, 
AUC0-∞, and the apparent terminal half-life.
8.5.1.2.
Part 2 (Dose-range Finding)
Individual and mean serum MPA concentration-time profiles, and estimated noncompartmental 
pharmacokinetic parameters, including but not limited to: Cmax, tmax, C182, C210 (week 30), 
AUC0-182, AUC0-210, AUC0-∞, and apparent terminal half-life.
8.5.2.
Secondary Pharmacokinetic Endpoints
Release rates, relative bioavailability, and other pharmacokinetic parameters derived from 
non-linear mixed model compartmental analysis of serum MPA concentrations over time.
8.5.3.
Planned Method of Analysis
There are 5 planned reviews of the interim data; 2 reviews in Part 1 and 3 reviews in Part 2, 
although their number and timing may change based on the findings. The 2nd interim data review 
in Part 1 is intended to inform the decision to move into, and the selection of doses for, Part 2. 
The timing of interim data reviews may change based on the findings. For details, see 
Section 8.10.
For both Part 1 and Part 2, individual MPA profiles will be displayed through month 12 
following treatment initiation or earlier date of withdrawal from the study using the Primary 
Evaluable Analysis Set, with any post-baseline MPA concentrations that fall below the limit of 
quantification (LOQ) replaced by half the applicable LOQ. If 120 mg/mL is selected as one of 
the doses in Part 2, then subjects in that treatment group in Part 1 will be incorporated in the 
Part 2 pharmacokinetics analysis. Data from the subset of 6 subjects (2 per treatment group) with 
extreme obesity (BMI ≥40) in Part 2, and subjects with detectable MPA at baseline or who used 
drugs known to interfere with pharmacokinetics or pharmacodynamics of MPA prior to return to 
ovulation, will be excluded from the primary analysis but will be described separately. Sparse 
data collected after month 12 will likewise be described separately for the subset of subjects who 


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have not ovulated by month 12. Pharmacokinetic parameters will be estimated for each subject in 
the Primary Evaluable Population using non-compartmental analysis. 
Summaries of pharmacokinetics parameters and metrics will include means, medians, geometric 
means, minima, maxima, as well as standard deviation (SD), percent coefficient of variation 
(%CV) and 95% CIs for means and geometric means. The time to achieve MPA concentration 
greater than 0.2 ng/mL, and the number and percentage of subjects with MPA serum 
concentrations below 0.1 ng/mL and 0.2 ng/mL at days 182 and 210, will likewise be 
summarized by treatment group. Treatment group comparisons will be based on 90% confidence 
intervals for geometric mean ratios of pharmacokinetic parameters or analysis of covariance 
based on log-transformed responses. Specific variables included in covariate adjusted analyses 
(eg, age, BMI) will be specified in the separate statistical analysis plan.
In addition to assessing non-compartmental pharmacokinetic parameters by treatment group in 
Part 1, population pharmacokinetic effects modeling and simulation will be performed to inform 
dose selection and sample size for Part 2.
 
8.5.3.1.
Sensitivity Analysis
Sensitivity analyses will be performed excluding subjects determined to be outliers (eg, due to 
strong suspicion of injection on or near a blood vessel).
8.5.3.2.
Exploratory Analysis
 
 
 
 
 
 
8.6.
Pharmacodynamic Analysis
The primary pharmacodynamic objective in Part 2 will be assessed by estimating the cumulative 
probability of return to ovulation (occurrence of progesterone ≥4.7 ng/mL) through 52 weeks 
from start of study drug treatment in the Primary Evaluable Population; if 120 mg/mL is selected 
as one of the doses in Part 2, then subjects assigned to that treatment group in Part 1 will be 
incorporated in the analysis. Cumulative probabilities will be estimated for each treatment group 
based on the Kaplan Meier method and 95% CIs derived using the complementary log-log 
transformation. Differences in the distribution of return to ovulation between dose groups will be 
explored based on two-sided log-rank tests conducted at the 0.05 significance level, stratified on 
investigational center. For descriptive purposes the median, inter-quartile range, minimum, and 
maximum time to ovulation will be reported by treatment group. Data from the subset of 
6 subjects (2 per treatment group) with extreme obesity (BMI ≥40), and subjects with detectable 
MPA at baseline or who used drugs known to interfere with the pharmacokinetics or 


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pharmacodynamics of MPA prior to return to ovulation will be excluded from the primary 
analysis but will be described separately.
Nonlinear mixed effects pharmacokinetic/pharmacodynamic modeling and simulation will be 
used to explore the relationship between individual serum MPA concentrations and duration of 
ovulation suppression, with particular emphasis on characterizing the distribution of any 
apparent ovulatory suppression threshold and the lowest dose, which may reliably inhibit 
ovulation for 6 months.
8.7.
Multiple Comparisons and Multiplicity
No adjustments will be made for the planned or unplanned multiple comparisons of primary or 
secondary pharmacokinetic or pharmacodynamic endpoints.
8.8.
Safety Endpoints and Analysis
Safety analyses will be performed on the Treated Population.
8.8.1.
Safety Endpoints
Safety measures and time points are provided in Section 3.5 and Table 1.
8.8.2.
Safety Analysis
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) by preferred term and system organ class (SOC). The number and percentage of 
participants experiencing adverse events will be presented by treatment group: overall, by 
severity grade, relatedness to treatment, and according to whether or not the event had an onset 
date within 7.5 months of initiation of study drug treatment (the intended dosing interval plus 
1.5 months). Serious adverse events and adverse events leading to withdrawal from the study 
will be summarized separately. All relevant information on any deaths will be discussed in the 
subject narrative included in the clinical study report.
Summaries of ISR data will be provided by group in frequency tables and using subject-data 
listings, and the differences in proportions of subjects experiencing ISRs between treatment 
groups will be compared descriptively using Fisher’s exact tests. The probability of return to 
ovulation more than 12 months after treatment initiation with TV-46046 will be estimated using 
Kaplan-Meier methods, with corresponding 95% CIs presented by group.
The percentage of women experiencing amenorrhea or other menstrual bleeding disturbances 
(irregular bleeding or spotting) will be assessed at monthly intervals during scheduled laboratory 
visits (in Part 1 only) and at follow-up visits at week 13 and week 32 only, and the final study 
visit. In addition, in Part 2 weekly self-reported menstrual data will be assessed, and compared 
between treatment groups using frequency tables; details are found in the Statistical Analysis 
Plan (SAP). In Part 2 only, liver function tests, including but not limited to ALT and AST, will 
be assessed by tabulating and graphing change from screening to week 13 (month 3), week 32 
(month 7.5), and final study visit data. In Part 2 only mood will be assessed in frequency tables 
at screening and at week 13 (month 3), week 32 (month 7.5), and final study visits. Vital signs 
and body weight will be summarized graphically and using shift-tables, by investigational center 
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The use of concomitant medications during follow-up will be summarized by therapeutic class 
using descriptive statistics.
8.9.
Acceptability Variables and Analysis
The responses to acceptability questions regarding menstrual patterns will be assessed at 
week 13, week 32, and the final study visit, and compared between treatment groups. Perceptions 
of pain at time of injection and responses on other acceptability questionnaire items, as well as 
assessment of ease of injection by the study staff, will likewise be summarized and descriptively 
compared between treatment groups.
8.10.
Planned Interim Analyses
This Phase1 study has a data-driven, 2-part design. The purpose of Part 1 is to select an 
appropriate drug concentration and dose levels for further study. If undiluted TV-46046 has an 
appropriate pharmacokinetic profile based on the results of Part 1, then the study will move 
seamlessly into a dose-range finding component (Part 2). If the undiluted formulation does not 
have an appropriate pharmacokinetic profile, and/or one of the saline-diluted TV-46046 
concentrations has a more acceptable profile, then a less concentrated formulation may be 
recommended for further development and testing in a separate protocol.
There are several planned reviews of the interim data, although their number and timing may 
change based on the findings. The 1st review will be performed after the 6 subjects in treatment 
group 1 of Part 1 (receiving undiluted TV-46046) have completed 1 month of post-injection 
follow-up, and is intended to inform the early part of the pharmacokinetic profile (eg, whether or 
not the contraceptive threshold is likely to be achieved within 24 hours with a dose of no more 
than 300 mg). The 2nd review will be performed after the same 6 subjects in treatment group 1 of 
Part 1 have completed 4 months post-injection, and is intended to inform the decision to move 
into, and the selection of doses for, Part 2. At that time, available pharmacokinetics data from 
women in treatment group 2 (ie, the next 6 women receiving diluted TV-46046) will also be 
analyzed. Additional assessments will be made if warranted (eg, when the 12 women in both the 
undiluted and diluted groups complete 4 months (17 weeks)). Other features of the undiluted 
drug may also be considered in the decision-making process, including stability, re-
suspendability, syringeability, and safety, although these will not be part of the formal analysis.
At least two interim reviews are planned to occur in Part 2 (after 50% of subjects have completed 
approximately 4 months and 7.5 months post-injection, respectively). These analyses are 
primarily intended to help inform the decision to move to and the dose selection for a Phase 3 
clinical study. Additional interim analyses of Part 2 data may be conducted if needed to inform 
potential modifications to the Phase 1 study. The final planned data review will occur when 
100% of subjects in Part 2 have completed 7.5 months post-injection (ie, the entire intended 
dosing interval plus 1.5 months); those data may be submitted to the FDA in the pre-Phase 3 
submission.
The decision to move into Part 2 will be based on predicted pharmacokinetic parameters for a 
range of potential Part 2 doses, as informed by observed Part 1 pharmacokinetic data. Part 2 will 
only be implemented if the administration of undiluted TV-46046 (400 mg/mL) in Part 1 
demonstrates an appropriate pharmacokinetic profile. Pharmacokinetic criteria considered before 
moving into Part 2 include predicted mean Cmax less than 3 ng/mL, predicted time to achieve 


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0.2 ng/mL no more than 24 hours after study drug administration for all subjects, predicted 
6-month concentration greater than 0.1 ng/mL in 95% of subjects, and predicted concentration 
24 months after the last injection below 0.1 ng/mL in 90% of subjects for all treatment groups
selected for Part 2.
As no formal hypothesis testing is being conducted in this study, no adjustment for multiple 
comparisons will be made to account for these interim analyses. Early evidence of unexpected, 
severe, or serious adverse events, including ISRs, could lead the DSMB to recommend 
termination of enrollment into one or more treatment groups, recognizing that enrollment may be 
completed before an informative interim analysis takes place. A schedule of planned reviews of 
the interim data, DSMB meetings, DSMB operation and responsibilities, and guidelines for 
premature discontinuation of the study will be provided in the statistical analysis plan and a 
separate DSMB operational plan.
8.11.
Reporting Deviations from the Statistical Plan
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, amendments to the statistical analysis plan, the clinical study report, or 
any combination of these, as appropriate, and in accordance with applicable local and regional 
requirements and regulations.


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9.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The study monitors, auditors, IEC/IRB, and health authority inspectors (or their agents) will be 
given direct access to source data and documentation (eg, medical charts/records, laboratory test 
results, printouts, videotapes) for source data verification, provided that subject confidentiality is 
maintained in accordance with local requirements.
The investigator must maintain the original records (ie, source documents) of each subject’s data 
at all times. Examples of source documents are hospital records, office visit records, examining 
physician’s finding or notes, consultant’s written opinion or notes, laboratory reports, drug 
inventory, study drug label records, and CRFs that are used as the source (see Section 3.13).
The investigator will maintain a confidential subject identification list that allows the 
unambiguous identification of each subject. All study-related documents must be kept until 
notification by the sponsor.


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10.
QUALITY CONTROL AND QUALITY ASSURANCE
10.1.
Protocol Amendments and Protocol Deviations and Violations
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 IEC/IRB and national and local 
competent 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 principal investigator at each investigational center, the coordinating 
investigator (if applicable), and the sponsor will sign the protocol amendment.
10.1.2.
Protocol Violations
Any deviation from the protocol that affects, to a significant degree, (a) the safety, physical, or 
mental integrity of the subjects of the study and/or (b) the scientific value of the study will be 
considered a protocol violation. Protocol violations 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; noncompliance to study drug 
administration; or use of prohibited medications. Protocol violations will be identified and 
recorded by investigational center personnel in the CRF. All protocol violations will be reported 
to the responsible IEC/IRB, as required.
Changes in the inclusion and exclusion criteria of the protocol are not prospectively granted by 
the sponsor. If investigational center personnel learn that a subject who did not meet protocol 
inclusion and exclusion criteria was entered in a study, they must immediately inform the 
sponsor of the protocol violation. If such subject has already completed the study or has 
withdrawn early, no action will be taken but the violation will be recorded.
Lesser protocol deviations, i.e. those that do not significantly affect subject safety or scientific 
value of the data, will be recorded in a Protocol Deviation Log. The cumulative Log will be 
submitted to the responsible IEC/IRB at annual reviews.
10.2.
Information to Study Personnel
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 course of the study (eg, when new staff become involved). The investigator must 
assure that all study staff members are qualified by education, experience, and training to 
perform their specific responsibilities. These study staff members must be listed on the 
investigational center staff responsibility log, which includes a clear description of each staff 
member’s responsibilities. This list must be updated throughout the study, as necessary.
FHI 360 is responsible for explaining the protocol to all study staff, including the investigator, 
and for ensuring they comply with the protocol. Additional information will be made available 
during the study when new staff become involved in the study and as otherwise agreed upon with 
either the investigator or the study monitor.


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10.3.
Study Monitoring
Qualified FHI 360 or contract clinical monitors will conduct periodic study monitoring in 
accordance with FHI 360 policies. The monitor will make site visits as needed and as feasible, 
with a minimum of one initiation training visit, interim monitoring visits approximately every 
6 months, and one close-out visit to assure that the study is being conducted and informed 
consent is being obtained according to the approved protocol, and to monitor recruitment and 
data accuracy. Before the study begins, FHI 360 will develop a detailed clinical monitoring plan. 
Briefly, the study clinical monitors will:

Review informed consent forms and documentation

Assess compliance with the study protocol, GCP guidelines, and applicable 
regulatory requirements (US and non-US)

Verify that all serious adverse events in source documents have been reported on 
CRFs and in accordance with regulatory guidelines

Perform source document verification to ensure the accuracy and completeness of 
study data

Verify proper collection and storage of biological specimens

Verify proper storage, dispensing, and accountability of study products

Verify that current license/certification is available on site for study staff listed on the 
current Statement of Investigator Form, and Delegation of Responsibilities Log
During the course of this study, a qualified FHI 360 monitor or contract monitor will maintain 
regular contact with the investigational centers and regularly review clinical data received at 
FHI 360.
The center investigator or designee will securely maintain all source documents used to complete 
CRFs, including medical notes and laboratory reports. All study records will be retained 
following FHI 360 SOPs unless an exception is granted.
Investigators and study staff will allow the monitors to inspect the regulatory file, study 
documents (eg, consent forms, case report forms, other source documents) and pertinent clinic 
records for verification of the study data. Investigators and staff will allow clinical monitors to 
inspect study facilities and documentation.
As part of the supervision of study progress, other FHI 360 staff or representatives may, on 
request, accompany the study monitor on visits to the investigational center. The center 
investigator and assisting staff must agree to cooperate with the study monitor to resolve any 
problems, errors, or possible misunderstandings concerning the findings detected in the course of 
these monitoring visits and/or provided in follow up written communication. Investigational 
centers will maintain a site visit log to document all visits.
10.4.
Clinical Product Complaints
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical drug supplies and/or clinical device supplies used in a 


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clinical research study sponsored by Teva. 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 site 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 Teva 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 a drug product, all relevant samples (eg, the remainder of the subject’s drug supply) 
should be sent back to the sponsor for investigative testing whenever possible. 
10.4.1.
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 principal investigator name

name, phone number, and address of the source of the complaint 

clinical protocol number

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 according to 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 


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Note: Reporting a complaint must not be delayed because 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.
10.4.2.
Handling the Study Drug at the Investigational Center
The investigator is responsible for retaining the product in question in a location separate from 
the investigator’s clinical study supplies. The sponsor may request that the investigator return the 
product for further evaluation and/or analysis. If this is necessary, the clinical study monitor or 
designee will provide the information needed for returning the study drug. Details may be found 
in the Pharmacy Manual.
If it is determined that the investigational center must return all of the study drug, the sponsor 
will provide the information needed to handle the return.
The integrity of the randomization code and corresponding blinded clinical supplies will be 
maintained whenever possible. A serious adverse event or the potential for a product quality 
problem existing beyond the scope of the complaint may be a reason to unblind the clinical 
supplies for an affected subject.
10.4.3.
Adverse Events or Serious Adverse Events Associated with a Product Complaint
If there is an adverse event or serious adverse event due to product complaint, the protocol 
should be followed for recording and reporting (Section 7.1.2 and Section 7.1.5.3, respectively).
10.4.4.
Documenting a Product Complaint
The investigator will record a description of the product complaint in the source documentation 
as well as 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.
10.5.
Audit and Inspection
The sponsor 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 regulatory authorities and sponsor representatives may conduct 
inspections to verify compliance with GCP guidelines.


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11.
ETHICS
Details of compliance with regulatory guidances and applicable laws are provided in Section 1.6.
11.1.
Informed Consent
A participant will not be enrolled into this research study until the center investigator has 
obtained her legally effective (signed and/or witnessed) informed consent. The center
investigator shall seek such consent under circumstances that provide the prospective participant 
with sufficient opportunity to learn about the study and consider whether or not to participate in 
it. Informed consent will be obtained without coercion, undue influence or misrepresentation of 
the potential benefits and risks that might be associated with participation in the research study. 
Informed consent encompasses all oral or written information given to the participant about the 
study and the study materials. This includes the consent form signed by the participant and any 
other information provided to the participant. All such information that is given to the participant 
will be in a language that is understandable to her. The participant must agree that she 
understands the investigational nature of the study, its inherent risks and benefits, other treatment 
alternatives, her rights to terminate participation in the study without affecting her health care at 
the site, whom to contact with questions regarding the study, and that she has freely given 
informed consent to participate in the study and to have her medical records reviewed as part of 
the study.
Informed consent will be documented by the use of a written consent form that is signed by the 
participant (or with the participant’s mark if she cannot sign). A copy of the signed informed 
consent form will be given to her. The original signed consent form for each participant will be 
stored in a secure location separately from the study data forms. The consent form must include 
each of the basic and additional elements of informed consent described in 45 CFR Part 46.116 
and must describe each of the risks or discomforts to the participant that have been identified by 
FHI 360 as reasonably foreseeable. The information will not include any language in which the 
participant is made to waive any of her rights or which releases or appears to release the center
investigator, the center investigator’s institution, or the sponsor from liability for negligence.
11.2.
Health Authorities and Independent Ethics Committees/Institutional 
Review Boards
This protocol, the informed consent forms, and other documentation (as required) will be 
reviewed and approved by the PHSC at FHI 360 and the site IRBs. The center investigator at 
each research site is responsible for ensuring that all requirements of the local IEC/IRB are met. 
Before implementing any changes to the protocol, informed consent, or participant written 
materials, the center investigator must have the changes approved by FHI 360’s PHSC and the 
local IEC/IRB, and applicable health regulatory agencies, except where necessary to eliminate 
immediate hazards to human participants. If the local IEC/IRB withdraws its approval of this 
research at any time before its completion, the investigator must notify FHI 360 as soon possible, 
but no later than within 48 hours.
The center investigator is responsible for making progress reports to the local IEC/IRB and to 
FHI 360 annually and within 3 months of study termination or completion. The reports should 


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include at a minimum the total number of participants enrolled, the numbers and reason(s) for 
discontinuation, a description of all serious adverse events, the number of participants 
completing the study, all changes in the research activity, and all unanticipated problems 
involving risks to human participants or others. Copies of all study-related correspondence with 
the local IEC/IRB must be sent to FHI 360.
11.3.
Confidentiality Regarding Study Subjects
The investigator must ensure that the privacy of the subjects, including their identity and all 
personal medical information, will be maintained at all times. All study visit procedures will be 
conducted in private. In CRFs and other documents or image material submitted to the sponsor, 
subject s will be identified not by their names, but by a subject identification number.
Personal medical information may be reviewed for the purpose of subject safety and/or 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, the quality assurance unit, and/or 
regulatory authorities. Personal medical information will always be treated as confidential.
11.4.
Declaration of the End of the Clinical Study
The definition of the end of study is the date of the last visit of the last subject.
11.5.
Registration of the Clinical Study
In compliance with local regulations and in accordance with Teva standard procedures, this 
clinical study will be registered on ClinTrials.gov.


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12.
DATA HANDLING, DATA QUALITY CONTROL, AND RECORD 
KEEPING
12.1.
Data Collection
Most data will be collected using 1-ply CRFs that are specifically designed for this study. The 
data collected on the CRFs will be captured in a clinical data management system (CDMS) that 
meets the technical requirements described in 21CFR Part 11. 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 who require access to 
the system will receive training on the system and study-specific training. After they are trained, 
those users will be provided with individual system access rights.
Data will be collected at the investigational center by appropriately designated and trained 
personnel, and CRFs must be completed for each subject who provided informed consent. 
Subject identity should not be discernible from the data provided on the CRF. Data will be 
verified using the data source by the study monitor, and reviewed for consistency by Data 
Management using both automated logical checks and manual review. 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.
In Part 2 only, data on menstrual bleeding will be collected weekly using the validated, Part 11-
compliant on-line Participate application module of OpenClinica, the CDMS. Women will be 
prompted by text message and/or e-mail to open a unique link, with access code, to access the 
application and submit answers to a brief question set. These data will be automatically uploaded 
in real-time into the OpenClinica clinical database. 
If data are processed from other sources, (eg, central laboratory, bioanalytical laboratory, central 
image center, electronic patient-reported outcome [ePRO] Tablet), the results will be sent to the 
investigational center, where they will be retained but not entered into the CRF unless otherwise 
specified in the protocol. These data may also be sent electronically to the sponsor (or 
organization performing data management) for direct entry into the clinical database. Laboratory 
test results will not be entered into the CRF unless otherwise noted in the protocol. All data from 
other sources will be available to the investigators.
For subjects who enter a study but do not meet entry criteria, at a minimum, data for screen 
failure reason, demography, and adverse events from the time of informed consent will be 
entered into the CRF.
12.2.
Data Quality Control 
Data Management 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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Case report forms received 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 CDMS. Discrepancies found will be queried.
Data corrections in the CDMS will be made using the CDMS functionality. In compliance with 
21 CRF Part 11, 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.
12.3.
Archiving of Case Report Forms and Source Documents
12.3.1.
Sponsor 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. FHI 360 will maintain electronic files of the 
scanned CRFs.
Ultimately, the sponsor will have final responsibility for the processing and quality control of the 
data.
12.3.2.
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 other local laws, including, but not limited to, the following:

full case histories

signed informed consent forms

subject identification lists

case report forms for each subject on a per-visit basis

data results from other sources (eg, central laboratory, bioanalytical laboratory, 
central image center, electronic diary)

safety reports

financial disclosure reports/forms

reports of receipt, use, and disposition of the study drug

copies of all correspondence with sponsor, the IRB/IEC, and any regulatory authority


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The investigator will retain all records related to the study and any additional records required, as 
indicated by the protocol and according to applicable laws and regulations, until the contract 
research organization (CRO) or sponsor sends written notification that records may be destroyed.
If, after 25 years from study completion, or earlier in the case of the investigational center 
closing or going out of business, the investigator reasonably determines that study record 
retention has become unduly burdensome, and sponsor has not provided written notification of 
destruction, then the investigator may submit a written request to sponsor at least 60 days before 
any planned disposition of study records. Upon receipt of such request, the sponsor may make 
arrangements for appropriate archival or disposition, including requiring that the investigator 
deliver such records to the sponsor. The investigator shall notify the sponsor and 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 
principal 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.
The policy of Clinical Trials Insurance will be provided to the investigational centers by the 
sponsor.
For covered clinical studies (see 21CFR54), the investigator will provide the sponsor with 
financial information required to complete Form FDA 3454. Each investigator will notify the 
sponsor of any relevant changes during the conduct of the study and for 1 year after the study has 
been completed.


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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 
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 by the FHI 360 Coordinating Investigator.
When the sponsor generates reports from the data collected in this study for presentation to 
regulatory authorities, drafts will be circulated to the FHI 360 coordinating investigator 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 Teva 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.
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lentivirus-induced protection in rhesus macaques by administration of depo-provera before 
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Baumgartner JN, Morroni C, Mlobeli RD, Otterness C, Myer L, Janowitz B, et al. Timeliness of 
contraceptive reinjections in South Africa and its relation to unintentional discontinuation. 
International family planning perspectives. 2007;33(2):66-74.
Brache V, Sitruk-Ware R, Williams A, Blithe D, Croxatto H, Kumar N, et al. Effects of a novel 
estrogen-free, progesterone receptor modulator contraceptive vaginal ring on inhibition of 
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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.
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Centers for Disease Control and Prevention. Update to CDC's U.S. medical eligibility criteria for 
contraceptive use, 2010: revised recommendations for the use of contraceptive methods during 
the postpartum period. MMWR. 2011;60(26):869-905.
Depo-Provera Contraceptive Injection [package insert]. New York, NY: Pfizer Inc; 2016.
Depo subQ Provera 104 [package insert]. New York, NY: Pfizer Inc; 2016.
Genesca M, Li J, Fritts L, Chohan P, Bost K, Rourke T, et al. Depo-Provera abrogates attenuated 
lentivirus-induced protection in male rhesus macaques challenged intravenously with pathogenic 
SIVmac239. J Med Primatol. 2007;36(4-5):266-75.
Halpern V, Stalter RM, Owen DH, Dorflinger LJ, Lendvay A, Rademacher KH. Towards the 
development of a longer-acting injectable contraceptive: past research and current trends. 
Contraception. 2015;92:3-9.
Hild-Petito S, Veazey RS, Larner JM, Reel JR, Blye RP. Effects of two progestin-only 
contraceptives, Depo-Provera and Norplant-II, on the vaginal epithelium of rhesus monkeys. 
AIDS Res Hum Retroviruses. 1998;14(Suppl 1):S125-S130.
Jain J, Dutton C, Nicosia A, Wajszczuk C, Bode FR, Mishell DRJr. Pharmacokinetics, ovulation 
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Jesam C, Salvatierra AM, Schwartz JL, Fuentes A, Croxatto HB. Effect of oral administration of 
a continuous 18 day regimen of meloxicam on ovulation: experience of a randomized controlled 
trial. Contraception. 2014;90(2):168-73.
Jordan A. Toxicology of depot medroxyprogesterone acetate. Contraception.
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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.
Kaushic C, Ashkar AA, Reid LA, Rosenthal KL. Progesterone increases susceptibility and 
decreases immune responses to genital herpes infection. J Virol. 2003;77(8):4558-65.
Lakha F, Henderson C, Glasier A. The acceptability of self-administration of subcutaneous 
Depo-Provera. Contraception. 2005; 72(1):14-8.
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. JNCL. 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 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.
MHRA. SAYANA PRESS 104 mg/0.65 mL suspension for injection. Public Assessment Report, 
Mutual Recognition Decentralised Procedure. UK/H/0960/002/DC: Pfizer Limited;2015. 
Available at: 
http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con126147.pdf.
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.
Paul C, Skewgg DCG, Spears GFS. Depot medroxyprogesterone (Depoi-Provera) and risk of 
breast cancer. BMJ 1989:299(6702);759-62.
Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN, etc. An updated 
systematic review of epidemiological evidence on hormonal contraceptive methods and HIV 
acquisition in women. AIDS. 2016 Nov 13;30(17):2665-2683.
PRDEPO-PROVERA and PRDEPO-PROVERA-SC [product monograph]. Kirkland, Quebec: 
Pfizer Canada, Inc;2013.
Rahimy MH, Ryan KK, Hopkins NK. Lunelle monthly contraceptive injection 
(medroxyprogesterone acetate and estradiol cypionate injectable suspension): steady-state 
pharmacokinetics of MPA and E2 in surgically sterile women. Contraception. 1999;60(4):209-
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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.


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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.
Stanback J, Spieler J, Shah I, Finger WR. Community-based health workers can safely and 
effectively administer injectable contraceptives: conclusions from a technical consultation. 
Contraception. 2010;81(3):181-4.
Toh YC, Jain J, Rahimy MH, Bode FR, Ross D. Suppression of ovulation by a new 
subcutaneous depot medroxyprogesterone acetate (104 mg/0.65 mL) contraceptive formulation 
in Asian women. Clinical therapeutics. 2004;26(11):1845-54.
United Nations Department of Economic and Social Affairs, Population Division. World 
Contraceptive Use, 2011.
Westhoff CL, Torgal AH, Mayeda ER, Stanczynk FZ, Lerner JP, Benn EKT, et al. Ovarian 
suppression in normal-weight and obese women during oral contraceptive use: a randomized 
controlled trial. Obstet and Gynecol. 2010;116(No. 2 Part 1):275-83.
World Health Organization. Breast cancer and depot-medroxyprogesterone acetate: a 
multinational study. Lancet. 1991;338(8771):833-8.
World Health Organization. Depot-medroxyprogesterone acetate (DMPA) and cancer: 
Memorandum from a WHO meeting. Bull World Health Organ. 1993;71(6):669-76.
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contraceptive eligibility for women at high risk of HIV: 2017 guidance statement 
(WHO/RHR/17.04). Geneva: World Health Organization; 2017. Available at: 
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Williams DL, Hagen AA, Runyan JW, Jr. Chromosome alterations produced in germ cells of 
dogs by progesterone. J Lab Clin Med. 1971;77(3):417-29.
Williams DL, Runyan JW, Jr, Hagen AA. Progesterone-induced alterations of oogenesis in the 
Chinese hamster. J Lab Clin Med. 1972;79(6):972-77.
Wright CE III, Antal EJ, Gillespie WR, Albert KS. Effect of injection volume on the 
bioavailability of sterile medroxyprogesterone acetate suspension. Clin Pharmacy.
1983;(2):435-8.


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16.
SUMMARY OF CHANGES TO PROTOCOL
16.1.
Protocol Amendment 04 Dated 09 August 2017
The primary reasons for this amendment are additions, corrections and clarifications. These 
revisions are considered to be substantial by the sponsor’s Authorized Representative. 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 Laboratory And Other Departments And Institutions
Comité Ético Científico del Servicio de 
Salud Metropolitano Central
Victoria Subercaseaux #381
Santiago, Chile
Comité de Ética de PROFAMILIA 
Clínica Abreu, Calle Beller #42 esq. 
Ave. Independencia
Santo Domingo, Dominican Republic
Comité Ético Científico del Servicio 
de Salud Metropolitano Central
Victoria Subercaseaux #381
Santiago, Chile
Comité de Ética de PROFAMILIA 
Clínica Abreu, Calle Beller #42 esq. 
Ave. Independencia
Santo Domingo, Dominican Republic
Addition. A new 
Investigational Center 
Ethics Committee was 
added.
Clinical Laboratoriesy
University of Pennsylvania 
Endocrinology Laboratory
8th Floor
3701 Market Street
Philadelphia, Pennsylvania 19104
United States of America
Clinical Laboratories
University of Pennsylvania 
Endocrinology Laboratory
8th Floor
3701 Market Street
Philadelphia, Pennsylvania 19104
United States of America
Correction.
Jones Institute for Reproductive 
Medicine Endocrinology Laboratory
601 Colley Avenue 
Norfolk, VA 23507
United States of America
Jones Institute for Reproductive 
Medicine Endocrinology Laboratory
601 Colley Avenue 
Norfolk, VA 23507
United States of America
Correction.
Laboratorios Clinicos PUC - Centro 
Medico San Joaquin 
Vicuna Mackenna 4686 Macul 
Santiago, Chile
Referencia Laboratorio Clínico
Avenida Independencia 202, 3er piso
Edificio Santa Ana
Santo Domingo, Dominican Republic
Laboratorios Clinicos PUC - Centro 
Medico San Joaquin 
Vicuna Mackenna 4686 Macul 
Santiago, Chile
Referencia Laboratorio Clínico
Avenida Independencia 202, 3er piso
Edificio Santa Ana
Santo Domingo, Dominican Republic
Addition. A new clinical 
lab was added.


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Instituto Chileno de Medicina 
Reproductiva 
Jose Victorino Lastarria 29 of 101
Santiago Centro, Santiago
Chile
Asociación Dominicana Pro Bienestar 
de la Familia, Inc.
(PROFAMILIA)
Nicolas de Ovando esq. Calle 16
Ens. Luperon
Santo Domingo, Dominican Republic
Instituto Chileno de Medicina 
Reproductiva 
Jose Victorino Lastarria 29 of 101
Santiago Centro, Santiago
Chile
Asociación Dominicana Pro Bienestar 
de la Familia, Inc.
(PROFAMILIA)
Nicolas de Ovando esq. Calle 16
Ens. Luperon
Santo Domingo, Dominican Republic
Addition. A new 
investigational center 
was added.
Clinical Study Personnel Contact Information
 
FHI 360
Medical Monitor
Tel: 
Tel: 
Fax: 
,  FHI 360
Medical Monitor
Tel: 
Tel: 
Fax: 
Correction.
Clinical Study Protocol Synopsis
Countries Planned: United States 
(US), Chile, and the Dominican 
Republic other Latin American 
countries pending
Countries Planned: United States 
(US), Chile, and the Dominican 
Republic 
Addition. The 
Dominican Republic 
added to the list of 
countries.
Section 1.2.  Name and Description of Investigational Product (Sections 5.1.1 and 7.1.5.3.1)
The 300 and 200 mg/mL 
concentrations will be achieved by 
diluting the original 400 mg/mL 
formulation with sterile saline by a 
pharmacist or other trained 
personnel prior to injection.
The 300 and 200 mg/mL 
concentrations will be achieved by 
diluting the original 400 mg/mL 
formulation with sterile saline by a 
pharmacist or other trained 
personnel prior to injection.
Clarification.


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Section 1.7.  Study Population and Justification
The study will enroll healthy women 18 
to 40 years of age, inclusive, who are at 
low risk of pregnancy (ie, eg, sterilized, 
in exclusively same-sex partnership, in 
monogamous relationship with 
vasectomized partner, using non-
hormonal IUD), and who are confirmed 
to have ovulated during the pre-
treatment phase of the study.
The study will enroll healthy women 
18 to 40 years of age, inclusive, who 
are at low risk of pregnancy (ie, 
sterilized, in exclusively same-sex 
partnership, in monogamous 
relationship with vasectomized 
partner, using non-hormonal IUD), 
and who are confirmed to have 
ovulated during the pre-treatment
phase of the study.
Correction.
Section 1.8.Location and Duration of Study
For Part 2, up to 3 more investigational 
centers will be added (at least two
tentatively all in Latin America).
For Part 2, up to 3 more 
investigational centers will be added 
(at least two in Latin America).
Clarification.
Section 3.1.General Design and Study Schematic Diagram
Prior to injection, ovulation will be 
confirmed in all subjects by measuring 
serum progesterone approximately
twice a week during the approximately
2 to 3 weeks preceding expected 
menses.
Prior to injection, ovulation will be 
confirmed in all subjects by measuring 
serum progesterone approximately 
twice a week during the 
approximately 2 to 3 weeks preceding 
expected menses.
Clarification.
During the pre-treatment phase 
ovulation will be confirmed in all 
subjects who are otherwise eligible for 
the study by measuring serum 
progesterone approximately twice a 
week (preferably 3 days apart) during 
the approximately 2 to 3 weeks 
preceding expected menses.
During the pre-treatment phase 
ovulation will be confirmed in all 
subjects who are otherwise eligible for 
the study by measuring serum 
progesterone approximately twice a 
week (preferably 3 days apart) during 
the approximately 2 to 3 weeks 
preceding expected menses.
Clarification.
In addition to frequent laboratory visits 
to collect blood samples, there will be 
3 scheduled follow-up visits: at day 7, 
month 3 (13 weeks), and month 7.5 
(32 weeks) after start of study drug 
treatment, during which subjects will be 
weighed and evaluated for ISRs, vital 
signs, and acceptabilityincluding 
responses to questions about injection 
pain, ISR complaints, and menstrual 
bleeding patterns.
In addition to frequent laboratory 
visits to collect blood samples, there 
will be 3 scheduled follow-up visits: at 
day 7, month 3 (13 weeks), and 
month 7.5 (32 weeks) after start of 
study drug treatment, during which 
subjects will be weighed and 
evaluated for ISRs, vital signs, and 
acceptability.
Clarification.


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The subject’s menstrual bleeding 
patterns will be obtained by an 
interview questionnaire at monthly 
intervals (in Part 1 only), by weekly 
diary completed by the subjects on-line 
(in Part 2 only), and at follow-up visits 
(month 3 and month 7.5 only), and the 
final study visit. In Part 2 only,: liver 
function will be assessed by tabulating 
and graphing change in liver function 
tests including but not limited to ALT 
and AST, from screening to week 13 
(month 3), week 32 (month 7.5), and 
final study visit. In Part 2 only,: mood 
will be assessed in frequency tables at 
screening and at week 13 (month 3), 
week 32 (month 7.5), and final study 
visits.
The subject’s menstrual bleeding 
patterns will be obtained by an 
interview questionnaire at monthly 
intervals (in Part 1 only), by weekly 
diary completed by the subjects on-
line (in Part 2 only), and at follow-up 
visits (month 3 and month 7.5 only), 
and the final study visit. In Part 2 
only, liver function will be assessed 
by tabulating and graphing change in 
liver function tests including but not 
limited to ALT and AST, from 
screening to week 13 (month 3), 
week 32 (month 7.5), and final study 
visit. In Part 2 only, mood will be 
assessed in frequency tables at 
screening and at week 13 (month 3), 
week 32 (month 7.5), and final study 
visits.
Clarification.
Up to 4 additional investigational 
centers will be added for Part 2 
including Eastern Virginia Medical 
School in the US, and Instituto Chileno 
de Medicina Reproductiva (ICMER) in 
Chile and the Biomedical Research 
Department with Profamilia in the 
Dominican Republic (Profamilia).
Up to 4 additional investigational 
centers will be added for Part 2 
including Eastern Virginia Medical 
School in the US, Instituto Chileno de 
Medicina Reproductiva (ICMER) in 
Chile and the Biomedical Research 
Department with Profamilia in the 
Dominican Republic (Profamilia).
Addition. Investigational 
site added.
Section 3.3. 
Pharmacokinetic Measures and Time Points
For Part 1, blood samples for 
measurement of serum concentrations 
will be obtained on days 0 (baseline), 1, 
2, 3, 5, 7, 10, 12, 14, 18, 21,0; 28, 35, 
and 42; weeks 8, 10, 12, 13, 15, 17, 19, 
21, 23, 25, 26, 28, 30, and 32; and then 
every 28 days until week 52, regardless 
of ovulation status.
For Part 1, blood samples for 
measurement of serum concentrations 
will be obtained on days 0 (baseline), 
1, 2, 3, 5, 7, 10, 12, 14, 18, 21, 28, 35, 
and 42; weeks 8, 10, 12, 13, 15, 17, 
19, 21, 23, 25, 26, 28, 30, and 32; and 
then every 28 days until week 52, 
regardless of ovulation status.
Clarification.


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Among sSubjects infor whom ovulation 
has not returned by month 12 
(week 52), blood samples for MPA will 
be tested collected up to 2 more times 
(once at week 61 and once at week 74), 
but not past return to ovulation. The 
sampling schedule and duration of 
MPA testing may be modified based on 
the interim results of Part 1 to ensure 
that accumulating data for a more 
accurate characterization of the 
pharmacokinetic profile of TV-46046
primary and secondary outcomes are 
precisely measured in both parts of the 
study.
Among subjects in whom ovulation 
has not returned by month 12 
(week 52), blood samples for MPA 
will be tested up to 2 more times (once 
at week 61 and once at week 74), but 
not past return to ovulation. The 
sampling schedule and duration of 
MPA testing may be modified based 
on accumulating data for a more 
accurate characterization of the 
pharmacokinetic profile of TV-46046.
Clarification.
In addition, blood samples will also be 
collected and stored for possible future 
MPA testing (if necessary) at all 
weekly visits up to 12 months when 
samples are collected for serum 
progesterone and estradiol, except for 
pre-treatment visits and visits for
confirmation of ovulation.
In addition, blood samples will also be 
collected and stored for possible 
future MPA testing (if necessary) at 
all weekly visits when samples are 
collected for serum progesterone and 
estradiol, except for pre-treatment 
visits and visits for confirmation of 
ovulation.
Clarification.
Section 3.4.    Pharmacodynamic Measures and Time Points
Blood samples for measurement of 
progesterone and estradiol will be 
obtained as follows: on day 0 
(baseline); then at day 7weeks 1 and, 2,
4, 6, 8, 10, and 12; then weekly through 
week 32, regardless of ovulation status.
Blood samples for measurement of 
progesterone and estradiol will be 
obtained as follows: on day 0 
(baseline); then at day 7 and then 
weekly through week 32, regardless of 
ovulation status.
Addition. Estradiol 
levels will be measured
for pharmacodynamics 
analysis.
If there is no ovulation by week 52, 
then blood samples for serum 
progesterone and estradiol will be 
collected weekly between weeks 61 
through 65 and between weeks 74 
through 78, until ovulation (but not 
past return to ovulation).
If there is no ovulation by week 52, 
then blood samples for serum 
progesterone and estradiol will be 
collected weekly between weeks 61 
through 65 and between weeks 74 
through 78, but not past return to 
ovulation.
Clarification.


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At any time point during follow-up, a 
subject with progesterone ≥3.0 ng/mL 
will be asked to return within 5 days for 
repeated progesterone measurement to 
ensure close monitoring of the potential 
post-ovulatory rise of progesterone. If 
the repeated measurement within 5 days 
is at or below 3.0 ng/mL, the subject 
will continue follow-up per her visit 
schedule. At any time point during 
follow-up, a subject with initial 
progesterone ≥4.7 ng/mL will be asked 
to return within 5 days for repeated 
progesterone measurement for more 
accurate ascertainment of ovarian 
function.
At any time point during follow-up, a 
subject with progesterone ≥3.0 ng/mL 
will be asked to return within 5 days 
for repeated progesterone 
measurement to ensure close 
monitoring of the potential post-
ovulatory rise of progesterone. If the 
repeated measurement within 5 days is 
at or below 3.0 ng/mL, the subject will 
continue follow-up per her visit 
schedule. At any time point during 
follow-up, a subject with initial 
progesterone ≥4.7 ng/mL will be 
asked to return within 5 days for 
repeated progesterone measurement 
for more accurate ascertainment of 
ovarian function.
Addition. Statement 
added to describe 
requirements for the 
repeated measurement 
of progesterone.
Estradiol will be measured at the same 
time points as progesterone as a 
supporting pharmacodynamics 
measure. For a detailed description of 
progesterone sampling, see Table 1 and 
Section 3.14.3.2.2.
Estradiol will be measured at the same 
time points as progesterone as a 
supporting pharmacodynamics 
measure.
Correction. 
Section 3.6.Acceptability Measures and Time Points
Acceptability of the menstrual bleeding 
patterns will be assessed through 
responses by subjects obtained by an 
interview questionnaire at monthly 
intervals during scheduled laboratory 
visits (in Part 1 only); at scheduled nd
orfollow-up visits (except day 7); and at 
the final study visit.
Acceptability of the menstrual 
bleeding patterns will be assessed 
through responses by subjects 
obtained by an interview questionnaire 
at monthly intervals during scheduled 
laboratory visits (in Part 1 only); at 
scheduled follow-up visits (except 
day 7); and at the final study visit.
Clarification.
Section 3.13.
Source Data Recorded on the Case Report Form
The CRFs are filed in the clinical 
sites’ponsor’s central files and CRFs 
will be shipped to the sponsor at the 
end of the trial.
The CRFs are filed in the clinical 
sites’ files and CRFs will be shipped 
to the sponsor at the end of the trial.
Process clarification.


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Section 3.14.
Study Procedures
Participants will come to the study 
clinic for 1 screening visit, up 4 to 
6 pre-treatment visits, 
1 enrollment/injection visit, 3 scheduled 
follow-up visits, a final visit, and 
frequent laboratory visits to draw blood 
samples for progesterone, estradiol, 
and/or MPA.
Participants will come to the study 
clinic for 1 screening visit, up to 
6 pre-treatment visits, 
1 enrollment/injection visit, 
3 scheduled follow-up visits, a final 
visit, and frequent laboratory visits to 
draw blood samples for progesterone, 
estradiol, and/or MPA.
Clarification.
Table 1. Study Procedures and Assessments (Parts 1 and 2)
Row: Mammogram mo Screening (x), 
Pretreatment (x)
Mammogram m  Screening (x)
Correction. 
Mammogram at 
pretreatment removed.
c Day 0; within the 1st 5 days of the 
start of subject's menstrual cycle.
c Day 0; within the 1st 5 days of the 
start of subject's menstrual cycle.
Clarification
d At any time during the study, subjects 
with initial serum progesterone 
≥3.0 ng/mL will be asked to return 
within 5 days for repeated 
progesterone measurement. If 
repeated progesterone is at 3 ng/mL or 
below, the subject will continue 
follow up per their visit schedule.
e In addition, at any time during the 
study, if the serum progesterone level 
is equal to or greater than 4.7 ng/mL, 
subjects in all treatment groups will 
be asked to return to repeat the serum 
progesterone measurement within 
5 days.
f d During pretreatment, bBlood 
samples for serum progesterone and 
estradiol will be collected 
approximately twice weekly during the 
approximately 2 to 3 weeks preceding 
the subject's expected menses for 
confirmation of ovulation (ideally at 
least 4 measurements).
d Blood samples for serum 
progesterone and estradiol will be 
collected approximately twice weekly 
during the approximately 2 to 3 weeks 
preceding the subject's expected 
menses for confirmation of ovulation 
(ideally at least 4 measurements).
Clarification


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e gDuring the follow up laboratory 
visits, bBlood samples for serum 
progesterone and estradiol will be 
collected on day 0 (baseline); then at 
day 7 and then weekly through week 
32, regardless of ovulation status.  If 
ovulation does not return by week 32, 
then weekly blood samples for serum 
progesterone and estradiol will 
continue to be collected until 
ovulation or at weeks 1, 2, 4, 6, 8, 10, 
and 12; then weekly through week 52,
whichever is earlier. If there is no 
ovulation by week 52, then blood 
samples for progesterone and estradiol 
will be collectedadditional laboratory 
visits for these subjects will be 
scheduled at weeks 61, 62, 63, 64, and 
65; and at weeks 74, 75, 76, 77, and 
78, if ovulation has not returned by 
week 65. During these additional 
laboratory visits, blood samples will 
be collected and tested for serum 
progesterone and estradiol at (all 
visits), but not past return to 
ovulation. 
e Blood samples for serum 
progesterone and estradiol will be 
collected on day 0 (baseline); then at 
day 7 and then weekly through week 
32, regardless of ovulation status.  If 
ovulation does not return by week 
32, then weekly blood samples for 
serum progesterone and estradiol 
will continue to be collected until 
ovulation or through week 52, 
whichever is earlier. If there is no 
ovulation by week 52, then blood 
samples for progesterone and 
estradiol will be collected at 
weeks 61, 62, 63, 64, and 65; and at 
weeks 74, 75, 76, 77, and 78, if 
ovulation has not returned by 
week 65. During these additional 
laboratory visits, blood samples will 
be collected and tested for serum 
progesterone and estradiol at all 
visits, but not past return to 
ovulation. 
Clarification
f At any time during follow-up, subjects 
with initial serum progesterone 
≥3.0 ng/mL will be asked to return 
within 5 days for repeated 
progesterone and estradiol 
measurement. If repeated 
progesterone is at 3 ng/mL or below, 
the subject will continue follow-up 
per their visit schedule.
f At any time during follow-up, 
subjects with initial serum 
progesterone ≥3.0 ng/mL will be 
asked to return within 5 days for 
repeated progesterone and estradiol 
measurement. If repeated 
progesterone is at 3 ng/mL or below, 
the subject will continue follow-up 
per their visit schedule.
Addition. Details 
included to describe the 
follow-up process for 
subjects with initial 
serum progesterone 
greater than 3.0 ng/mL.


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g At any time during follow-up, if the 
serum progesterone level is 
≥4.7 ng/mL, subjects will be asked to 
return within 5 days for repeated
progesterone and estradiol 
measurement within 5 days.
and serum MPA at (weeks 61 and 74). 
Estradiol will be measured at all of the 
same time points as progesterone as a 
supporting pharmacodynamics 
measure.h If the estradiol level is at or 
greater than 75 pg/mL during weeks 2 
to 12 or weeks 52 to 78, then blood 
samples for progesterone and estradiol 
will be collected weekly.
g At any time during follow-up, if the 
serum progesterone level is 
≥4.7 ng/mL, subjects will be asked 
to return within 5 days for repeated 
progesterone and estradiol 
measurement.
Clarification.
h i  During the follow up visits, b Blood 
samples for MPA will be collected on 
day 0; then on at days 1, 2, 3, 5, 7, 10, 
12, 14, 18, 201, 28, 35, and 42; then at 
weeks 8, 10, 12, 13, 15, 17, 19, 21, 23, 
25, 26, 28, 30, and 32; and then every 
28 days until week 52, regardless of 
ovulation status.
h Blood samples for MPA will be 
collected on day 0; then on days 1, 2, 
3, 5, 7, 10, 12, 14, 18, 21, 28, 35, and 
42; then at weeks 8, 10, 12, 13, 15, 17, 
19, 21, 23, 25, 26, 28, 30, and 32; and 
then every 28 days until week 52, 
regardless of ovulation status.
Clarification.
i j A blood sample will be collected if 
the last MPA sample was taken more 
than 2 weeks ago. Injection site 
reactions will be recorded on day 0 
immediately after the injection (within 
10 minutes) and within the 1st hour 
after injection; at days 1, 2, 3, 5, and 7; 
week 13 and week 32 visits; at the final 
visit; and at other visits, if indicated
i Injection site reactions will be 
recorded on day 0 immediately after 
the injection (within 10 minutes) and 
within the 1st hour after injection; at 
days 1, 2, 3, 5, and 7; week 13 and 
week 32 visits; at the final visit; and at 
other visits, if indicated
Clarification.
j k During laboratory visits, information 
on adverse events and concomitant 
medications will not be solicited, but 
will be documented if reported by the 
subject.
j During laboratory visits, information 
on adverse events and concomitant 
medications will not be solicited, but 
will be documented if reported by 
the subject.
Clarification.
k mLiver function testing and mood 
evaluation will be evaluated at the
screening, week 13 and, week 32 
follow-up visitsand the final visit 
only.
k Liver function testing and mood 
evaluation will be evaluated at the 
week 13 and week 32 follow-up 
visits.
Clarification.


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l n In Part 1, mMenstrual bleeding 
patterns will be obtained by an 
interview questionnaire approximately 
monthly; at scheduled follow-up visits 
(weeks 13 and 32 only); and the final 
study visit. In addition, in Part 2 
menstrual data will be collected 
weekly via an on-line diary.
l Menstrual bleeding patterns will be 
obtained by an interview 
questionnaire approximately 
monthly; at scheduled follow-up 
visits (weeks 13 and 32 only); and 
the final study visit. In addition, in 
Part 2 menstrual data will be 
collected weekly via an on-line 
diary.
Clarification.
o m Part 1 only, prior to enrollment.
m Part 1 only, prior to enrollment.
Clarification.
Section 3.14.1.
Procedures Before Study Drug Treatment
Eligible subjects will be scheduled to 
return to the clinic up to 4 to 6 times for 
serum progesterone and estradiol 
measurements to confirm their 
ovulatory cycle (approximately twice a 
week preferably 3 days apart during 
approximately the 2 to 3 weeks 
preceding their next expected menses).
Eligible subjects will be scheduled to 
return to the clinic up to 6 times for 
serum progesterone and estradiol 
measurements to confirm their 
ovulatory cycle (approximately twice 
a week preferably 3 days apart during 
approximately the 2 to 3 weeks 
preceding their next expected 
menses).
Clarification.
Section 3.14.2.
Pretreatment
Subjects who meet the 
inclusion/exclusion criteria at screening 
visit will return to the clinic 
approximately twice a week (preferably 
3 days apart) during the approximately 
2 to 3 weeks preceding their next 
expected menses (ideally at least 4 to 6
times) for serum progesterone and 
estradiol measurements to confirm 
ovulation.
Subjects who meet the 
inclusion/exclusion criteria at 
screening visit will return to the clinic 
approximately twice a week 
(preferably 3 days apart) during the 
approximately 2 to 3 weeks preceding 
their next expected menses (ideally at 
least 4 times) for serum progesterone 
and estradiol measurements to confirm 
ovulation.
Clarification.
Section 3.14.3.2.
Follow-up (Day 1 to Week 78)
Regardless of ovulation status, all 
subjects should remain in follow-up for 
at least 52 weeks post-injection.
There are 2 types of follow-up visits in 
this study: scheduled follow-up visits 
and laboratory visits.
Regardless of ovulation status, all 
subjects should remain in follow-up 
for at least 52 weeks post-injection.
There are 2 types of follow-up visits 
in this study: scheduled follow-up 
visits and laboratory visits.
Clarification.


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Section 3.14.3.2.1. Scheduled Follow-up Visits (Day 7, Month 3, and Month 7.5)
In Part 1, mMenstrual bleeding 
patterns, mood (for Part 2 only) and 
acceptability will be evaluated through 
an interview questionnaire.
Menstrual bleeding patterns, mood 
(for Part 2 only) and acceptability will 
be evaluated through an interview 
questionnaire.
Clarification.
For Part 2, in addition to the scheduled 
follow-up visits menstrual bleeding 
patterns will be evaluated weekly 
through on-line diaries; mood and 
acceptability will be evaluated through 
an interview administered 
questionnaire.
For Part 2, in addition to the scheduled 
follow-up visits menstrual bleeding 
patterns will be evaluated weekly 
through on-line diaries.
Clarification.

interview about menstrual 
bleeding pattern (month 3 
and month 7.5; Part 1 only) 

interview about menstrual 
bleeding pattern (month 3 
and month 7.5)
Clarification.
Section 3.14.3.2.2. Laboratory Visits
During the laboratory visits, blood 
samples will be obtained for serum 
MPA, serum progesterone, and 
estradiol per the sampling schedule (see 
Sections 3.3 and 3.4, and Table 1).
During the laboratory visits, blood 
samples will be obtained for serum 
MPA, serum progesterone, and 
estradiol per the sampling schedule 
(see Sections 3.3 and 3.4, and Table 
1).
Clarification.

obtain blood sample (up to 
approximately 15 mL) for 
serum MPA, serum 
progesterone, and estradiol
per the sampling schedule

obtain blood sample (up 
to approximately 15 mL) 
for serum MPA, serum 
progesterone, and 
estradiol per the sampling 
schedule 
Clarification.
Blood samples for MPA will be 
collected and stored for possible future 
MPA testing (if necessary) any time 
when samples are collected for serum 
progesterone and estradiol up until 
month 12, except for pre-treatment 
visits and visits for confirmation of 
ovulation.
Blood samples for MPA will be 
collected and stored for possible 
future MPA testing (if necessary) any 
time when samples are collected for 
serum progesterone and estradiol, 
except for pre-treatment visits and 
visits for confirmation of ovulation.
Clarification.


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3.14.3.2.3. Laboratory Visits after Week 52
During these additional laboratory 
visits, blood samples will be collected 
and tested for serum progesterone and 
estradiol (all visits) and serum MPA 
(weeks 61 and 74), but not past 
ovulation. Blood samples for MPA will 
be collected at all weekly visits after 
Week 52 and stored for possible future 
MPA testing (if necessary).
During these additional laboratory 
visits, blood samples will be collected 
and tested for serum progesterone and 
estradiol (all visits) and serum MPA 
(weeks 61 and 74), but not past 
ovulation. Blood samples for MPA 
will be collected at all weekly visits 
after Week 52 and stored for possible 
future MPA testing (if necessary).
Clarification.
Section 3.14.4.1.
Final Visit

obtain blood sample for 
serum MPA 
(approximately 5 mL) (if 
previous MPA was 
completed more than 
2 weeks ago)

obtain blood sample for 
serum progesterone, 
estradiol (approximately 
10 mL), if indicated; and 
liver function tests (Part 2 
only, approximately 5 mL)

obtain blood sample for 
serum MPA 
(approximately 5 mL) 

obtain blood sample for 
serum progesterone, 
estradiol (approximately 
10 mL), if indicated;  and 
liver function tests (Part 2 
only, approximately 
5 mL)
Clarification.
Section 4.2.  Subject Exclusion Criteria
m.
has one or more baseline liver 
function test(s) outside the local 
laboratory’s normal range (Part 2 only)
m. has one or more baseline liver 
function test(s) outside the local 
laboratory’s normal range (Part 2 
only)
Clarification.
Section 5.3. Prior and Concomitant Medication or Treatment

aminoglutethimide

chronic use of systemic 
glucocorticoids

St. John’s wort 

aminoglutethimide

St. John’s wort
Correction.


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Section 6.2.Pharmacodynamics
During the pre-treatment phase 
ovulation will be confirmed in all 
women by measuring progesterone 
approximately twice a week during the 
approximately 2 to 3 weeks preceding 
their expected menses.
During the pre-treatment phase 
ovulation will be confirmed in all 
women by measuring progesterone 
approximately twice a week during 
the approximately 2 to 3 weeks 
preceding their expected menses.
Clarification.
Estradiol, an additional 
pharmacodynamic indicator, will be 
measured every time progesterone is 
measured. It will be used to more 
accurately characterize ovarian 
function. Before the time period when 
progesterone is measured weekly, 
subjects in any group who have an 
estradiol result of 75 pg/mL or higher 
(ie, during weeks 2 to 12 or weeks 52 to 
78) will be asked to return for weekly 
progesterone and estradiol testing.
Estradiol, an additional 
pharmacodynamic indicator, will be 
measured every time progesterone is 
measured. It will be used to more 
accurately characterize ovarian 
function.
Correction.
Section 7. Assessment Of Safety
In this study, safety will be assessed by 
qualified study personnel by evaluating 
the following: vital signs (BP 
[systolic/diastolic], pulse, and 
respiration), body weight, adverse 
events, concomitant medication usage, 
changes in menstrual bleeding patterns, 
mood, liver function tests, occurrence 
of ISRs, and return to ovulation after 12 
months after the study drug injection.
In this study, safety will be assessed 
by qualified study personnel by 
evaluating the following: vital signs
(BP [systolic/diastolic], pulse, and 
respiration), body weight, adverse 
events, concomitant medication usage, 
changes in menstrual bleeding 
patterns, mood, liver function tests, 
occurrence of ISRs, and return to 
ovulation after 12 months after the 
study drug injection.
Clarification.
Section 7.8.Menstrual Bleeding Patterns
Study subjects will be asked about 
changes in their menstrual bleeding 
patterns, including no bleeding, since 
last assessment, at monthly intervals (in 
Part 1 only) and during the scheduled 
follow-up visits in both Part 1 and Part 
2 at week 13 (month 3) and week 32 
(month 7.5), and at the final study visit.
Study subjects will be asked about 
changes in their menstrual bleeding 
patterns, including no bleeding since 
last assessment, at monthly intervals 
(in Part 1 only) and during the 
scheduled follow-up visits in both Part 
1 and Part 2 at week 13 (month 3) and 
week 32 (month 7.5), and at the final 
study visit.
Clarification.


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Reason/Justification 
for change
Section 7.12.
Assessment Of Acceptability
Other acceptability questions will 
include but not be limited to questions 
about acceptability of the bleeding 
patterns (only during month 3 and, 
month 7.5 follow-up visits, and final 
visits) and other side effects, what she 
likes and dislikes most about this 
method, whether she would use this 
method in the future and/or recommend 
it to a friend, and whether the schedule 
of re-injections was acceptable.
Other acceptability questions will 
include but not be limited to questions 
about acceptability of the bleeding 
patterns (only during month 3 and, 
month 7.5 follow-up visits, and final 
visit) and other side effects, what she 
likes and dislikes most about this 
method, whether she would use this 
method in the future and/or
recommend it to a friend, and whether 
the schedule of re-injections was 
acceptable.
Clarification.
Section 8.1.Sample Size and Power Considerations
Scientific judgment will be used to 
determine if the sample size in Part 2 
can be reduced from 20 subjects per 
group, depending on the variability of 
population pharmacokinetic parameter 
estimates and rates of return to 
ovulation observed in Part 1 or interim 
Part 2 data.
Scientific judgment will be used to 
determine if the sample size in Part 2 
can be reduced from 20 subjects per 
group, depending on the variability of 
population pharmacokinetic parameter 
estimates and rates of return to 
ovulation observed in Part 1 or interim 
Part 2 data.
Clarification.
Section 8.10.
Planned Interim Analyses
There are several planned reviews of 
the interim data, although their number 
and timing may change based on the 
findings.
There are several planned reviews of 
the interim data, although their 
number and timing may change based 
on the findings.
Clarification.
At least The 3rd and 4th two interim 
reviews are planned to occur in Part 2 
(after 50% of subjects in Part 2 have 
completed approximately 4 months and 
7.5 months post-injection, 
respectively). These analyses, and are 
primarily intended to help inform the 
decision to move to and the dose 
selection for a Phase 3 clinical study,. 
Additional interim analyses of Part 2 
data may be conducted if needed to 
inform potential modifications to the 
Phase 1 study. The 5th and final 
planned data review will occur when 
100% of subjects in Part 2 have 
completed 7.5 months post-injection 
(ie, the entire intended dosing interval 
plus 1.5 months); those data may be 
At least two interim reviews are 
planned to occur in Part 2 (after 50% 
of subjects have completed 
approximately 4 months and 
7.5 months post-injection, 
respectively). These analyses are 
primarily intended to help inform the 
decision to move to and the dose 
selection for a Phase 3 clinical study. 
Additional interim analyses of Part 2 
data may be conducted if needed to 
inform potential modifications to the 
Phase 1 study. The final planned data 
review will occur when 100% of 
subjects in Part 2 have completed 
7.5 months post-injection (ie, the 
Clarification.


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Reason/Justification 
for change
submitted to the FDA in the pre Phase 3 
submission.
entire intended dosing interval plus 
1.5 months); those data may be 
submitted to the FDA in the pre-Phase 
3 submission.
Section 10.1.2. Protocol Violations
Protocol violations 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; 
noncompliance to study drug 
administration; or use of prohibited 
medications.
Protocol violations 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; 
noncompliance to study drug 
administration; or use of prohibited 
medications.
Correction.
When a protocol violation is reported, 
the sponsor will determine whether to 
discontinue the subject from the study 
or permit the subject to continue in the 
study, with documented approval from 
the medical expert. 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 
investigational center personnel learn 
that a subject who did not meet protocol 
inclusion and exclusion criteria was 
entered in a study, they must 
immediately inform the sponsor of the 
protocol violation. If such subject has 
already completed the study or has 
withdrawn early, no action will be 
taken but the violation will be recorded.
Lesser protocol deviations, i.e. those 
that do not significantly affect subject 
safety or scientific value of the data, 
will be recorded in a Protocol Deviation 
Log. The cumulative Log will be 
submitted to the responsible IEC/IRB at 
Changes in the inclusion and 
exclusion criteria of the protocol are 
not prospectively granted by the 
sponsor. If investigational center 
personnel learn that a subject who did 
not meet protocol inclusion and 
exclusion criteria was entered in a 
study, they must immediately inform 
the sponsor of the protocol violation. 
If such subject has already completed 
the study or has withdrawn early, no 
action will be taken but the violation 
will be recorded.
Lesser protocol deviations, i.e. those 
that do not significantly affect subject 
safety or scientific value of the data, 
will be recorded in a Protocol 
Deviation Log. The cumulative Log 
will be submitted to the responsible 
IEC/IRB at annual reviews.
Correction.


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Reason/Justification 
for change
annual reviews.
Section 12.3.1. Sponsor Responsibilities
The original CRFs will be stored at
archived by the respective 
investigational centers until the end of 
the study.
The original CRFs will be stored at 
the respective investigational centers 
until the end of the study.
Clarification.
Section 14 Reporting and Publication of Results
FHI 360 will prepare the The sponsor is 
responsible for the preparation of a 
clinical study report, in cooperation 
with the sponsor the FHI 360 
coordinating investigator. The final 
report is signed by the sponsor and by 
the FHI 360 Coordinating Investigator.
FHI 360 will prepare the clinical study 
report, in cooperation with the
sponsor. The final report is signed by 
the sponsor and by the FHI 360 
Coordinating Investigator.
Clarification.
When the sponsor generates reports 
from the data collected in this study for 
presentation to regulatory authorities or 
the DSMB, drafts will be circulated to 
the FHI 360 coordinating investigator 
for comments and suggestions. An 
endorsement of the final report will be 
sought from the FHI 360 coordinating 
investigator.
When the sponsor generates reports 
from the data collected in this study 
for presentation to regulatory 
authorities, drafts will be circulated to 
the FHI 360 coordinating investigator 
for comments and suggestions.
Clarification.


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16.2.
Protocol Amendment 03 Dated 27 March 2017
The primary reasons for this amendment are additions. These revisions are considered to be 
substantial by the sponsor’s Authorized Representative. 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 Laboratory and Other Departments and Institutions
Investigational Center Ethics 
CommitteeCommittees
Investigational Center Ethics 
Committees
Correction.
Chesapeake IRB
6940 Columbia Gateway Drive, Suite 
110 
Columbia, Maryland 21046
United States of America
Comité Ético Científico del Servicio de 
Salud Metropolitano Central
Victoria Subercaseaux #381
Santiago
Chile
Chesapeake IRB
6940 Columbia Gateway Drive, Suite 
110 
Columbia, Maryland 21046
United States of America
Comité Ético Científico del Servicio 
de Salud Metropolitano Central
Victoria Subercaseaux #381
Santiago
Chile
Addition. Text includes 
names and addresses of
recently added
Investigational Center 
Ethics Committees.
Clinical Laboratory
Jones Institute for Reproductive 
Medicine Endocrinology Laboratory
601 Colley Avenue 
Norfolk, VA 23507
Laboratorios Clinicos PUC - Centro 
Medico San Joaquin 
Vicuna Mackenna 4686 Macul 
Santiago, Chile
Jones Institute for Reproductive 
Medicine Endocrinology Laboratory
601 Colley Avenue 
Norfolk, VA 23507
Laboratorios Clinicos PUC - Centro 
Medico San Joaquin 
Vicuna Mackenna 4686 Macul 
Santiago, Chile
Addition. Text includes 
names and addresses of 
recently added Central 
Labs.
Investigational CenterCenters
Investigational Centers
Correction.
Conrad Clinical Research Center
Eastern Virginia Medical School
601 Colley Avenue
Norfolk, VA 23507
Unites States of America
Instituto Chileno de Medicina 
Reproductiva 
Conrad Clinical Research Center
Eastern Virginia Medical School
601 Colley Avenue
Norfolk, VA 23507
Unites States of America
Instituto Chileno de Medicina 
Reproductiva 
Addition. Text includes 
names and addresses of 
recently added 
Investigational Centers.


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Jose Victorino Lastarria 29 of 101
Santiago Centro, Santiago
Chile
Jose Victorino Lastarria 29 of 101
Santiago Centro, Santiago
Chile
Clinical Study Protocol
Countries Planned: United States 
(US) and, Chile, other Latin America 
(American countries pending)
Countries Planned: United States 
(US) , Chile, other Latin American 
countries pending
Addition. Text lists the 
location of additional 
study sites.
Section 1.4.2.
Risks of TV-46046
While some observational data have 
suggested an association between the 
use of Depo-Provera CI and increased 
risk of HIV acquisition (Morrison et al 
2015; Ralph et al 2015; Polis 2016) the 
data are inconsistent and causality has 
not been established.
While some observational data have 
suggested an association between the 
use of Depo-Provera CI and increased 
risk of HIV acquisition (Morrison et 
al 2015; Ralph et al 2015; Polis 2016) 
the data are inconsistent and causality 
has not been established.
Reference added.
In light of the inconclusive evidence, 
the WHO recently revised their 
Medical Eligibility Criteria 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. The World Health 
Organization (WHO) and CDC 
recommend that women at high risk of 
HIV who choose to use Depo Provera 
CI or any other hormonal product 
should be counseled to use condoms 
consistently and correctly (WHO 
2014).
In light of the inconclusive evidence, 
the WHO recently revised their 
Medical Eligibility Criteria 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.
Text revised to include 
the updated WHO 
Medical Eligibility 
Criteria for contraceptive 
use.


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Reason/Justification 
for change
This FIH 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 However,
recommendation to use condoms for 
protection against HIV and sexually 
transmitted infections (STIs) will be 
provided to all subjects in this study.
This FIH 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 (STIs) will be 
provided to all subjects in this study.
Text revised to state that 
this study will not recruit 
women at high risk for 
HIV.
Section 1.8 Location and Duration of Study
For Part 1, the study is planned to be 
conducted at 1 to 2 investigational 
center centers in the US. An additional 
US-based investigational center may 
will only be considered if necessary to 
accomplish enrollment in a timely 
fashion.
For Part 1, the study is planned to be 
conducted at 1 to 2 investigational 
centers in the US. An additional 
US-based investigational center will 
only be considered if necessary to 
accomplish enrollment in a timely 
fashion.
Addition. The number of 
study centers increased.
Section 2.2.1
Primary Endpoints (also Sections 2.2.2, 3.1, 3.9, 5.1, and 8.1)
The primary objective of Part 2 is to 
evaluate the pharmacodynamics of 
MPA after a single subcutaneous 
injection in the abdomen of undiluted 
TV-46046 at up to 3 dose levels (where 
pharmacodynamics response is defined 
as suppression of ovulation determined 
through serum progesterone 
concentrations).
The primary objective of Part 2 is to 
evaluate the pharmacodynamics of 
MPA after a single subcutaneous 
injection in the abdomen of undiluted 
TV-46046 at up to 3 additional dose 
levels (where pharmacodynamics 
response is defined as suppression of 
ovulation determined through serum 
progesterone concentrations).
Clarification. Text added 
to state that up to 3 
additional dose levels 
may be evaluated in this 
study.
Section 2.3.3
Safety Endpoints

change in menstrual 
bleeding patterns

change in mood (Part 2 
only)

change in liver function 
tests (Part 2 only)

use of concomitant 
medications

change in menstrual 
bleeding patterns

change in mood (Part 2 
only)

change in liver function 
tests (Part 2 only)

use of concomitant 
medications
Safety endpoints added 
to Part 2 of study.


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Section 3.1
General Design and Study Schematic Diagram
An interim pharmacokinetic analysis is 
planned to inform the decision to move 
into Part 2 and will be performed after 
all subjects in treatment group 1 (ie, the 
first six women receiving undiluted 
TV-46046) in Part 1 have had a chance 
to complete at least 4 months 
(17 weeks) of treatment with additional
At that time, available PK data from 
women in treatment group 2 (ie, the 
next six women receiving diluted TV-
46046) will also be analyzed. 
Additional assessments will be made if 
warranted (eg, when 12 women [in 
both the undiluted and diluted groups] 
complete 4 months [17 weeks]).
An interim pharmacokinetic analysis 
is planned to inform the decision to 
move into Part 2 and will be 
performed after all subjects in 
treatment group 1 (ie, the first six 
women receiving undiluted TV-
46046) in Part 1 have had a chance to 
complete at least 4 months (17 weeks) 
of treatment. At that time, available 
PK data from women in treatment 
group 2 (ie, the next six women 
receiving diluted TV-46046) will also 
be analyzed. Additional assessments 
will be made if warranted (eg, when 
12 women [in both the undiluted and 
diluted groups] complete 4 months 
[17 weeks]).
Addition. Text added to 
describe the collection of 
PK data.
Part 2 will only be implemented if the 
administration of undiluted TV-46046 
(400 mg/mL) in Part 1 demonstrates an 
appropriate pharmacokinetic profile.
Other features of the undiluted drug 
may also enter the decision-making, 
including stability, re-suspendability, 
syringeability and safety.
Part 2 will only be implemented if the 
administration of undiluted TV-46046 
(400 mg/mL) in Part 1 demonstrates 
an appropriate pharmacokinetic 
profile. Other features of the undiluted 
drug may also enter the decision-
making, including stability, re-
suspendability, syringeability and 
safety.
Addition. Text added to 
describe factors that will 
impact the decision to 
move into Part 2 of the 
study.
Enrolled subjects will receive an 
injection of the study drug and then be 
followed for at least 12 months 
(52 weeks) to characterize 
pharmacodynamics and 
pharmacokinetics of MPA 
(ie, 6 months of treatment plus 
6 months of post-treatment follow-up), 
regardless of earlier return to ovulation. 
Medroxyprogesterone acetate sampling 
will be extended to 52 weeks from 
study drug administration among 
participants with earlier return of 
ovulation to properly characterize the 
Enrolled subjects will receive an 
injection of the study drug and then be 
followed for at least 12 months 
(52 weeks) to characterize 
pharmacodynamics and 
pharmacokinetics of MPA 
(ie, 6 months of treatment plus 
6 months of post-treatment 
follow-up), regardless of earlier return 
to ovulation. 
Correction. Text no 
longer applicable.


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Reason/Justification 
for change
apparent terminal half life of TV
46046.
In addition to frequent laboratory visits 
to collect blood samples, there will be 
3 scheduled follow-up visits: at day 7, 
month 3 (13 weeks), and month 7.5 
(32 weeks) after start of study drug 
treatment, during which subjects will 
be weighed and evaluated for ISRs, 
vital signs, and acceptability (eg,.
including responses to questions about 
injection pain, ISR complaints, and 
menstrual bleeding patterns).
In addition to frequent laboratory 
visits to collect blood samples, there 
will be 3 scheduled follow-up visits: 
at day 7, month 3 (13 weeks), and 
month 7.5 (32 weeks) after start of 
study drug treatment, during which 
subjects will be weighed and 
evaluated for ISRs, vital signs, and 
acceptability. including responses to 
questions about injection pain, ISR 
complaints, and menstrual bleeding 
patterns.
Correction.
The subject’s menstrual bleeding 
patterns will be obtained by an 
interview questionnaire at monthly 
intervals during scheduled laboratory 
or(in Part 1 only), at follow-up visits 
(weeks 13month 3 and 32month 7.5 
only);), and the final study visit. 
The subject’s menstrual bleeding 
patterns will be obtained by an 
interview questionnaire at monthly 
intervals (in Part 1 only), at follow-up 
visits (month 3 and month 7.5 only), 
and the final study visit. 
Correction. Text edited 
to state that an interview 
questionnaire will be 
given in Part 1 and 
weeks changed to 
months.
In Part 2 only: liver function will be 
assessed by tabulating and graphing 
change in liver function tests including 
but not limited to ALT and AST, from 
screening to week 13 (month 3), week 
32 (month 7.5), and final study visit. In 
Part 2 only: mood will be assessed in 
frequency tables at screening and at 
week 13 (month 3), week 32 (month 
7.5), and final study visits. Information 
on adverse events and concomitant 
medicines will be collected throughout 
the study. The study staff will provide 
assessment on the ease of the injection.
In Part 2 only: liver function will be 
assessed by tabulating and graphing 
change in liver function tests 
including but not limited to ALT and 
AST, at screening to week 13 (month 
3), week 32 (month 7.5), and final 
study visit. In Part 2 only: mood will 
be assessed in frequency tables at 
screening and at week 13 (month 3), 
week 32 (month 7.5), and final study 
visits. Information on adverse events 
and concomitant medicines will be 
collected throughout the study. The 
study staff will provide assessment on 
the ease of the injection.
Added to describe the 
addition of liver function
and mood test in Part 2 
of the study.
Up to 4 additional investigational 
centers will be added for Part 2 
including Eastern Virginia Medical 
School in the US and Instituto Chileno 
Up to 4 additional investigational 
centers will be added for Part 2 
including Eastern Virginia Medical 
School in the US and Instituto 
Addition. Text added to 
list additional 
investigational centers.


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Original text with changes shown
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Reason/Justification 
for change
de Medicina Reproductiva (ICMER) in 
Chile.
Chileno de Medicina Reproductiva 
(ICMER) in Chile.
Figure 2
Overall Study Schematic Diagram
X.X=will be determined on the basis of 
Part 1 results. Part 2 will include from 
1 to 3 groups, depending on Part 1 
results.
X.X=will be determined on the basis 
of Part 1 results. Part 2 will include up 
to 3 additional groups, depending on 
Part 1 results.
Addition. Text added to 
state Part 2 will include 
up to 3 additional 
groups.
Section 3.5
Safety Measures and Time Points

data on menstrual bleeding 
pattern by interview
monthly, (in Part 1 only),
as well as at the week 13 
(month 3)and), week 32 
(month 7.5)), and final 
visits

in Part 2 only: 

in addition to the 
scheduled and final 
visits, menstrual 
bleeding data weekly 
via an on-line diary

data on mood at the 
week 13 (month 3), 
week 32 (month 7.5), 
and final study 
visitvisits

liver function testing at 
the week 13 (month 3), 
week 32 (month 7.5), 
and final study visits

data on menstrual 
bleeding pattern by 
interview monthly (in 
Part 1 only), as well as at 
the week 13 (month 3), 
week 32 (month 7.5), and 
final visits

in Part 2 only: 

in addition to the 
scheduled and final 
visits, menstrual 
bleeding data weekly 
via an on-line diary 

data on mood at the 
week 13 (month 3), 
week 32 (month 7.5), 
and final study visits

liver function testing 
at the week 13 
(month 3), week 32 
(month 7.5), and final 
study visits
Addition. Text added to 
detail measures recorded 
in Part 1 and Part 2.
Section 3.7.
Randomization
In Part 2 (dose-range finding), from 1 
to 3 doses will be studied, depending 
on the interim results of Part 1.
In Part 2 (dose-range finding), from 
up to 3 additional doses will be 
studied, depending on the interim 
results of Part 1. 
Addition. Text added to 
state the number of 
doses to be included in 
Part 2.
The treatment allocation ratio will 
depend on the number of doses 
selected for study, and whether or not 
The treatment allocation ratio will 
depend on the number of doses 
selected for study, and whether or not 
Addition. Text added to 
detail treatment 
allocation.


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Reason/Justification 
for change
the 120 mg dose of undiluted TV-
46046 is selected for inclusion. 
the 120 mg dose of undiluted TV-
46046 is selected for inclusion. 
If yesIf only one dose is selected for 
Part 2, no randomization will be done. 
If more than one dose is selected, 
including the 120 mg dose, then up to 
12 subjects will be randomized to the 
120 mg dose that group, and up to 
18 subjects will be randomized to each 
of the other 2 selected treatment groups 
in a 2:3:3 allocation ratio..
If only one dose is selected for Part 2, 
no randomization will be done. If 
more than one dose is selected, 
including the 120 mg dose, then up to 
12 subjects will be randomized to that 
group, and up to 18 subjects will be 
randomized to each of the other 
selected treatment groups. 
Addition. Text added to 
describe randomization.
If the 120 mg dose is not selected for 
inclusion in Part 2 then the allocation 
ratio will be 1:1:balanced (1:1 or 1:1:1)
at each investigational center, with up 
to 18 subjects randomized to each 
treatment group. 
If the 120 mg dose is not selected for 
inclusion in Part 2 then the allocation 
ratio will be balanced (1:1 or 1:1:1) at 
each investigational center, with up to 
18 subjects randomized to each 
treatment group. 
Addition. Text added to 
describe randomization.
In addition, 2 subjects with a body 
mass index (BMI) ≥40 (preferably in a 
single investigational center) will be 
separately randomized into each 
treatment group (equaling a total of 
20 subjects in each treatment group in 
Part 2) for exploratory analyses of the 
effect of extreme obesity on 
pharmacokinetics of MPA.
In addition, 2 subjects with a body 
mass index (BMI) ≥40 will be 
separately randomized into each 
treatment group (equaling a total of 
20 subjects in each treatment group in 
Part 2) for exploratory analyses of the 
effect of extreme obesity on 
pharmacokinetics of MPA.
Correction. Text no 
longer applicable.
However, enrollment in Part 2 may be 
expanded if more than 10% of subjects 
discontinue (or are predicted to 
discontinue) before week 52 from start 
of study drug treatment, have 
detectable levels of MPA at 
enrollment, or have protocol violations 
identified that may adversely affect 
assessment of pharmacokinetics or 
pharmacodynamics.
However, enrollment may be 
expanded if more than 10% of 
subjects discontinue (or are predicted 
to discontinue) before week 52 from 
start of study drug treatment, have 
detectable levels of MPA at 
enrollment, or have protocol 
violations identified that may 
adversely affect assessment of 
pharmacokinetics or 
pharmacodynamics.
Correction. Enrollment 
may be expanded in Part 
1 or 2.


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Section 3.11.
Duration of Subject Participation and Justification
MinimalIf Part 2 of the study is not 
initiated, minimal participation in Part 
1 of the study may be as short as is
approximately 137 months (56 , or 30
weeks) (approximately 1 month of pre-
treatment and approximately 126 
months of treatment), if Part 2 of the 
study is not initiated.).
If Part 2 of the study is not initiated, 
minimal participation in Part 1 of the 
study may be as short as
approximately 7 months, or 30 weeks 
(approximately 1 month of pre-
treatment and 6 months of treatment).
Clarification. Minimal 
time for study 
participation is defined.
Section 3.12.
Stopping Rules and Discontinuation Criteria
This determination is intended to be 
made after all subjects enrolled in 
treatment group 1 of Part 1 (ie, 6 
subjects receiving undiluted TV-
46046) have had a chance to complete 
at least 4 months (17 weeks) of follow-
up, but the timing may be modified 
based on accumulating data. (eg, 
additional review of the data for all 12 
women [in both undiluted and diluted 
groups] when they complete 4 months 
[17 weeks] may be needed).
This determination is intended to be 
made after all subjects enrolled in 
treatment group 1 of Part 1 (ie, 6 
subjects receiving undiluted TV-
46046) have had a chance to complete 
at least 4 months (17 weeks) of 
follow-up, but the timing may be 
modified based on accumulating data 
(eg, additional review of the data for 
all 12 women [in both undiluted and 
diluted groups] when they complete 4 
months [17 weeks] may be needed).
Addition. Text added to 
explain that an 
additional review of the 
data may occur after all 
12 subjects have 
completed 4 months of 
treatment.
Section 3.13.
Source Data Recorded on the Case Report Form
Subject data should have supportive 
original source documentation in the 
medical records, or equivalent, before 
they are transcribed to the CRF; data 
will not be recorded directly on the 
CRF and considered as source data 
unless the sponsorFHI 360 provides 
written instructions specifying which 
data are permitted to be recorded 
directly to the CRF (eg, subject’s 
responses to interview questions about 
menstrual bleeding patterns and 
acceptability).
Subject data should have supportive 
original source documentation in the 
medical records, or equivalent, before 
they are transcribed to the CRF; data 
will not be recorded directly on the 
CRF and considered as source data 
unless FHI 360 provides written 
instructions specifying which data are 
permitted to be recorded directly to 
the CRF (eg, subject’s responses to 
interview questions about menstrual 
bleeding patterns and acceptability).
Correction. Change to 
text indicates that 
FHI 360 will provide 
instructions for adding 
data to the CRF.
If data are processed from other 
institutions or means (eg, clinical 
laboratory, central image center, or 
If data are processed from other 
institutions or means (eg, clinical 
laboratory, central image center, or 
Correction. Text 
changed to reflect the 
use of an online data 
diary. Data may be 


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Reason/Justification 
for change
electronic on-line diary data), the 
results will be sent to the 
investigational center, where they will 
be retained but not transcribed to the 
CRF, unless otherwise noted in the 
protocol. These data may also be sent 
electronically to the sponsor (or 
organization performing data 
management) FHI 360 for direct entry 
into the clinical database (see 
Section 12.1).
on-line diary data), the results will be 
sent to the investigational center, 
where they will be retained but not 
transcribed to the CRF, unless 
otherwise noted in the protocol. These 
data may also be sent electronically to
FHI 360 for direct entry into the 
clinical database (see Section 12.1).
forwarded to FHI 360.
Hemoglobin, liver function testing, 
progesterone, and estradiol testing will
be conducted at the local laboratories 
and made available to source verify.
Hemoglobin, liver function testing, 
progesterone, and estradiol testing 
will be conducted at the local 
laboratories and made available to 
source verify.
Addition. Liver function 
testing included with 
testing to be performed 
at local labs.
Table 1.
Study Procedures and Assessment (Parts 1 and 2)
Demographics and baseline 
characteristics
Physical examination
Height
Demographics and baseline 
characteristics
Height
Row removed from 
table.
Liver Function Testing (Part 2 only)
Liver Function Testing (Part 2 only)
Test added to table.
Mood evaluation (Part 2 only)
Mood evaluation (Part 2 only)
Evaluation added to 
table.
iDuring the follow-up visits, blood 
samples for MPA will be collected at 
days 1, 2, 3, 5, 7, 10, 12, 14, 18, 20, 28, 
35, and 42; then at weeks 8, 10, 12, 13, 
15, 17, 19, 21, 23, 25, 26, 28, 30, and 
32; and then every 28 days until 
week 52 (in Part 1).).
iDuring the follow-up visits, blood 
samples for MPA will be collected at 
days 1, 2, 3, 5, 7, 10, 12, 14, 18, 20, 
28, 35, and 42; then at weeks 8, 10, 
12, 13, 15, 17, 19, 21, 23, 25, 26, 28, 
30, and 32; and then every 28 days 
until week 52.
Correction. Footnote 
corrected to indicate that 
blood sampling is not 
limited to Part 1.
mLiver function testing and mood 
evaluation will be evaluated at 
screening, week 13, week 32 and the 
final visit only
mLiver function testing and mood 
evaluation will be evaluated at 
screening, week 13, week 32 and the 
final visit only
Addition. Footnote 
added to clarify that liver 
function testing and 
mood evaluation will be 
evaluated at t screening, 
week 13, week 32 and 
the final visit only


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nIn Part 1, mMenstrual bleeding 
patterns will be obtained by an 
interview questionnaire at monthly;
intervals (during Part 1 only), at 
scheduled laboratory or follow-up 
visits (weeks 13 and 32 only); and the 
final study visit. In addition, in Part 2 
menstrual data will be collected 
weekly via an on-line diary.
nIn Part 1, menstrual bleeding patterns 
will be obtained by an interview 
questionnaire monthly; at scheduled 
follow-up visits (weeks 13 and 32 
only); and the final study visit. In 
addition, in Part 2 menstrual data 
will be collected weekly via an on-
line diary.
Addition. Text added to 
footnote to indicate that 
an on-line diary will be 
used to reflect menstrual 
data.
Section 3.14.1 Procedures Before Study Drug Treatment
Women who sign the informed consent 
form will be assigned a participant 
number and have a screening interview 
to obtain the following: medical history 
and demographic information, breast 
examination, blood sample for 
hemoglobin and liver function, height, 
weight, and vital signs measurements 
(BP, pulse, and respiration) and an 
interview about mood.
Women who sign the informed 
consent form will be assigned a 
participant number and have a 
screening interview to obtain the 
following: medical history and 
demographic information, breast 
examination, blood sample for 
hemoglobin and liver function, height, 
weight, and vital signs measurements 
(BP, pulse, and respiration) and an 
interview about mood.
Addition. Mood change 
interview and liver 
function testing added.

perform physical 
examination to: 

measure vital signs (BP, 
heart rate
[systolic/diastolic], pulse,
and respiration)

measure vital signs (BP 
[systolic/diastolic], pulse, 
and respiration)
Addition. Vital signs 
measured before 
treatment listed.

interview about mood (Part 
2 only)

obtain a blood sample for 
liver function testing 
(approximately 5 mL; Part 
2 only)

interview about mood 
(Part 2 only)

obtain a blood sample for 
liver function testing 
(approximately 5 mL; 
Part 2 only)
Addition. Mood change 
interview and liver 
function testing added.
Section 3.14.3.1. 
Enrollment (injection) Visit (Day 0)
The pharmaciststudy staff member will 
prepare the assigned study drug for 
injection according to the dilution 
procedures, and, unless s/he is the one 
The study staff member will prepare 
the assigned study drug for injection 
according to the dilution procedures, 
and, unless s/he is the one 
Correction. 


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administering the injection, pass it to 
the study staff who will inject the study 
drug subcutaneously in the fatty tissue 
over the abdomen while shielding the 
study drug injection from the subject’s 
sight, as described in Section 5.1.
administering the injection, pass it to 
the study staff who will inject the 
study drug subcutaneously in the fatty 
tissue over the abdomen while 
shielding the study drug injection 
from the subject’s sight, as described 
in Section 5.1.

confirm eligibility

perform physical 
examination to: 

measure vital signs (BP 
[systolic/diastolic], pulse, 
and respiration)

confirm eligibility 

measure vital signs (BP 
[systolic/diastolic], pulse, 
and respiration)
Correction.

(prior to injection) obtain a 
blood sample 
(approximately 15 mL) for 
serum MPA, serum 
progesterone and, estradiol 

(prior to injection) obtain 
a blood sample 
(approximately 15 mL) 
for serum MPA, serum 
progesterone and, 
estradiol 
Addition. Volume of 
blood sample collected 
in Part 2 added.
Section 3.14.3.2.1.
Scheduled Follow-up Visits (Day 7, Month 3 and Month 7.5)
A physical examination will be 
performed including measurement 
Measurement of vital signs and body 
weight will be performed. Subjects will 
be asked if they experienced any 
medical problems or took any 
medications since the previous report.
Measurement of vital signs and body 
weight will be performed. Subjects 
will be asked if they experienced any 
medical problems or took any 
medications since the previous report.
Correction. 
In Part 1, mMenstrual bleeding patterns 
and acceptability will be evaluated 
through an interview questionnaire. For 
Part 2, menstrual bleeding patterns will 
be evaluated through on-line diaries; 
mood and acceptability will be 
evaluated through an interview 
administered questionnaire.
In Part 1, menstrual bleeding patterns 
and acceptability will be evaluated 
through an interview questionnaire. 
For Part 2, menstrual bleeding 
patterns will be evaluated through on-
line diaries; mood and acceptability 
will be evaluated through an interview 
administered questionnaire. 
Addition. Details 
describing evaluation of 
menstrual bleeding 
patterns added to 
section.


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
perform physical 
examination to: 

measure vital signs (BP 
[systolic/diastolic], pulse, 
and respiration)

measure vital signs (BP 
[systolic/diastolic], pulse, 
and respiration)
Correction.

obtain blood sample 
(approximately 15 mL ) for 
serum MPA, serum 
progesterone, and estradiol 

obtain blood sample 
(approximately 15 mL ) 
for serum MPA, serum 
progesterone, and 
estradiol
Addition. Volume of 
blood sample collected 
in Part 2 

obtain blood sample 
(approximately 5 mL) for
liver function tests (month 
3 and month 7.5, Part 2 
only) 

obtain blood sample 
(approximately 5 mL) for 
liver function tests 
(month 3 and month 7.5, 
Part 2 only) 
Addition. Liver function 
test added

interview about mood 
(month 3 and month 7.5, 
Part 2 only)
interview about mood (month 
3 and month 7.5, Part 2 
only)
Addition. Interview 
about mood will be 
conducted during visit.

interview about menstrual 
bleeding pattern (month 3 
and month 7.5 only; Part 1 
only)

interview about menstrual 
bleeding pattern (month 3 
and month 7.5 only; Part 
1 only)
Addition. Interview 
about menstrual bleeding 
patterns will be 
conducted during visit in 
Part 1 only.

interview about menstrual 
bleeding pattern (once 
monthly (Part 1 only)

interview about menstrual 
bleeding pattern once 
monthly (Part 1 only)
Addition. Interview 
about menstrual bleeding 
patterns will be 
conducted during visit in 
Part 1 only.
Section 3.14.4.1
Final Visit

obtain blood sample for 
serum progesteroneand, 
estradiol (approximately 
10 mL), and liver function 
tests (Part 2 only, 
approximately 5 mL)

obtain blood sample for 
serum progesterone, 
estradiol (approximately 
10 mL), and liver 
function tests (Part 2 
only, approximately 5 
mL)
Addition. Volume of 
blood sample collected 
in Part 2 and liver 
function test added.

interviews about mood 

interviews about mood 
Addition. Interview 
about mood will be 


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Reason/Justification 
for change
(Part 2 only) and menstrual 
bleeding pattern.
(Part 2 only) and 
menstrual bleeding 
pattern.
conducted during visit.
Section 4.2. Subject Exclusion Criteria
b.
has current and or history of 
ischemic heart disease
b.
has current or history of ischemic 
heart disease
Correction.
l.
has severe cirrhosis 
(decompensated) or liver tumors
m. has one or more baseline liver 
function test(s) outside the local 
laboratory’s normal range
l.
has severe cirrhosis 
(decompensated) or liver tumors
m. has one or more baseline liver 
function test(s) outside the local 
laboratory’s normal range
Exclusion criteria added
k.
has current or history of cervical 
cancer
l. has severe cirrhosis (decompensated)
m. has liver tumors
k.
has current or history of cervical 
cancer
Exclusion criteria 
removed
o. history of diagnosed clinical 
depression or bipolar disorder, with or 
without suicidal ideation, and/or 
history of suicide attempt
p.
in last two years, history of either 
hospitalization or medication 
management for 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
o. history of diagnosed clinical 
depression or bipolar disorder, with or 
without suicidal ideation, and/or 
history of suicide attempt
p.
in last two years, history of either 
hospitalization or medication 
management for 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
Exclusion criteria added
o. has history of medical treatment for 
clinical depression
p.used DMPA products (Depo-Provera 
CI or Depo-subQ Provera 104) in the 
past 12 months
q.used DMPA products (Depo-
Provera CI or Depo-subQ Provera 
104) in the past 12 months
Exclusion criteria 
removed
y.
in the opinion of the 
investigator, potentially at elevated risk 
of HIV infection (eg, HIV-positive 
y.
in the opinion of the investigator, 
potentially at elevated risk of HIV 
infection (eg, HIV-positive partner, 
Exclusion criteria added


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Reason/Justification 
for change
partner, IV drug use by self or by 
partner)
IV drug use by self or by partner)
Section 5.1.1 Dilution Procedure of TV-46046
Diluted TV-46046 will be prepared by 
the investigational center pharmacist or 
other trained study staff member
Diluted TV-46046 will be prepared by 
the investigational center pharmacist 
or other trained study staff member
Addition. Other trained 
staff can now prepare 
diluted TV-46046. 
Table 2
Approximate Blood Volume
Liver Function
Liver Function
Addition. Liver function 
test added to table listing 
total blood volumes 
collected.
about 5
about 5
Addition. Approximate 
volume of blood 
collected for liver 
function test.
4
4
Addition. Approximate 
number of samples 
collected liver function 
tests.
~20
~20
Addition. Approximate 
total volume of blood 
collected for liver 
function tests.
~117121
~121
Addition. Increase in 
total number of samples 
collected.
~909924
~924
Addition. Increase in 
total volume of blood 
collected.
Section 6.1.4.
Shipment and Analysis of Samples
Computer print outs will serve as 
source Source documentation for 
theMPA data and will be stored by
maintained at PPD and available for 
clinical monitoring if needed..
Source documentation for MPA will 
be maintained at PPD. 
Clarification. Location 
of source documentation 
stated.
Section 6.2 Pharmacodynamics
Detailed instructions on how to draw 
and prepare serum samples for 
Detailed instructions on how to draw 
and prepare serum samples for 
Addition. Text added to 
describe progesterone 
and estradiol sampling 


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Reason/Justification 
for change
progesterone and estradiol analysis and 
liver function analysis (Part 2 only)
will be investigational center-specific 
and provided in the laboratory SOPs 
and/or Study Manual.
progesterone and estradiol analysis 
and liver function analysis (Part 2 
only) will be investigational center-
specific and provided in the 
laboratory SOPs and/or Study 
Manual.
and liver function 
analysis.
Briefly, blood samples for progesterone 
and estradiol (up to 10 mL) will be 
collected via venipuncture, centrifuged, 
and then transferred into 2 aliquots.
Briefly, blood samples for 
progesterone and estradiol (up to 
10 mL) will be collected via 
venipuncture, centrifuged, and then 
transferred into 2 aliquots.
Addition. Text added to 
state how much blood 
will be collected for 
progesterone and 
estradiol sampling.
Collection and movement of 
progesterone and estradiol samples will 
be recorded on appropriate study CRFs 
and/or tracking tools. 
Collection and movement of 
progesterone and estradiol samples 
will be recorded on appropriate study 
CRFs and/or tracking tools. 
Addition. Text added to 
state how estradiol 
sampling will be 
recorded. 
In Part 2 blood samples for liver 
function analysis (up to 5 mL) will be 
collected via venipuncture, centrifuged 
and then transferred to one aliquot for 
analysis.
In Part 2 blood samples for liver 
function analysis (up to 5 mL) will be 
collected via venipuncture, 
centrifuged and then transferred to 
one aliquot for analysis.
Addition. Liver function 
analysis detailed.
Section 7.1.4.
Relationship of an Adverse Event to the Study Drug
The relationship of an adverse event to 
the study drug is characterized as 
follows and will be determined by 
Teva:
The relationship of an adverse event 
to the study drug is characterized as 
follows and will be determined by 
Teva:
Clarification. Text added 
to explain that Teva will 
determine the relationship
of an adverse event to the 
study drug.
Section 7.4
Clinical Laboratory Tests
Liver function testing including, but 
not limited to, ALT and AST will be 
performed in Part 2 only by the 
investigational center laboratory at the 
screening visit, as well as at the month 
3, month 7.5 and final visits. Detailed 
instructions on how to draw and 
prepare samples for liver function 
testing will be investigational center-
specific and provided in the laboratory 
SOPs and/or Study Manual.
Liver function testing including, but 
not limited to, ALT and AST will be 
performed in Part 2 only by the 
investigational center laboratory at the 
screening visit, as well as at the month 
3, month 7.5 and final visits. Detailed 
instructions on how to draw and 
prepare samples for liver function 
testing will be investigational center-
specific and provided in the 
laboratory SOPs and/or Study 
Manual.
Addition. Liver function 
testing details included.


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Reason/Justification 
for change
Section 7.6 Body Weight
7.6 Physical examinations, including 
height (to be obtained at the screening 
and enrollment visits only), body Body 
Weight
7.6 Body Weight
Correction. Section 
heading updated.
Body weight, and vital signs (see 
Section 7.5) will be 
performedmeasured at the time points 
detailed in Table 1. and documented 
on appropriate study CRF. A 
standardized protocol for weight 
measurement will be provided in the 
study manual.
Body weight will be measured at the 
time points detailed in Table 1 and 
documented on appropriate study 
CRF. A standardized protocol for 
weight measurement will be provided 
in the study manual.
Correction. 
Measurement of vital 
signs removed from 
body weight section.
Weight gain or loss will be 
documentdocumented as an adverse 
event only if reported by the subject.
Weight gain or loss will be 
documented as an adverse event only 
if reported by the subject.
Correction.
Section 7.8 Menstrual Bleeding Patterns 
SubjectsStudy subjects will be asked 
about changes in their menstrual 
bleeding patterns, including no 
bleeding, since last assessment at 
monthly intervals (in Part 1 only) and 
during the scheduled laboratory or
follow-up visits at week 13 (month 3) 
and week 32 (month 7.5), and at the 
final study visit.
Study subjects will be asked about 
changes in their menstrual bleeding 
patterns, including no bleeding, since 
last assessment at monthly intervals 
(in Part 1 only) and during the 
scheduled follow-up visits at week 13 
(month 3) and week 32 (month 7.5), 
and at the final study visit.
Addition. Text added to 
describe how subjects 
will record changes in 
their menstrual bleeding 
patterns.
Interview items will include date of last 
bleeding, description of bleeding 
pattern since last visit, as well as 
frequency of bleeding, duration of 
episodes, pain/cramps, and volume, all 
compared with the pre-study period. 
The acceptability and tolerability of the 
bleeding pattern will be queried.
Interview items will include date of 
last bleeding, description of bleeding 
pattern since last visit, as well as 
frequency of bleeding, duration of 
episodes, pain/cramps, and volume, 
all compared with the pre-study 
period. The acceptability and 
tolerability of the bleeding pattern 
will be queried.
Addition. Interview 
topics to describe 
menstrual bleeding 
patterns. 


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for change
In addition, in Part 2, subjects will be 
trained to use and prompted to 
complete weekly menstrual diaries on-
line. On these diaries, subjects will 
record daily occurrence of no flow, 
spotting (pantyliner or no protection 
needed), bleeding (tampons or sanitary 
pads needed), and pain (none/mild or 
moderate/severe) for the last seven 
days. These data will be automatically 
uploaded into the clinical data base 
using the OpenClinica Participate
module.
In addition, in Part 2, subjects will be 
trained to use and prompted to 
complete weekly menstrual diaries 
on-line. On these diaries, subjects will 
record daily occurrence of no flow, 
spotting (pantyliner or no protection 
needed), bleeding (tampons or 
sanitary pads needed), and pain 
(none/mild or moderate/severe) for 
the last seven days. These data will be 
automatically uploaded into the 
clinical data base using the 
OpenClinica Participate module.
Addition. Text added to 
describe how subjects 
will record changes in 
their menstrual bleeding 
patterns.
Section 7.9 Mood Changes
In Part 2, subjects will be interviewed 
about aspects of and changes in mood 
at screening and at the scheduled 
follow-up visits at month 3 and month 
7.5, and at the final study visit. To 
measure depression or psychological 
distress, a selected validated scale, such 
as the 10-item Patient Health 
Questionnaire (PHQ-9) that screens for 
depression, will ascertain the frequency 
of a variety of somatic and emotional 
indicators of well-being and produce an 
overall score that can be compared at 
different time points in the study. The 
PHQ-9 includes items on pleasure in 
doing things, having little energy, 
feeling bad about yourself, and having 
trouble concentrating, among others. 
The frequency of each indicator is then 
summed to produce a single overall 
score for the severity of depression.
In Part 2, subjects will be interviewed 
about aspects of and changes in mood 
at screening and at the scheduled 
follow-up visits at month 3 and month 
7.5, and at the final study visit. To 
measure depression or psychological 
distress, a selected validated scale, 
such as the 10-item Patient Health 
Questionnaire (PHQ-9) that screens 
for depression, will ascertain the 
frequency of a variety of somatic and 
emotional indicators of well-being 
and produce an overall score that can 
be compared at different time points 
in the study. The PHQ-9 includes 
items on pleasure in doing things, 
having little energy, feeling bad about 
yourself, and having trouble 
concentrating, among others. The 
frequency of each indicator is then 
summed to produce a single overall 
score for the severity of depression.
Addition. Text added to 
describe the evaluation 
of mood changes over 
the course of the study.
Section 8.1
Sample Size and Power Considerations
Scientific judgment will be used to 
determine if the sample size in Part 2 
can be reduced from 20 subjects per 
Scientific judgment will be used to 
determine if the sample size in Part 2 
can be reduced from 20 subjects per 
Correction. Text no
longer applicable.


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Reason/Justification 
for change
groupto 12 or 15 subjects per treatment 
group, depending on the variability of 
population pharmacokinetic parameter 
estimates observed in Part 1.
group, depending on the variability of 
population pharmacokinetic parameter 
estimates observed in Part 1.
Section 8.5.3.
Planned Method of Analysis
There are 5 planned reviews of the 
interim data; 2 reviews in Part 1 and 3 
reviews in Part 2,although their number 
and timing may change based on the 
findings
There are 5 planned reviews of the 
interim data; 2 reviews in Part 1 and 3 
reviews in Part 2, although their 
number and timing may change based 
on the findings
Addition. Text added to 
explain that the timing of 
interim data reviews 
may change over the 
course of the study.
Section 8.8.2. 
Safety Analysis
The percentage of women experiencing 
amenorrhea or other menstrual 
bleeding disturbances (irregular 
bleeding or spotting) will be assessed 
at monthly intervals during scheduled 
laboratory orvisits (in Part 1 only) and 
at follow-up visits (at week 13 and 
week 32 only), and the final study visit.
The percentage of women 
experiencing amenorrhea or other 
menstrual bleeding disturbances 
(irregular bleeding or spotting) will be 
assessed at monthly intervals during 
scheduled laboratory visits (in Part 1 
only) and at follow-up visits at 
week 13 and week 32 only, and the 
final study visit. 
Clarification. Text edited 
to state when 
assessments for 
amenorrhea or other 
menstrual bleeding 
disturbances will occur.
In addition, in Part 2 weekly self-
reported menstrual data will be 
assessed, and compared between
treatment groups for the Treated 
Populations in Part 1 and Part 2. 
Likewise, vital using frequency tables; 
details are found in the Statistical 
Analysis Plan. In Part 2 only, liver 
function tests, including but not limited 
to ALT and AST, will be assessed by 
tabulating and graphing change from 
screening to week 13 (month 3), 
week 32 (month 7.5), and final study 
visit data. In Part 2 only mood will be 
assessed in frequency tables at 
screening and at week 13 (month 3), 
week 32 (month 7.5), and final study 
visits.
In addition, in Part 2 weekly self-
reported menstrual data will be 
assessed, and compared between 
treatment groups using frequency 
tables; details are found in the 
Statistical Analysis Plan. In Part 2 
only, liver function tests, including 
but not limited to ALT and AST, will 
be assessed by tabulating and 
graphing change from screening to 
week 13 (month 3), week 32 
(month 7.5), and final study visit data.
In Part 2 only mood will be assessed 
in frequency tables at screening and at 
week 13 (month 3), week 32 
(month 7.5), and final study visits.
Addition. Text added to 
describe additional 
safety assessments.


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Vital signs and body weight will be 
summarized graphically and using 
shift-tables, by investigational center 
and treatment group.
Vital signs and body weight will be 
summarized graphically and using 
shift-tables, by investigational center 
and treatment group.
Correction.
Section 8.10.
Planned Interim Analysis
At that time, available PK data from 
women in treatment group 2 (ie, the 
next six women receiving diluted TV-
46046) will also be analyzed. 
Additional assessments will be made if 
warranted (eg, when the 12 women in 
both the undiluted and diluted groups 
complete 4 months (17 weeks)). Other 
features of the undiluted drug may also 
be considered in the decision-making 
process, including stability, re-
suspendability, syringeability, and 
safety, although these will not be part 
of the formal analysis.
At that time, available PK data from 
women in treatment group 2 (ie, the 
next six women receiving diluted TV-
46046) will also be analyzed. 
Additional assessments will be made 
if warranted (eg, when the 12 women 
in both the undiluted and diluted 
groups complete 4 months (17 
weeks)). Other features of the 
undiluted drug may also be 
considered in the decision-making 
process, including stability, re-
suspendability, syringeability, and 
safety, although these will not be part 
of the formal analysis.
Addition. Text added to 
describe other 
formulation features that 
may impact the decision-
making process.
Section 9. Direct Access To Source Data/Documents
Examples of source documents are 
hospital records, office visit records, 
examining physician’s finding or notes, 
consultant’s written opinion or notes, 
laboratory reports, drug inventory, 
study drug label records, diary data, 
protocol required worksheets, and 
CRFs that are used as the source (see 
Section 3.13).
Examples of source documents are 
hospital records, office visit records, 
examining physician’s finding or 
notes, consultant’s written opinion or 
notes, laboratory reports, drug 
inventory, study drug label records, 
and CRFs that are used as the source 
(see Section 3.13).
Correction. Text no 
longer applicable.
Section 12.1.
Data Collection
DataMost data will be collected using 
1-ply CRFs that are specifically 
designed for this study.
Most data will be collected using 1-
ply CRFs that are specifically 
designed for this study.
Clarification. Text edited 
to describe collection of 
data.
In Part 2 only data on menstrual 
bleeding will be collected weekly using 
a validated, Part 11-compliant on-line 
application of OpenClinica, the clinical 
In Part 2 only data on menstrual 
bleeding will be collected weekly 
using a validated, Part 11-compliant 
on-line application of OpenClinica, 
Addition. Text added to 
describe collection of 
weekly bleeding data.


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data management system. Women will 
be prompted by text message or e-mail 
to access the website and submit 
answers to a brief question set. These 
data will be entered automatically 
uploaded into the OpenClinica clinical 
database. 
the clinical data management system. 
Women will be prompted by text 
message or e-mail to access the 
website and submit answers to a brief 
question set. These data will be 
entered automatically uploaded into 
the OpenClinica clinical database. 
If data are processed from other 
sources (eg, central laboratory, 
bioanalytical laboratory, central image 
center, electronic diary data, electronic 
patient-reported outcome [ePRO] 
Tablet), the results will be sent to the 
investigational center, where they will 
be retained but not entered into the 
CRF unless otherwise specified in the 
protocol.
If data are processed from other 
sources (eg, central laboratory, 
bioanalytical laboratory, central image 
center, electronic patient-reported 
outcome [ePRO] Tablet), the results 
will be sent to the investigational 
center, where they will be retained but 
not entered into the CRF unless 
otherwise specified in the protocol.
Correction.
Section 12.3.1. Sponsor 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. These 
SOPs will be reviewed by the sponsor 
before the start of data management 
activities.
All data management tasks for this 
study are delegated to FHI 360; these 
functions will be carried out as 
described in FHI 360 SOPs.
Correction.
Section 12.3.2.
Investigator Responsibilities

data results from other sources 
(eg, central laboratory, 
bioanalytical laboratory, 
central image center, electronic 
diarydata)

data results from other 
sources (eg, central 
laboratory, bioanalytical 
laboratory, central image 
center, electronic diary)
Correction.
References
Depo-Provera Contraceptive 
Injection [package insert]. New 
York, NY: Pfizer Inc; 20156.
Depo subQ Provera 104 [package 
insert]. New York, NY: Pfizer Inc; 
20156.
Depo-Provera Contraceptive 
Injection [package insert]. New 
York, NY: Pfizer Inc; 2016.
Depo subQ Provera 104 [package 
insert]. New York, NY: Pfizer Inc; 
2016.
Most recent Prescribing 
Information referenced.


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16.3.
Protocol Amendment 02 Dated 04 November 2016
The primary reasons for this amendment are corrections. These changes are unlikely to affect to a 
significant degree the safety or rights (physical or mental integrity) of the subjects in the clinical study or 
the scientific value of the clinical study. 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 Laboratory And Other Departments And Institutions
 
, Global Clinical Development
, Women’s 
Health
Teva Pharmaceutical Industries, Ltd.
, Women’s 
Health
Teva Pharmaceutical Industries, Ltd.
Correction. Study 
personnel updated.
Global Patient Safety & 
Pharmacovigilance
Teva Branded Pharmaceutical Products 
R&D, Inc.
41 Moores Road
Frazer 2 West Liberty Blvd, Suite 300 
Malvern, Pennsylvania 19355
United States of America
Global Patient Safety & 
Pharmacovigilance
Teva Branded Pharmaceutical 
Products R&D, Inc.
2 West Liberty Blvd, Suite 300 
Malvern, Pennsylvania 19355
United States of America
Correction. Study 
personnel updated.
Clinical Study Protocol Synopsis
Planned Study Period: July November
2016 (first subject screened) to 
November 2019 (last subject last visit).
Planned Study Period: November
2016 (first subject screened) to 
November 2019 (last subject last 
visit).
Date Corrected
Section 1.1 Introduction
When compared to Depo-Provera CI, 
Depo-subQ 104 exhibited a lower 
average maximum observed plasma/
serum drug concentration (Cmax) 
(1.56 ng/mL compared to 3.73 ng/mL), 
a longer mean half-life (43 days 
compared to 13 days), and lower 
overall drug exposure (area under the 
plasma/serum drug concentration by-
time curve from time 0 to infinity 
[AUC0-∞] of 92.84 ng•day/mL 
compared to 134 ng•day/mL) (Jain et al 
2004).
When compared to Depo-Provera CI, 
Depo-subQ 104 exhibited a lower 
average maximum observed serum 
drug concentration (Cmax) (1.56 ng/mL 
compared to 3.73 ng/mL), a longer 
mean half-life (43 days compared to 
13 days), and lower overall drug 
exposure (area under the serum drug 
concentration by-time curve from 
time 0 to infinity [AUC0-∞] of 
92.84 ng•day/mL compared to 
134 ng•day/mL) (Jain et al 2004).
Correction. Text updated 
to reflect literature.


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Section 1.3.1
Nonclinical Studies
Published nonclinical pharmacological 
and toxicological studies from 
literature, including nonclinical 
biological pharmacology and 
toxicology/toxicokinetic activities of 
DMPA/MPA support the contraception 
indication, nonclinical 
pharmacokinetics, and expected safety 
profile of TV-46046.
Published nonclinical 
pharmacological and toxicological 
studies from literature, including 
nonclinical pharmacology and 
toxicology/toxicokinetic activities of 
DMPA/MPA support the 
contraception indication, nonclinical 
pharmacokinetics, and expected safety 
profile of TV-46046.
Correction.
Section 1.3.1.1 Nonclinical Studies Conducted by Teva
Teva’s current nonclinical safety 
program consists of 4 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 2014
064)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).
Teva’s current nonclinical safety 
program consists of 4 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).
Correction. Text updated 
to reflect previous 
studies.
However, the slight increase in the 
magnitude of effects in the TV-46046 
group correlates with the higher MPA 
exposure levels observed on study, as 
measured by Cmax (8.6 ng/mL), area 
under the plasma/serum plasma drug 
concentration by time curve from time 
0 to day 6 (AUC0-6) (42.6 ng•day/mL), 
and area under the plasma/serum
plasma drug concentration by time 
curve from time 0 to day 89 (AUC0-89) 
(504.3 ng•day/mL). No toxic effects 
were associated with TV-46046 
excipients.
However, the slight increase in the 
magnitude of effects in the TV-46046 
group correlates with the higher MPA 
exposure levels observed on study, as 
measured by Cmax (8.6 ng/mL), area 
under the plasma drug concentration 
by time curve from time 0 to day 6 
(AUC0-6) (42.6 ng•day/mL), and area 
under the plasma drug concentration 
by time curve from time 0 to day 89 
(AUC0-89) (504.3 ng•day/mL). No 
toxic effects were associated with TV-
46046 excipients.
Correction. Text updated 
to reflect previous 
studies.


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Reason/Justification 
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Section 1.3.1.2 Nonclinical Literature
Depo In in vitro genotoxicity studies, 
Depomedroxyprogesterone acetate
(DMPA)/MPA was negative in bacteria
bacterial and mammalian somatic cells 
using a large series of in vitro and in 
vivo genotoxicity studiescell lines.
In in vitro genotoxicity studies, 
DMPA/MPA was negative in 
bacterial and mammalian somatic cell 
lines.
Correction. Text 
corrected to reflect 
literature.
Based on the published literature and 
results of Teva’s GLP-compliant
nonclinical studies, subcutaneous 
administration of TV-46046 in humans 
should have a safety profile similar to 
that of the FDA-approved Depo-subQ 
104.
Based on the published literature and 
results of Teva’s GLP-compliant
nonclinical studies, subcutaneous 
administration of TV-46046 in 
humans should have a safety profile 
similar to that of the FDA-approved 
Depo-subQ 104.
Clarification.
Section 1.8 Location and Duration of Study
The expected duration of the 2-part 
study is from July November 2016 
(first subject screened) to November 
2019 (last subject last visit).
The expected duration of the 2-part 
study is from November 2016 (first 
subject screened) to November 2019 
(last subject last visit).
Date Corrected
Section 2.3.1
Primary Endpoints (also Sections 2.3.2, 3.3, and 3.4)
In Part 1 (exploratory 
pharmacokinetics), the primary 
endpoints are individual and mean 
serum MPA concentration-time 
profiles measured during follow-up 
visits, and estimated noncompartmental 
pharmacokinetics parameters,
including but not limited to Cmax, tmax, 
maximum observed plasma/serum drug 
concentration at day 182 (C182), area 
under the plasma/serum drug 
concentration by time curve from time 
0 to day 182 (AUC0-182), AUC0-∞, and 
apparent terminal half-life.
In Part 1 (exploratory 
pharmacokinetics), the primary 
endpoints are individual and mean 
serum MPA concentration-time 
profiles measured during follow-up 
visits, and estimated 
noncompartmental pharmacokinetics 
parameters, including but not limited 
to Cmax, tmax, observed serum drug 
concentration at day 182 (C182), area 
under the serum drug concentration by 
time curve from time 0 to day 182 
(AUC0-182), AUC0-∞, and apparent 
terminal half-life.
Text corrected to 
indicate that only serum 
levels will be used to 
estimate 
pharmacokinetic and 
pharmacodynamic
parameters.
Section 2.3.2
Secondary Endpoints
In Part 2, secondary endpoints include 
pharmacokinetics of MPA based on 
individual and mean serum MPA 
concentration-time profiles measured 
during follow up visits and estimated 
noncompartmental pharmacokinetics 
In Part 2, secondary endpoints include 
pharmacokinetics of MPA based on 
individual and mean serum MPA 
concentration-time profiles and 
estimated noncompartmental 
pharmacokinetics parameters,
Correction. Text 
corrected to indicate that 
only serum will be 
collected.


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Reason/Justification 
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parameters, including but not limited to 
Cmax, tmax, C182, maximum observed 
plasma/serum drug concentration at 
day 210 (C210), AUC0-182, area under 
the plasma/serum drug concentration 
by time curve from time 0 to day 210 
(AUC0-210), AUC0-∞, and apparent 
terminal half-life.
including but not limited to Cmax, tmax, 
C182, observed serum drug 
concentration at day 210 (C210), 
AUC0-182, area under the serum drug 
concentration by time curve from time 
0 to day 210 (AUC0-210), AUC0-∞, and 
apparent terminal half-life.
Section 3.3 Pharmacokinetic Measures and Time Points
For Part 1, blood samples for 
measurement of serum concentrations
will be obtained on days 0 (baseline), 
1, 2, 3, 5, 7, 10, 12, 14, 18, 2120; 28, 
35, and 42; weeks 8, 10, 12, 13, 15, 17, 
19, 21, 23, 25, 26, 28, 30, and 32; and 
then every 28 days until week 52.
For Part 1, blood samples for 
measurement of serum concentrations 
will be obtained on days 0 (baseline), 
1, 2, 3, 5, 7, 10, 12, 14, 18, 20; 28, 35, 
and 42; weeks 8, 10, 12, 13, 15, 17, 
19, 21, 23, 25, 26, 28, 30, and 32; and 
then every 28 days until week 52.
Correction. The 21 day 
collection time changed 
to 20.
In addition, sSubjects for whom 
ovulation has not returned by month 12 
(week 52), blood samples for MPA will 
be collected up to 2 more times (once 
at week 61 and 65 and once atmore
week 74 and78), but not past return to 
ovulation. 
Subjects for whom ovulation has not 
returned by month 12 (week 52), 
blood samples for MPA will be 
collected up to 2 more times (once at 
week 61 and once at week 74), but not 
past return to ovulation.
Clarification to explain 
when sampling will 
occur in subjects for 
whom ovulation has not 
returned by month 12 
(week 52)
In addition, blood samples will also be 
collected and stored for possible future 
MPA testing (if necessary) any time at 
all weekly visits up to 12 months when 
samples are collected for serum 
progesterone and estradiol, except for 
pre-treatment visits and visits for 
confirmation of ovulation.
In addition, blood samples will also be 
collected and stored for possible 
future MPA testing (if necessary) a at 
all weekly visits up to 12 months 
when samples are collected for serum 
progesterone and estradiol, except for 
pre-treatment visits and visits for 
confirmation of ovulation. 
Correction
Section 3.11 
Duration of Subject Participation and Justification
Minimal participation in the study is 
approximately 713 months 
(3056 weeks) (approximately 1 month 
of pre-treatment and approximately 
612 months of treatment), if Part 2 of 
the study is not initiated.
Minimal participation in the study is 
approximately 13 months (56 weeks) 
(approximately 1 month of pre-
treatment and approximately 
12 months of treatment), if Part 2 of 
the study is not initiated
Corrected to lengthen 
minimal participation 
period.
Section 3.12
Stopping Rules and Discontinuation Criteria
Others reasons the study may be 
stopped include:
•
The sponsor decides to reduce 
the scope (eg, reduce sample 
size, drop one or more study 
Others reasons the study may be 
stopped include:
•
The sponsor decides to reduce 
the scope (eg, reduce sample 
size, drop one or more study 
Text added to clarify the 
role of the sponsor and 
FHI 360 and present 
reasons for early 
termination of the study.


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Reason/Justification 
for change
groups) or discontinue the 
study (eg, due to 
noncompliance with protocol 
or regulatory requirements, 
feasibility, etc.).
•
FHI 360’s Protection of 
Human Subjects Committee 
(PHSC) recommends to 
terminate the study
•
Local IRB(s) recommend to 
terminate the study
•
The FDA requests that the 
study be discontinued or 
placed on hold
groups) or discontinue the 
study (eg, due to 
noncompliance with protocol 
or regulatory requirements, 
feasibility, etc.).
•
FHI 360’s Protection of 
Human Subjects Committee 
(PHSC) recommends to 
terminate the study
•
Local IRB(s) recommend to 
terminate the study
•
The FDA requests that the 
study be discontinued or 
placed on hold
Section 3.14.1. Procedures Before Study Drug Treatment
•
perform physical examination to: 
measure BP, heart rate, and 
respiration
measure body weight and height to 
estimate BMI
•
perform physical examination to: 
measure BP, heart rate, and 
respiration
measure body weight and height 
to estimate BMI
Revision to presentation.
Section 3.14.2 Pretreatment
Subjects who meet the 
inclusion/exclusion criteria at screening 
visit will return to the clinic twice a 
week (preferably 3 days apart) during 
the 2 to 3 weeks preceding their next 
expected menses (4 to 6 times) for 
serum progesterone and estradiol 
measurements to confirm ovulation. 
They will also have a mammogram 
scheduled during this time if they have 
not had a mammogram within the last 
12 months during Part 1 only.
Subjects who meet the 
inclusion/exclusion criteria at 
screening visit will return to the clinic 
twice a week (preferably 3 days apart) 
during the 2 to 3 weeks preceding 
their next expected menses (4 to 6 
times) for serum progesterone and 
estradiol measurements to confirm 
ovulation. They will also have a 
mammogram scheduled during this 
time if they have not had a 
mammogram within the last 12 
months during Part 1 only.
Text added to state that 
subjects will have a 
mammogram scheduled 
if they have not had one 
within the last 12 
months.
Section 3.14.3.1.
Enrollment (Injection) Visit (Day 0) (also Section 3.14.3.2.1, Section 3.14.4.1)
•perform physical examination to:
•perform measure vital signs 
measurement(BP [systolic/diastolic], 
pulse, and respiration)
•perform physical examination to: 
measure vital signs measurement 
(BP [systolic/diastolic], pulse, and 
respiration)
Typo.
Section 3.14.3.2.1. Scheduled Follow-up Visits (Day 7, Month 3, and Month 7.5)
•perform physical examination to:
measure vital signs measurement (BP 
•
perform physical examination to: 
measure vital signs measurement 
Typo


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[systolic/diastolic], pulse, and 
respiration)
measure body weight
(BP [systolic/diastolic], pulse, and 
respiration)
measure body weight
•interview about menstrual bleeding 
pattern (month 3 and month 7.5 only)
•
interview about menstrual 
bleeding pattern (month 3 and month 
7.5 only)
Clarification to explain 
when interviewing will 
occur.
Section 3.14.3.2.2. Laboratory Visits
Blood samples for MPA will be 
collected and stored for possible future 
MPA testing (if necessary) any time 
when samples are collected for serum 
progesterone and estradiol up until 
Month 12, except for pre-treatment 
visits and visits for confirmation of 
ovulation.
Blood samples for MPA will be 
collected and stored for possible future 
MPA testing (if necessary) any time 
when samples are collected for serum 
progesterone and estradiol up until 
Month 12, except for pre-treatment 
visits and visits for confirmation of 
ovulation.
Text moved to month 12 
section.
Section 3.14.3.2.3. Laboratory Visits after Week 52
During these additional laboratory 
visits, blood samples will be collected 
and tested for serum progesterone and 
estradiol (all visits) and serum MPA 
(weeks 615 and 748).Blood samples 
for MPA will be collected and stored 
for possible future MPA testing (if
necessary) any time when samples are 
collected for serum progesterone and 
estradiol.
During these additional laboratory 
visits, blood samples will be collected 
and tested for serum progesterone and 
estradiol (all visits) and serum MPA 
(weeks 61 and 74).
Text revised to replicate 
collection times in 
similar studies.
Table 1:
Study Procedures and Assessments (Parts 1 and 2)
Mammogramn
Mammogramn
Added
g. During the follow-up laboratory 
visits, blood samples for serum 
progesterone and estradiol will be 
collected at weeks 1, 2, 4, 6, 8, 10, and 
12; then weekly through week 3252. If 
ovulation does not return by week 32, 
then weekly blood samples for serum 
progesterone and estradiol will 
continue to be collected until ovulation 
or through week 52, whichever is 
earlier.
g. During the follow-up laboratory 
visits, blood samples for serum 
progesterone and estradiol will be 
collected at weeks 1, 2, 4, 6, 8, 10, and 
12; then weekly through week 52. 
Correction. Text revised 
to replicate collection 
times in similar studies.
g. During these additional laboratory 
visits, blood samples will be collected 
and tested for serum progesterone and 
estradiol (all visits) and serum MPA 
g. During these additional laboratory 
visits, blood samples will be collected 
and tested for serum progesterone and 
estradiol (all visits) and serum MPA 
Correction. Text revised 
to replicate collection 
times in similar studies.


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(weeks 6561 and 7874).
(weeks 61 and 74).
i. During the follow-up visits, blood 
samples for MPA will be collected at 
days 1, 2, 3, 5, 7, 10, 12, 14, 18, 201, 
28, 35, and 42; then at weeks 8, 10, 12, 
13, 15, 17, 19, 21, 23, 25, 26, 28, 30, 
and 32; and then every 28 days until 
week 52 (in Part 1). Among subjects in 
whom ovulation does not return by 
week 52, blood samples for MPA will 
be collected up to 2 more times (at 
weeks 615 and 748), but not past return 
to ovulation. Blood samples will also 
be collected and stored for possible 
future MPA testing (if necessary) at all 
weekly visits up to 12 months any time 
when samples are collected for serum 
progesterone and estradiol, except for 
pre-treatment visits and visits for 
confirmation of ovulation.
i. During the follow-up visits, blood 
samples for MPA will be collected at 
days 1, 2, 3, 5, 7, 10, 12, 14, 18, 20, 
28, 35, and 42; then at weeks 8, 10, 
12, 13, 15, 17, 19, 21, 23, 25, 26, 28, 
30, and 32; and then every 28 days 
until week 52 (in Part 1). Among 
subjects in whom ovulation does not 
return by week 52, blood samples for 
MPA will be collected up to 2 more 
times (at weeks 61 and 74), but not 
past return to ovulation. Blood 
samples will also be collected and 
stored for possible future MPA testing 
(if necessary) at all weekly visits up to 
12 months when samples are collected 
for serum progesterone and estradiol, 
except for pre-treatment visits and 
visits for confirmation of ovulation.
Correction. Text revised 
to replicate collection 
times in similar studies.
n. Part 1 only
n. Part 1 only
Footnote added to state 
that subjects will have a 
mammogram scheduled 
if they have not had one 
within the last 12 
months during Part 1 
only.
Section 3.14.3.2.1
Scheduled Follow-up Visits (Day 7, Month 3, and Month 7.5)
interview about menstrual bleeding 
pattern (month 3 and month 7.5 only)
interview about menstrual bleeding 
pattern (month 3 and month 7.5 only)
Clarification. Text added
to indicate that this 
interview will only take 
place during the 3 and 
7.5 month visit.
Section 3.14.3.2.2
Laboratory Visits 
Blood samples for MPA will be 
collected and stored for possible future 
MPA testing (if necessary) any time 
when samples are collected for serum 
progesterone and estradiol up until 
Month 12, except for pre-treatment 
visits and visits for confirmation of 
ovulation.
Blood samples for MPA will be 
collected and stored for possible 
future MPA testing (if necessary) any 
time when samples are collected for 
serum progesterone and estradiol up 
until Month 12, except for pre-
treatment visits and visits for 
confirmation of ovulation.
Clarification. Text 
moved from 
Section 3.14.3.2.3 and 
added to define the 
amount of time blood 
samples will be stored 
for MPA testing.


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for change
Section 3.14.3.2.3
Laboratory Visits after Week 52
During these additional laboratory 
visits, blood samples will be collected 
and tested for serum progesterone and 
estradiol (all visits) and serum MPA 
(weeks 615 and 748).Blood samples 
for MPA will be collected and stored 
for possible future MPA testing (if 
necessary) any time when samples are 
collected for serum progesterone and 
estradiol.
During these additional laboratory 
visits, blood samples will be collected 
and tested for serum progesterone and 
estradiol (all visits) and serum MPA 
(weeks 61 and 74).
Correction. Text revised 
to replicate collection 
times in similar studies.
Section 3.14.4.1.
Final Visit
•
perform physical examination to:
measure body weight
perform measure vital signs 
measurement (BP [systolic/diastolic], 
pulse, and respiration)
•
perform physical examination to: 
measure body weight
measure vital signs (BP 
[systolic/diastolic], pulse, and 
respiration)
Correction.
Section 4.1 Subject Inclusion
h. has a BMI of 18.0 to 30.0 35, 
inclusive, (unless included in subset of 
subjects with extreme obesity 
(BMI ≥40), 2 in each dose-range 
finding group from a single 
investigational center, in Part 2)
h. has a BMI of 18 to 35, inclusive, 
(unless included in subset of subjects 
with extreme obesity (BMI ≥40), 2 in 
each dose-range finding group from a 
single investigational center, in Part 2)
Correction. BMI range 
expanded for 
consistency with similar 
studies.
Section 4.2 Subject Exclusion
j. has 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, and any male 
family member with breast cancer), or 
current or history of breast cancer, or 
undiagnosed mass detected by breast 
exam
j. has 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, and any 
male family member with breast 
cancer), or current or history of breast 
cancer, or undiagnosed mass detected 
by breast exam
Clarification. Text added 
to describe a “strong” 
family history of breast 
cancer.
Section 4.3 Justification for Key Inclusion and Exclusion Criteria
The study will not enroll female 
subjects who have medical 
contraindications to DMPA nor 
medical or social conditions that may 
make study participation unsafe, 
interfere with drug absorption and 
metabolism, have a strong family 
The study will not enroll female 
subjects who have medical 
contraindications to DMPA nor 
medical or social conditions that may 
make study participation unsafe, 
interfere with drug absorption and 
metabolism, have a strong family 
Clarification. Text added 
to describe a “strong” 
family history of breast 
cancer.


Pharmacokinetic Study–Contraception
Clinical Study Protocol with Amendment 04
Study TV46046-WH-10075
150
Original text with changes shown
New wording
Reason/Justification 
for change
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 and 
any male family member with breast 
cancer or complicate data 
interpretation.
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 
and any male family member with 
breast cancer, or complicate data
interpretation.
Section 5.3 Prior and Concomitant Medication or Treatment
•selective cyclooxygenase-2 (COX-2) 
inhibitors (eg, meloxicam, celecoxib) 
for 5 or more consecutive days
•selective cyclooxygenase-2 (COX-2) 
inhibitors (eg, meloxicam, celecoxib) 
for 5 or more consecutive days
Added. Text added to 
indicate that co-
administration of 
selective 
cyclooxygenase-2 
(COX-2) inhibitors are 
prohibited for if taken 
for more than 5 days.
Section 5.5 Total Blood Volume
by week 52 Pharmacokinetics (serum 
MPA)
-before study drug injection
-if ovulation by week 52
-if no ovulation by week 52 week 52
Pharmacokinetics (serum MPA)
-before study drug injection
-if ovulation by week 52
-if no ovulation by week 52 
Typo
about 10
(for both P and E2)
about 10
(for both P and E2)
Clarification. Added to 
indicate that volumes 
are approximate.
about 5
about 5
Clarification. Added to 
indicate that volumes 
are approximate.
about 4
about 4
Clarification. Added to 
indicate that volumes 
are approximate.
6.1.Pharmacokinetics
The MPA results will not be known 
until later in the study and, therefore, 
will not be used as exclusion criteria. 
Subjects with nonzero MPA levels at 
baseline (ie, more than 5% of their 
individual Cmax) will be excluded from 
the primary pharmacokinetic analyses 
(see Section 8.5.3).
The MPA results will not be known 
until later in the study and, therefore, 
will not be used as exclusion criteria. 
Subjects with nonzero MPA levels at 
baseline (ie, more than 5% of their 
individual Cmax) will be excluded from 
the primary pharmacokinetic analyses 
(see Section 8.5.3).
Clarification of 
concentration.


Pharmacokinetic Study–Contraception
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Original text with changes shown
New wording
Reason/Justification 
for change
In addition, subjects for whom 
ovulation has not returned by month 12 
(week 52), blood samples for MPA will 
be collected and tested up to 2 more 
times (at week 65 [month 15]61 and 
week 78 [(month 18]),74), but not past 
return to ovulation.
In addition, subjects for whom 
ovulation has not returned by month 
12 (week 52), blood samples for MPA 
will be collected and tested up to 2 
more times (at week 61 and week 74), 
but not past return to ovulation.
Clarification of testing 
for MPA for subjects for 
whom ovulation has not 
returned by month 12.
Section 6.2.Pharmacodynamics
Although repeated elevated 
progesterone is not needed for the 
primary definition of ovulation, this 
information will be used for more 
accurate ascertainment of ovarian 
function. Subjects with a single 
elevated progesterone measurement of 
≥4.7 ng/mL will be considered to have 
their ovulation restored. Women in 
whom ovulation returns before month 
12 (week 52) will continue weekly 
sampling for progesterone and estradiol 
until the month 12 visit. The subjects 
will then be asked to return for their 
final visit within 5 days to complete 
confirmatory progesterone 
measurement and final visit 
procedures.
Although repeated elevated 
progesterone is not needed for the 
primary definition of ovulation, this 
information will be used for more 
accurate ascertainment of ovarian 
function. Subjects with a single 
elevated progesterone measurement of 
≥4.7 ng/mL will be considered to have 
their ovulation restored. 
Correction. Deleted as 
this section addresses 
PK.
Section 7.8.Menstrual Bleeding Patterns
Subjects will be asked about changes in 
their menstrual bleeding patterns, 
including amenorrhea,no bleeding, 
since last assessment since last study 
visit at monthly intervals and during 
the scheduled laboratory or follow-up 
visits at week 13 (month 3) and week 
32 (month 7.5), and at the final study 
visit.
Subjects will be asked about changes 
in their menstrual bleeding patterns, 
including no bleeding, since last 
assessment at monthly intervals and 
during the scheduled laboratory or 
follow-up visits at week 13 (month 3) 
and week 32 (month 7.5), and at the 
final study visit.
Clarification. Question
regarding changes in 
menstrual bleeding 
patterns will be asked 
monthly.
Section 8.2.3 Primary Evaluable Population
The Primary Evaluable Population is a 
subset of the Treated Population, 
excluding subjects who have detectable 
MPA in their baseline specimen (more 
than 5% of their individual Cmax) or for 
whom a major protocol violation 
occurred at enrollment, including: the 
absence of a confirmed ovulation in the 
The Primary Evaluable Population is a 
subset of the Treated Population, 
excluding subjects who have 
detectable MPA in their baseline 
specimen (more than 5% of their 
individual Cmax) or for whom a major 
protocol violation occurred at 
enrollment, including: the absence of a 
Clarification. Added to 
define “detectable 
MPA”.


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Original text with changes shown
New wording
Reason/Justification 
for change
pre-treatment period; BMI outside the 
eligible range (including the 6 subjects 
purposefully enrolled with BMI ≥40);
or use of drugs known to impact 
ovulation or the pharmacokinetics of 
MPA.
confirmed ovulation in the pre-
treatment period; BMI outside the 
eligible range (including the 6 subjects 
purposefully enrolled with BMI ≥40); 
or use of drugs known to impact 
ovulation or the pharmacokinetics of 
MPA.
The Primary Evaluable Analysis Set 
includes all time contributed by 
participants in the Primary Evaluable 
Population during which a 
pharmacokinetic or pharmacodynamic 
outcome is assessed, (up to the 
initiation of any concomitant 
medication) known to impact ovulatory 
function or the pharmacokinetics of 
MPA .
The Primary Evaluable Analysis Set 
includes all time contributed by 
participants in the Primary Evaluable 
Population during which a 
pharmacokinetic or pharmacodynamic 
outcome is assessed, (up to the 
initiation of any concomitant 
medication) known to impact
ovulatory function or the 
pharmacokinetics of MPA.
Typo.
Appendix B
Insert the 26g 23g x 3/8” needle at a 45 
degree angle so that most of the needle 
is in the fatty tissue.
Insert the 23g x 3/8” needle at a 45 
degree angle so that most of the 
needle is in the fatty tissue.
Correction. Gauge of 
needle updated. 


Pharmacokinetic Study–Contraception
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16.4.
Protocol Amendment 01 Dated 29 May 2016
The primary reasons for this amendment are corrections. These revisions are considered to be 
substantial by the sponsor’s Authorized Representative. These changes are unlikely to affect to a 
significant degree the safety or rights (physical or mental integrity) of the subjects in the clinical 
study or the scientific value of the clinical study.
Original text with changes shown
New wording
Reason/Justification 
for change
Title page, Investigator Agreement, and Coordinating Investigator Agreement
FHI 360 Study Number: 780861 1
FHI 360 Study Number: 780861
Correction
Section 3.9 Drugs Used in the Study
Each TV-46046 dose will be presented in a 
3 mL United States Pharmacopeia (USP) 
Type 1 clear glass vial, 13-mm rubber 
stopper, and 13-mm aluminum seal 
covered with a green cap (STERI-TAMP®3
single-use tamper evident sticker)13 mm 
aluminum seal with green color flip off 
disc.
Each TV-46046 dose will be 
presented in a 3 mL United States 
Pharmacopeia (USP) Type 1 clear 
glass vial, 13-mm rubber stopper, 
and 13-mm aluminum seal 
covered with a green cap (STERI-
TAMP® single-use tamper evident 
sticker).
Correction
Not Applicable
3STERI-TAMP is a registered 
trademark of STERI-TAMP, 
LLC.
Added
Section 3.10.2 Drug Accountability
Empty and unused units of study product 
will be disposed of, retained, or returned to 
the sponsor per FHI 360 instructions.
Empty and partially used containers of 
study drug 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 study drug, the 
study drug will be disposed of, retained, or 
returned to the sponsor or designee per FHI 
360 instructions.
Empty and partially used 
containers of study drug 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 study drug, the study drug 
will be disposed of, retained, or 
returned to the sponsor or 
designee per FHI 360 instructions.
Correction


Pharmacokinetic Study–Contraception
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APPENDIX A. DAIDS TABLE FOR GRADING ADULT AND PEDIATRIC 
ADVERSE EVENTS
Notes: According to the DAIDS Grading Table, Grade 5 indicates death; however, this grade is not specifically 
presented in the table. 
Refer to the full source for complete information: US Department of Health and Human Services. National Institute 
of Allergy and Infectious Diseases. National Institutes of Health. Division of AIDS (DAIDS) Table for grading the 
severity of adult and pediatric adverse events. Version 2.0; November 2014.
US=United States; AIDS=acquired immune deficiency syndrome.


Pharmacokinetic Study–Contraception
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APPENDIX B. INJECTION INSTRUCTIONS
FOR SUBCUTANEOUS ADMINISTRATION ONLY
Please read these instructions carefully. It is very important that the indicated dose of TV-46046 
is given accurately.
Step 1: Getting ready
Subjects enrolled in Part 1 of this study will be assigned to 1 of the following 2 treatment groups
comprising of 6 women in each:
1. Treatment group 1: 0.3 mL of 400 mg/mL of undiluted TV-46046
2. Treatment group 2: 0.6 mL of 200 mg/mL of saline-diluted TV-46046
If warranted, Part 1 treatment group 3 will be enrolled subsequently (N=6), receiving 0.4 mL of 
300 mg/mL of saline-diluted TV-46046.
Do not refrigerate the study product. Ensure that the vial is at room temperature prior to injection 
(to ensure appropriate viscosity of the suspension). Inspect the vial visually for particulate matter 
and discoloration prior to administration. (If particulate matter and/or discoloration are noted, do 
not use the vial. Collect the vial for return to the manufacturer. Refer to the Pharmacy Manual 
for return instructions.)
Details of product administration are found in the Pharmacy Manual. Briefly, at the time of 
product administration, disperse the product by shaking the vial vigorously until a homogeneous 
suspension is observed. Withdraw the indicated volume of the study drug from the vial using the 
provided 23G x 3/8” needle. Expel extra air and adjust the volume if necessary.
If not administered within a few minutes, shake the syringe vigorously prior to administration. 
Administer the subcutaneous injection using the same 23G x 3/8” needle.


Pharmacokinetic Study–Contraception
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Step 2: Choosing & preparing the injection area
Choose the injection area.
The abdomen is the selected 
injection site for this clinical 
study. Avoid bony areas and the 
umbilicus.
Preferred injection area:
Use Abdomen area only
Use an alcohol pad to wipe the skin in 
the abdominal injection area.
Allow the skin to dry
Step 3: Injecting the dose
Gently grasp and squeeze a large 
area of skin in the chosen injection 
area between the thumb and forefinger, 
pulling it away from the body.


Pharmacokinetic Study–Contraception
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Insert the 23g x 3/8” needle at a 45 
degree angle so that most of the 
needle is in the fatty tissue.
The plastic hub of the needle 
should be nearly or almost 
touching the skin
Inject the medication slowly until the 
syringe is empty.
This should take about 5 to 
7 seconds
It is important that the entire dose 
is given
Inject slowly
(5 to 7 seconds)
Step 4: Disposing the needle and syringe
Use a clean cotton pad to press 
lightly on the injection area for a 
few seconds.
Do NOT rub the area
Do NOT use Band Aid®
Subject should stay in the clinic 
for at least 15 minutes after the 
injection for observation of
possible post-injection problems 
including anaphylactic reaction.
Following the administration of 
each dose, the used syringe 
should be discarded in a safe 
and proper manner.

SAP_001.pdf: 
 
 
 
 
St atistic al A n al ysis Pl a n  
 
 
A T w o -part, P hase 1, E x pl orat or y a n d D ose -ra n ge Fi n di n g St u d y t o E val uate 
S u p pressi o n of O v ulati o n a n d P har mac o ki netics  of Me dr o x y pr o gester o ne Acetate 
F oll o wi n g a Si n gle S u bc uta ne o us A d mi nistrati o n of T V -4 6 0 4 6 i n W o me n wit h  
O v ulat or y C ycle  
 
 
St u d y N u m ber T V 4 6 0 4 6 -W H -1 0 0 7 5  
 
 
N C T 0 2 8 1 7 4 6 4  
 
 
S A P A p pr o val Date: 2 6 Se pte m ber 2 0 1 8  


 
 P har mac o ki netics  St u d y – C o ntrace pti o n  
Statistical A nal ysis Pla n Versi o n 2. 0  
St u d y T V 4 6 0 4 6 -W H -1 0 0 7 5  
1  
 
 
St atistic al A n al ysis Pl a n  
Te v a St u d y N u m ber: T V 4 6 0 4 6 -W H -1 0 0 7 5  
F HI 3 6 0 St u d y N u m ber: 7 8 0 8 6 1 -1  
 
A T w o -p art, P h ase 1, E x pl or at or y a n d D ose -r a n ge Fi n di n g St u d y t o E v al u ate S u p pressi o n  
of O v ul ati o n a n d P h ar m a c o ki netics of Me dr o x y pr o gester o ne Acet ate F oll o wi n g a Si n gle  
S u bc ut a ne o us A d mi nistr ati o n of T V -4 6 0 4 6 i n W o me n wit h O v ul at or y C ycle  
 
P h ase : 1  
I N D N u m ber: 1 2 6 2 4 9 
 
I niti al A p pr o v al D ate: 1 4 Oct o ber  2 0 1 6  
Re vise d: 2 6  Se pte m ber 2 0 1 8  
 
St u d y S p o ns or  
T e v a Br a n d e d P h ar m a c e uti c al  
Pr o d u ct s R & D, I n c.  
4 1 M o or e s R o a d  
Fr a z er, P e n n s yl v a ni a 1 9 3 5 5  
U nit e d St at e s  of A m eri c a  
 
St u d y I m pl e m e nt ati o n  
F H I 3 6 0  
 
 
 
 
 
 
 
Pre p are d b y:  
  
                        F HI 3 6 0  
 




 
 P har mac o ki netics  St u d y – C o ntrace pti o n  
Statistical A nal ysis Pla n Versi o n 2. 0  
St u d y T V 4 6 0 4 6 -W H -1 0 0 7 5  
3  
T A B L E O F C O N T E N T S  
TI T L E P A G E  ...................................................................................................................................1  
S T A TI S TI C A L A N A L Y SI S  P L A N A P P R O V A L  ..........................................................................2  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S  ..................................................5  
I N T R O D U C TI O N ...........................................................................................................................6  
1.  
S T U D Y O BJ E C TI V E S A N D  E N D P OI N T S  ................................................................7  
1. 1.  
Pri mar y St u d y O bjecti ves a n d E n d p oi nts  .....................................................................7  
1. 1. 1.  
Pri mar y O bj ecti ves  .......................................................................................................7  
1. 1. 2.  
Pri mar y E n d p oi nts  ........................................................................................................7  
1. 2.  
Sec o n dar y St u d y O bjecti ves a n d E n d p oi nts  .................................................................7  
1. 2. 1.  
Sec o n dar y O bj ecti ves  ...................................................................................................7  
1. 2. 2.  
Sec o n dar y E n d p oi nts  ....................................................................................................8  
2.  
S T U D Y D E SI G N  .........................................................................................................9  
2. 1.  
Ra n d o mizati o n a n d Bli n di n g  ........................................................................................9  
2. 2.  
Data a n d Safet y M o nit ori n g B oar d  .............................................................................1 0  
2. 3.  
Sa m ple Siz e a n d P o wer C o nsi derati o ns  .....................................................................1 1  
2. 4.  
Se q ue nce of Pla n n e d A n al yses  ...................................................................................1 1  
2. 4. 1.  
Pla n ne d I nteri m A nal yses  ...........................................................................................1 1  
2. 4. 2.  
Fi nal A nal yses a n d Re p orti n g  .....................................................................................1 1  
3.  
A N A L Y SI S S E T S  ......................................................................................................1 3  
3. 1.  
Scree ne d P o p ulati o n  ...................................................................................................1 3  
3. 2.  
Treate d P o p ulati o n  ......................................................................................................1 3  
3. 3.  
Pri mar y E v al ua ble P o p ulati o n  ....................................................................................1 3  
4.  
G E N E R A L I S S U E S F O R D A T A A N A L Y SI S  ..........................................................1 4  
4. 1.  
Ge neral  ........................................................................................................................1 4  
4. 2.  
S pecificati o n of Bas eli ne Val ues  ................................................................................1 4  
4. 3.  
Ha n dli n g Wit h dra wals a n d Missi n g Data  ...................................................................1 4  
4. 4.  
St u d y Da ys a n d Visits  .................................................................................................1 4  
5.  
S T U D Y P O P U L A TI O N  .............................................................................................1 6  
5. 1.  
Ge neral  ........................................................................................................................1 6  
5. 2.  
S u bject Dis p ositi o n  .....................................................................................................1 6  
5. 3.  
De m o gra p hics a n d Baseli ne C haract eristics  ...............................................................1 6  


 
 P har mac o ki netics  St u d y – C o ntrace pti o n  
Statistical A nal ysis Pla n Versi o n 2. 0  
St u d y T V 4 6 0 4 6 -W H -1 0 0 7 5  
4  
5. 4.  
Pri or T hera p y a n d Me dic ati o n use  ..............................................................................1 6  
5. 5.  
M e dical Hist or y ..........................................................................................................1 6  
5. 6.  
P h ysical E x a mi nati o ns  ................................................................................................1 7  
5. 7.  
C hil d beari n g P ote ntial a n d Met h o ds of C o ntrace pti o n  ..............................................1 7  
5. 8.  
St u d y Pr ot o c ol Vi olati o ns  ...........................................................................................1 7  
6.  
E F FI C A C Y A N A L Y SI S  ............................................................................................1 8  
7.  
M U L TI P L E C O M P A RI S O N S  A N D M U L TI P LI CI T Y  ............................................1 9  
8.  
S A F E T Y A N A L Y SI S  ................................................................................................2 0  
8. 1.  
Ge neral  ........................................................................................................................2 0  
8. 2.  
A d v erse E v e nts  ...........................................................................................................2 0  
8. 3.  
I nje cti o n Site Reacti o ns ..............................................................................................2 0  
8. 4.  
Dela ye d Ret ur n t o O v ul ati o n  ......................................................................................2 0  
8. 5.  
Me nstr ual Ble e di n g Dist ur ba nces  ...............................................................................2 0  
8. 6.  
Li ver F u n cti o n Tests  ...................................................................................................2 1  
8. 7.  
M o o d  ...........................................................................................................................2 1  
8. 8.  
Vital Si g ns a n d B o d y Wei g ht  .....................................................................................2 1  
8. 9.  
C o nc o mita nt Me dicati o ns or T hera pi es  ......................................................................2 1  
9.  
A C C E P T A BI LI T Y D A T A A N A L Y SI S  ....................................................................2 2  
1 0.  
P H A R M A C O KI N E TI C S A N A L Y SI S  .......................................................................2 3  
1 1.  
P H A R M A C O D Y N A MI C S  A N A L Y SI S ....................................................................2 4  
1 1. 1.  
Ge neral  ........................................................................................................................2 4  
1 1. 2.  
Pri mar y P har mac o d y na mics  E n d p oi nts a n d A nal ysis  ................................................2 4  
1 1. 3.  
Sec o n dar y a n d E x pl ora t or y P har mac o d y n a mics  A nal yses  .........................................2 4  
1 2.  
S T A TI S TI C A L S O F T W A R E  ....................................................................................2 6  
1 3.  
C H A N G E S T O A N A L Y S E S S P E CI FI E D I N P R O T O C O L V 1. 0  ............................2 7  
1 3. 1.  
C ha n ges fr o m V 1. 0 of pr ot oc ol, Pri or t o St u d y I nitiati o n  ..........................................2 7  
1 3. 2.  
C ha n ges fr o m V 1. 0 of S A P, After I nitiati o n of Part 1 ( 2 6 Oct o ber 2 0 1 6) b ut 
Pri or t o A vaila bilit y of a n y P K/ P D data, i ncl u di n g c h a n ges ma d e i n 
a ntici pati o n of Pr ot oc ol A me n d me nt 3 ( 2 7 Marc h 2 0 1 7)  ...........................................2 7  
1 3. 3.  
C ha n ges fr o m V 1. 0 of S A P, After i nitial I nt eri m Re vie w o f P K/ P D data ( 2 7 
Marc h 2 0 1 7)  ................................................................................................................2 7  
1 4.  
C O N V E N TI O N U S E D W H E N  E S TI M A TI N G I N DI VI D U A L 
P H A R M A C O KI N E TI C P A R A M E T E R S  ..................................................................2 9  
1 5.  
R E F E R E N C E S  ...........................................................................................................3 0  


 
 P har mac o ki netics  St u d y – C o ntrace pti o n  
Statistical A nal ysis Pla n Versi o n 2. 0  
St u d y T V 4 6 0 4 6 -W H -1 0 0 7 5  
5  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S   
A b bre vi ati o n  
Ter m  
λ  
T er mi nal p hase  rate c o nsta nt 
A E  
a d verse e ve nt  
A U C  
area u n der t he ser u m dr u g c o nce ntrati o n b y ti me c ur ve  
A U C 0 -∞ 
area u n der t he ser u m dr u g c o nce ntrati o n b y ti me c ur ve fr o m ti me 0 t o i nfi nit y  
A U C 0 -x 
area u n der t he ser u m dr u g c o nce ntrati o n b y ti me c ur ve  fr o m ti me 0 t o da y x  
B MI  
b o d y mass i n de x  
C x 
ser u m dr u g c o nce ntrati o n at da y x  p ost -treat me nt i nitiati o n 
CI  
c o nfi de nce i nter val  
C M  
c o nc o mita nt me dicati o n  
C ma x  
ma xi m u m ser u m dr u g c o nce ntrati o n  
C R F  
case re p ort f or m  
C S R  
cli nical st u d y re p ort 
% C V  
perce nt c o efficie nt of variati o n  
D M P A  
de p ot me dr o x y pr o gester o ne acetate  
D S M B  
Data a n d Safet y M o nit ori n g B oar d  
E 2  
Estra di ol  
F D A  
F o o d a n d Dr u g A d mi nistrati o n ( U S)  
G M  
g e o metric m ea n  
I S R 
i nj ecti o n site reacti o n 
L O Q  
li mit of q ua ntificati o n 
Me d D R A  
Me dical Dic ti o nar y f or Re g ul at or y Acti vities 
M O P  
m a n ual of p r oce d ures 
M P A  
me dr o x y pr o gester o ne acetate  
P  
Pr o gester o ne  
S D  
sta n dar d d e viati o n  
S O C  
s yste m or ga n class 
t1/ 2 
A p pare nt t er mi nal half -life 
tma x  
ti me t o ma xi m u m ser u m dr u g c o nce ntrati o n 
W Y  
W o me n -years  


 
 P har mac o ki netics  St u d y – C o ntrace pti o n  
Statistical A nal ysis Pla n Versi o n 2. 0  
St u d y T V 4 6 0 4 6 -W H -1 0 0 7 5  
6  
I NT R O D U C TI O N  
T his Statistical A nal ysis Pla n ( S A P) descri bes  t he pla n ne d a nal ysis a n d re p orti n g f or A T w o -p art, 
P h ase 1, Ex pl or at ory a n d D ose -r a n ge Fi n di n g St u dy t o Ev al u ate S u p pressi o n of Ov ul ati o n a n d 
P h ar m ac oki netics of M e dr oxy pr o gester o ne Acet ate F oll o wi n g a Si n gle S u bc ut a ne o us  
A d mi nistr ati o n of T V -4 6 0 4 6 i n W o m e n wit h Ov ul at ory Cycle. T he st u d y is s p o ns ore d b y Te va 
Bra n d e d P har mace utical Pr o d ucts R & D, I nc . a n d i m ple me nte d b y F HI 3 6 0 . Versi o n 1. 0 of t he 
S A P  was writte n a n d a p pr o ve d pri or t o first s u bject e nr olle d.  
T he rea der of t his S A P  is e nc o ura ge d t o revi e w  t h e st u d y pr ot o c ol f or det ails o n t he c o n d uct of 
t he st u d y, t he o perati o nal as pects of cli nical assess me nts, a n d t he ti mi n g f or c o m pleti n g t he 
partici pati o n of a s u bject i n t his st u d y. T he S A P is i nte n de d t o be i n a gree m e nt wit h t he pr ot oc ol, 
es peciall y wit h re gar ds t o t he pri mar y a n d sec o n d ar y e n d p oi nts a n d t heir res pecti ve a nal ys es.  
H o we ver, t he S A P ma y c o ntai n m ore details re gar di n g t hese p artic ular p oi nts of i nterest, or ot her 
t y pes of a nal yses (e g, ot h er e n d p oi nts).  W he n differe nces e xist i n descri pti o ns or e x pla nati o ns 
pr o vi de d i n t he st u d y pr ot oc ol a n d t his Statistical A nal ysis Pla n , t he S A P  pre vails; a n y 
differe n ces  b et wee n t h e t w o will be e x plai ne d i n t he Cli nical St u d y R e p ort  ( C S R). 
C ha n ges  m a de t o t he S A P after st u d y i nitiati o n  ( ot her t ha n f or matti n g f or re g ul at or y 
s u b missi o ns), i ncl u di n g c ha n ges ma de t o a d dress r e visi o ns t o t he pr ot oc ol, will be d oc u me nte d 
i n Secti o n 1 3 . M oc k ta bles, fi g ures a n d listi n gs d esi g ne d t o ca pt ure t he res ults of a nal ys es 
s pecifie d here will be a p pr o ve d b y t he C o or di nati n g I n v esti gat or  pri or t o u n -bli n di n g of 
statisticia ns, a n d i ncl u de d i n a n a p pe n di x t o f ut ure versi o ns of t he S A P.  


 
 P har mac o ki netics  St u d y – C o ntrace pti o n  
Statistical A nal ysis Pla n Versi o n 2. 0  
St u d y T V 4 6 0 4 6 -W H -1 0 0 7 5  
7  
1.  
S T U D Y  O B J E C TI V E S  A N D E N D P OI N T S  
T he p ur p ose of t his p har mac o d y na mic a n d p h ar m ac o ki netic  st u d y is t o i de ntif y a d os e of T V -
4 6 0 4 6 ( wit hi n t he ra n ge 8 0 t o 3 0 0 m g) t hat is b ot h safe a n d c o nsiste nt wit h a hi g h d e gree of  
c o ntrace pti ve efficac y w he n i njecte d e v er y 6 m o nt hs.  
1. 1.  
Pri m ar y St u d y O bjecti ves a n d E n d p oi nts  
1. 1. 1.  
Pri m ar y O bjecti ves  
T his P hase 1 st u d y has a data -dri ve n, 2 -part d esi g n: a n e x pl orat or y p h ar mac o ki netics c o m p o ne nt 
( Part 1) a n d a d ose-ra n ge fi n di n g c o m p o ne nt ( Part 2).  
P art 1:  T o assess t he p har mac o ki netics of 1 2 0 m g me dr o x y pr o gester o ne acetate  (M P A ) 
f oll o wi n g a si n gle s u bc ut a ne o us i njecti on of u n dil ute d a n d sali ne -dil ute d T V -4 6 0 4 6.  T his 
i nf or mati o n will be use d t o i nf or m u p t o 3 d ose le vels of u n dil ute d T V -4 6 0 4 6 a n d t he st u d y siz e 
f or t he d ose-ra n ge fi n di n g c o m p o n e nt ( Part 2) of t he st u d y, or t o s elect a dr u g c o n ce ntr ati o n f or 
f urt her i n vesti gati o n if u n dil ute d T V-4 6 0 4 6 d oes n ot e x hi bit a n a p pr o priate p har mac o ki netic 
pr ofile . 
P art 2:  If u n dil ute d T V-4 6 0 4 6 e x hi bits a n a p pr o priate p har mac o ki netic pr ofile i n Part  1, t he n 
Part  2 will e val uate t he p har mac o d y n a mics of M P A after a si n gl e s u bc uta ne o us i njecti o n of 
u n dil ute d T V -4 6 0 4 6 at 3  d ose le vels ( w here p h ar mac o d y na mic res p o nse is defi ne d as 
s u p pressi o n of o v ulati o n deter mi ne d t hr o u g h ser u m pr o gest er o ne [ P] c o nce ntrati o ns) .1 
1. 1. 2.  
Pri m ar y E n d p oi nts  
P art 1:  I n di vi d ual a n d mea n ser u m M P A c o n ce ntr ati o n-ti me pr ofiles, a n d esti mate d n o n -
c o m part me ntal p har mac o ki netics para meters, i ncl u di n g b ut n ot li mite d t o : ma xi m u m ser u m dr u g 
c o nce ntr ati o n ( C ma x ), ti me t o ma xi m u m ser u m c o nce ntrati o n (tma x ), ser u m dr u g c o nce ntrati o n at 
da y 1 8 2 ( C 1 8 2), area u n d er t he ser u m dr ug c o nce ntrati o n b y ti me c ur ve fr o m ti me 0 t o da y 1 8 2 
( A U C0 -1 8 2), area u n der t h e ser u m dr u g c o nce ntr ati o n b y ti me c ur ve fr o m ti me 0 t o i nfi nit y 
( A U C0 -∞), a n d a p pare nt ter mi nal half-life (t1/ 2). 
P art 2:  Ti me t o o v ulati o n, w here o v ul ati o n is defi ne d as a si n g le-ele vate d s er u m P  ( ≥4. 7 n g/ m L).  
1. 2.  
Sec o n d ar y St u d y  O bjecti ves a n d E n d p oi nts  
1. 2. 1.  
Sec o n d ar y O bjecti ves  
T he sec o n d ar y o bjecti ves of t he st u d y are t he f oll o wi n g:  
•  T o c haracteriz e t he p h ar mac o ki netics of 3 d ose le vels of u n dil ute d T V -4 6 0 4 6  
•  T o e val uate t he relati o ns h i p bet wee n ser u m M P A c o nce ntr ati o n a n d ret ur n t o 
o v ulati o n  
•  T o e val uate t he s afet y of a s u bc uta ne o us i njecti o n of T V -4 6 0 4 6 o ver t he ra n ge of  
d iffere nt d os es a n d c o n ce ntrati o ns 
                                                 
1 Part 2 of t he st u d y was ne ver i m ple me nte d. As a c o nse q ue nce, n o a nal yses relate d t o Part 2 data 
descri be d i n t his S A P will be i m ple me nte d.  


 
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Statistical A nal ysis Pla n Versi o n 2. 0  
St u d y T V 4 6 0 4 6 -W H -1 0 0 7 5  
8  
•  T o e val uate t he acce pta bilit y of a s u bc ut a ne o us i njecti o n of T V -4 6 0 4 6 o v er t he ra n ge  
of  differe nt d oses a n d c o nce ntrati o ns  
1. 2. 2.  
Sec o n d ar y E n d p oi nts  
•  P har mac o ki netics of M P A base d o n i n di vi d ual a n d mea n ser u m c o n ce ntr ati o n -ti me 
pr ofiles o ver t he ra n ge of Part 2 d oses, as well as esti mate d n o n -c o m part me ntal 
p har mac o ki netics p ara m eters, i ncl u di n g b ut n ot li mite d t o : C ma x , tma x , C1 8 2, C2 1 0, 
A U C 0 -1 8 2, A U C0 -2 1 0, A U C0 -∞, a n d t 1/ 2. I n a d diti o n, releas e rates, relati ve 
bi oa vaila bilit y, a n d ot her p har mac o ki netic para m eters deri ve d fr o m n o n -li n ear mi x e d 
effects m o del c o m part me ntal a nal ysis of M P A c o n ce n trati o ns o ver ti me. 
•  Safet y e n d p oi nts i ncl u de b ut are n ot li mite d t o t he occ urre nce of c h a n ges i n vital 
si g ns a n d b o d y w ei g ht; d ela ye d ret ur n t o o v ulati o n ( >1 2 m o nt hs  after st u d y dr u g 
i njecti o n), a d vers e e ve nts ( A Es), i njecti o n site reacti o ns (I S Rs), c ha n ge i n m o o d ( Part 
2, o nl y) , c ha n ge i n li ver f u ncti o n tests ( Part 2, o nl y), us e of c o n c o mita nt me dicati o ns  
( C Ms), a n d c ha n ge i n me nstr ual blee di n g patter ns.  
•  Acce pt a bilit y e n d p oi nts i ncl u de s u bjects’ res p o nses t o q uesti o ns a b o ut i njecti o n pai n, 
I S Rs, a n d me nstr ual blee di n g patter ns; a n d t he st u d y staff’s ass ess me nt of t he ease of 
t he i njecti o n. 


 
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Statistical A nal ysis Pla n Versi o n 2. 0  
St u d y T V 4 6 0 4 6 -W H -1 0 0 7 5  
9  
2.  
S T U D Y D E SI G N  
T his is a 2 -part st u d y d esi g ne d t o e v al uate t he p har mac o ki netics a n d p h ar m ac o d y na mics of M P A 
i n healt h y fe male s u bjects after a si n gle s u b c uta ne o us i njecti on of T V -4 6 0 4 6. Part 1 is a n o n -
ra n d o mize d c o m p o ne nt w hic h will e x pl ore t he p har mac o ki netics of a 1 2 0 m g d ose of M P A w h e n 
T V -4 6 0 4 6 is a d mi nistere d at a n u n dil ute d c o nce ntrati o n of 4 0 0 m g/ m L ( 0. 3  m L i njecti o n  
v ol u me) or a 1: 1 sali ne -dil ute d c o nce ntrati o n of 2 0 0 m g/ m L ( 0. 6  m L i njecti o n v ol u me). C o h orts 
of n = 6 partici p a nts will be e nr olle d i n se q u e ntial or der: u n dil ute d dr u g f oll o we d b y 1: 1 sali ne 
dil ute d dr u g. If res ults i n dicate t hat i nf or mati o n o n a n i nter me diate c o nce ntrati o n is re q uire d t o 
c haracteriz e p ha r mac o ki netics, t he n a 3 r d c o h ort of 6 partici pa nts ma y be a d mi nistere d T V -4 6 0 4 6 
at a c o nce ntrati o n of 3 0 0 m g/ m L ( 0. 4  m L i njecti o n v ol u me).  
Part 2 is a ra n d o mize d, m ulti -ce nter, d ose -ra n ge fi n di n g c o m p o ne nt w hi c h will o nl y b e 
i m ple me nte d if u n dil ute d T V-4 6 0 4 6 is selecte d f or f urt her testi n g base d o n Part 1 data. Criteria 
use d t o select e ac h of u p t o 3 d oses of u n dil ute d T V -4 6 0 4 6 i n t he ra n ge of 8 0 t o 3 0 0 m g f or Part 
2 i ncl u de: mea n C ma x  pre dicte d t o be less t ha n 3 n g/ m L, ti me t o ac hie ve 0. 2 n g/ m L pre di cte d t o 
be n o m ore t ha n 2 4 h o urs after st u d y dr u g a d mi nistrati o n, 6 -m o nt h ser u m M P A c o nce ntrati o n 
pre dicte d t o be greater t h a n 0. 1 n g/ m L f or 9 5 % of w o me n, a n d ser u m M P A c o nce ntr ati o n 2 4 
m o nt hs after last i njecti o n pre dicte d t o be bel o w 0. 1 n g/ m L i n 9 0 % of w o m e n.  As o nl y a 1 2 0 m g 
d ose of T V -4 6 0 4 6 will b e teste d i n Part 1, pre dicti o ns a b o ut t he p har mac o ki netics of Part 2 d oses 
will be partl y i nf or me d b y d ose relati o ns hi ps o bser ve d i n pre vi o us st u dies of de p ot 
me dr o x y pr o gester o ne acetate  (D M P A ) d eli vere d s u bc uta ne o u sl y. T he fi n al st u d y siz e f or Part 2 
will be i nf or me d b y Part 1, b ut will n ot e x cee d 2 0 w o me n per d ose gr o u p (i ncl u di n g 2 o bes e 
w o me n per gr o u p).  
Eac h s u bject e nr olle d i n eit her Part 1 or Part 2 will c o ntri b ute u p t o 1 9 m o nt hs i n t he st u d y, 
i ncl u di n g u p to 1 -m o nt h pre -treat me nt, 6-m o nt hs treat me nt, a n d 6 -1 2 m o nt hs of p ost -treat me nt 
f oll o w-u p. St u d y  pr oce d ures a n d ass ess me nts wit h t heir ti mi n g are s u m marize d i n Ta ble  1  of t he 
st u d y pr ot oc ol . 
2. 1.  
R a n d o miz ati o n a n d Bli n di n g  
S u bjects  i n Part 1 will n ot be ra n d o mize d. Rat her, t he y will be e nr o lle d i n c o nsec uti ve c o h orts of 
n = 6 w o me n, as f oll o ws:  
•  C o h ort 1 A: a si n gle 0. 3 m L i njecti o n of u n dil ute d T V -4 6 0 4 6 ( 1 2 0 m g M P A)  
•  C o h ort 1 B: a si n gl e 0. 6 m L i njecti o n of 1: 1 sali ne dil ute d T V -4 6 0 4 6 ( 1 2 0 m g M P A)  
•  C o h ort 1 C: a si n gle 0. 4 m L i njecti o n of 3: 1 sali ne dil ute d T V -4 6 0 4 6 ( 1 2 0 m g M P A)  
  
( De pe n di n g o n t he res ults of C o h orts 1 A a n d 1 B, C o h ort 1 C ma y n ot be e nr olle d).  
T he ra n d o m all oc ati o n rati o f or t he d ose -ra n ge fi n di n g c o m p o ne nt of t h e st u d y will de pe n d o n 
w het her or n ot t he 1 2 0  m g d ose of u n dil ute d T V -4 6 0 4 6 use d i n Part 1 is selecte d f or Part 2. If it 
is, t he n u p t o 1 2 s u bjects will be ra n d o mize d t o t he 1 2 0 m g d ose, a n d u p t o 1 8 s u bjects will be 
ra n d o mize d t o eac h of t h e ot her 2 sele cte d d ose gr o u ps, i n a 2: 3: 3 all ocati o n rati o. If t he 1 2 0 m g 
d ose is n ot selecte d f or i n cl usi o n i n Part 2 t he n t he all ocati o n rati o will be 1: 1: 1. I n a d diti o n, 2 
s u bjects wit h a b o d y m ass i n de x ( B MI) ≥ 4 0 will be se paratel y ra n d o mize d i nt o eac h of t he 3 


 
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Statistical A nal ysis Pla n Versi o n 2. 0  
St u d y T V 4 6 0 4 6 -W H -1 0 0 7 5  
1 0  
treat me nt d ose gr o u ps f or e x pl orat or y a nal yses of t he effect of e xtre me o besit y o n 
p har mac o ki netics of M P A , res ulti n g i n a m a xi m u m of 2 0 partici pa nts i n eac h Part 2 d ose gr o u p.  
T he ra n d o mizati o n se q ue nce will be de v el o pe d b y a n F HI 3 6 0 Ra n d o mizati o n Statisticia n n ot 
ot her wise i n v ol ve d i n t he st u d y usi n g  a vali date d S A S ® pr o gra m. T h e ra n d o mizati o n will be 
stratifie d o n i n vesti gati o nal ce nter usi n g a p pr o priat e bl oc k sizes t o mi ni mize i m bala nce wit h 
res pect t o t he tar get all oc ati o n rati o at eac h pla n ne d i nteri m a n d fi nal a nal ysis. Details will be 
d oc u me nte d  i n a se p arat e Ra n d o mizati o n Pla n pri or t o i nitiati n g Part 2.  
Treat me nt assi g n me nts f or Part 2 will be c o nceale d wit hi n seale d, o pa q ue, se q ue ntiall y 
n u m bere d ra n d o mizati o n e n vel o pes pr o vi de d t o eac h i n vesti gati o nal ce nter. Trai ne d staff will 
o pe n t he ne xt a vaila ble e n vel o pe, a n d all ocate t he ne xt treat me nt assi g n me nt, o nl y after a 
partici pa nt has c o m plete d all ot her baseli ne pr oce d ures a n d is deter mi ne d t o be eli gi ble f or t he 
st u d y. T he ra n d o mizati o n e n vel o pes will be mai ntai ne d i n a sec ure l ocati o n at eac h  ce nter, wit h 
access li mite d t o a ut h orize d pers o n nel p er ce nter-s pecific st u d y pr oce d ures. 
N o e nr olle d s u bjects w h o ha ve recei ve d a st u d y dr u g i njecti o n will be re place d i n eit her p art of 
t he st u d y. H o we ver, e nr oll me nt i n Part 2 ma y be e x pa n de d if m ore t ha n 1 0 % of s u bjects 
disc o nti n ue ( or are pre di cte d t o disc o nti n ue) bef ore wee k 5 2 fr o m start of st u d y dr u g tr eat me nt, 
ha ve dete cta ble le v els of M P A at e nr oll me nt, or ha ve pr ot oc ol vi olati o ns i de ntifie d t hat ma y 
a d versel y affect assess m e nt of p har mac o ki netics or p har mac o d y na mics. A n y decisi o n t o e x pa n d 
e nr oll me nt will be i nf or me d b y rec o m me n d ati o ns fr o m t he D S M B, a n d will be i m ple me nte d s o 
as t o preser ve t he vali dit y of ra n d o mizati o n -base d i nfere n ces usi n g t he sa m e all ocati o n rati o.  
N o bli n di n g will occ ur i n Pa rt 1, a n d Part 2 will n ot be f ull y bli n de d d ue t o differe n ces i n v ol u me 
of st u d y dr u g. H o we v er, cli nical staff pr o vi di n g t h e i njecti o ns i n Part 2 will be trai ne d t o s hiel d 
t he s yri n ge fr o m vie w of t he s u bject or a n y ot her st u d y staff pri or t o a n d at t he time of i njecti o n. 
I n a d diti o n, F HI 3 6 0 staff res p o nsi ble f or c o di n g A Es , a n d la b orat or y staff a nal yzi n g M P A 
s peci me ns, will re mai n bli n de d f or t he le n gt h of t he st u d y. T h e C o or di nati n g I n v esti gat or, 
p har mac ol o gists, st u d y cli nicia n, statisticia ns, a n d ot her esse ntial st u d y staff will be u n-bli n de d 
at t he gr o u p le vel f oll o wi n g f or mal i nteri m a nal ys es of Part 2 data t o i nf or m pr oject 
de vel o p me nt . T hese re vi e ws of u n bli n de d data will ta ke place i n de pe n de ntl y of t he D S M B 
re vie ws des cri be d b el o w . I n di vi d ual treatme nt assi g n me nts will als o be ma de a vaila ble t o st u d y 
me dical m o nit or s h o ul d it be necess ar y t o i nf or m me dical treat me nt of t h e s u bjects . T he n u m ber 
of pers o n nel w h o are u n -bli n de d w hile t he st u d y is o n g oi n g will be ke pt as s mall as feasi ble, a n d 
t he p ote ntial i m plicati o ns of u n-bli n di n g o n st u d y c o n d uct a n d i nter pretati o n of st u d y dat a will be 
descri be d i n t he cli nical r e p ort. F urt h er details of bli n di n g a n d u n -bli n di n g pr oce d ures are 
pr o vi de d i n t he se parate D S M B o perati o nal pla n.  
2. 2.  
D at a a n d S afet y M o nit ori n g B o ar d  
A n i n de pe n de nt D ata a n d Safet y M o nit ori n g B oar d ( D S M B) will re vi e w acc u m ulati n g 
p har mac o d y n a mics, p har mac o ki netic, a n d safet y d ata t o e ns ure t h e c o nti n ui n g safet y of t he st u d y 
s u bjects a n d t he i nte grit y of t he st u d y. T h e D S M B will meet o nce bef ore  t h e st u d y b e gi ns a n d at 
2 sc he d ule d  p oi nts d uri n g t he st u d y. T here will be b ot h a n o pe n a n d cl ose d sessi o n at eac h  
D S M B meeti n g w here st u d y dat a are re vi e we d. D uri n g o pe n sessi o ns, re pr ese ntati ves of t he  
st u d y s p o ns or a n d st u d y i m ple me nt or ma y b e prese nt , a n d i nf or mati o n will be pr o vi de d a n d  
disc usse d i n a bli n de d fas hi o n. D uri n g cl ose d sessi o ns o nl y t he D S M B m e m bers, t he D S M B  
E x ec uti ve Secretar y (t o ta ke n otes o nl y), a n d a n F HI 3 6 0 statisticia n  (t o a ns wer q uesti o ns a b o ut 


 
 P har mac o ki netics  St u d y – C o ntrace pti o n  
Statistical A nal ysis Pla n Versi o n 2. 0  
St u d y T V 4 6 0 4 6 -W H -1 0 0 7 5  
1 1  
t he a nal ysis) will be pres e nt t o disc uss res ults b y treat me nt gr o u p. Details of t he D S M B 
pr oce d ure s a n d res p o nsi bilities are d oc u me nte d i n a se parate D S M B O perati o nal Pla n.  
2. 3.  
S a m ple Size a n d P o wer C o nsi der ati o ns  
Part 1 is n ot p o were d t o defi niti vel y ass ess p har m ac o ki netics. Rat her, if t he p h ar mac o ki netics 
pr ofile of u n dil ute d T V -4 6 0 4 6 a p pears c o nsiste nt wit h a safe a n d efficaci o us 6 -m o nt h i njecta ble 
c o ntrace pti ve met h o d, t he n 3 d ose le vels wit hi n t he d ose ra n ge of 8 0 t o 3 0 0 m g will be 
rec o m me n de d f or Part 2. Li ke wis e, t he st u d y siz e f or Part 2 was n ot c h ose n t o ma ke defi niti ve 
c o ncl usi o ns re gar di n g t h e effecti ve n ess of T V -4 6 0 4 6 i n t he ra n ge of d os es selecte d. H o we ver, u p 
t o 2 0 s u bjects per gr o u p s h o ul d be s ufficie nt t o pr o vi de mea ni n gf ul i nsi g hts i nt o t he distri b uti o ns 
of p har mac o ki netics a n d p har mac o d y n a mics o utc o mes, a n d t o i nf or m selecti o n of a d ose f or 
f urt her st u d y. Scie ntific j u d g me nt will be use d t o deter mi ne if t he sa m ple size i n Part 2 ca n be 
re d uce d fr o m 2 0 s u bjects per gr o u p, de p e n di n g o n t he varia bilit y of para meter esti mates 
o bser v e d i n Part 1. Partici pa nts w h o are wit h dr a w n fr o m t he st u d y will n ot be re place d.  
2. 4.  
Se q ue nce of Pl a n ne d A n al yses  
2. 4. 1.  
Pl a n ne d I nteri m A n al yses 
T here are fi ve pla n ne d re vie ws of t he i nteri m Part 1 a n d Part 2 data as o utli ne d bel o w, b ut t he 
n u m ber a n d ti mi n g of re v ie ws ma y c ha n ge base d o n i nteri m fi n di n gs. 
•  T he 1 st pla n ne d i nteri m a nal ysis  will be perf or me d after t he 6 s u bjects i n C o h ort 1 A 
of  Part 1 (recei vi n g u n dil ute d T V -4 6 0 4 6) h a ve c o m plete d 1 m o nt h of p ost -i njecti o n 
f oll o w-u p, a n d is i nte n de d t o i nf or m t he earl y  part of t he p har mac o ki netic pr ofile.  
•  T he 2 n d i nteri m a nal ysis will be perf or me d after t he sa me 6 s u bjects i n C o h ort 1 A  of 
Part 1 ha ve c o m plete d 4 m o nt hs of p ost -i njecti o n f oll o w-u p , a n d is i nte n de d t o i nf or m 
t he decisi o n t o m o ve i nt o, a n d t he selecti o n of d os es f or Part 2.    
•  T he 3 r d a n d 4 t h i nteri m a nal yses are pl a n ne d t o occ ur after 5 0 % of s u bjects i n Part 2 
ha ve c o m plete d 4 a n d 7. 5 m o nt hs of p ost -i njecti o n f oll o w-u p, res pecti vel y, a n d are 
i nte n de d t o hel p i nf or m t he decisi o n t o m o ve t o, a n d t he d ose sele cti o n f or f urt her 
cli nical st u d y.  
•  T he  5 t h a n d fi nal pla n ne d i n teri m a nal ysis is pla n n e d t o  occ ur w he n 1 0 0 % of s u bjects 
i n Part 2 ha ve c o m plete d 7. 5 m o nt hs of p ost -i njecti o n f oll o w-u p (t he e ntire i nte n de d 
d osi n g i nter val, pl us 1. 5 m o nt hs). A preli mi nar y re p ort of st u d y fi n di n gs b ase d o n t his 
a nal ysis ma y b e s u b mitte d t o t he U. S. F o o d a n d Dr u g A d mi nistrati o n ( F D A ) as part 
of t he pla n ni n g p h ase f or f ut ure st u dies.  
A m o n g t hes e 5 pla n ne d i nteri m a nal yses, t he D S M B ma y o nl y c o n ve n e t o re vie w dat a pri or t o 
i nitiati o n of Part 2 ( 2n d pla n ne d i nteri m a nal ysis) a n d at t he first i nteri m a nal ysis of Part 2 data  
(3 r d pla n ne d i nteri m a nal ysis) , wit h t he ot her a nal ys es us e d b y t he cli nical tea m t o i nf or m t he 
desi g n of Part 2 a n d/ or t h e pr o d uct de vel o p me nt pr o gra m . H o we ver, t h e D S M B ma y re q u est 
re vie w of ot h er pla n ne d or u n pla n ne d i nteri m a n al yses f or p ur p oses of m o nit ori n g partici p a nt 
safet y or t o ma ke rec o m me n dati o ns re gar di n g m o dificati o ns t o t he st u d y.  
2. 4. 2.  
Fi n al A n al yses a n d Re p orti n g  
All fi nal a nal yses i de ntifi e d i n t his S A P will be perf or me d after t he l ast partici pa nt has 
c o m plete d t he st u d y, alt h o u g h a n earlier re p ort of data c ollecte d t hr o u g h m o nt h 7. 5 of f oll o w -u p 


 
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i n Part 2 ma y be s u b mitt e d t o t he F D A i n a d va nce of a n y pla n ni n g meeti n g s f or f ut ure st u dies. 
A n y s u p p orti v e a nal yses w hic h were n ot i de ntifie d i n t he S A P pri or t o u n bli n di n g of statisticia ns 
will be d oc u me nte d as e x pl orat or y i n t he C S R.   


 
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3.  
A N A L Y SI S S E T S  
I n t he d efi niti o ns t hat f oll o w, a n A nal ysis P o p ulati o n refers t o a partic ul ar set of st u d y s u bjects 
a n d a n A nal ysis Set refers t o t he ti me c o ntri b ute d t o a nal ys es b y s u bjects i n a gi v e n p o p ulati o n. 
U nless ot her wise n ote d, t he defi niti o ns f or i ncl usi o n i n t hese a nal ysis p o p ulati o ns a n d sets are 
ass u me d t o be t he sa me f or Part 1 a n d Part 2.  
3. 1.  
Scree ne d P o p ul ati o n  
T he S cree ne d P o p ulati o n c o nsists of all scree n e d partici pa nts w h o are c o ns e nte d t o partici pate i n 
t he st u d y, re gar dless of t heir e nr oll me nt stat us. 
3. 2.  
Tre ate d P o p ul ati o n  
T he Treate d P o p ulati o n c o nsists of all scree ne d p artici pa nts w h o are e nr olle d a n d recei ve a d o s e 
of st u d y dr u g, a n d is t he pri mar y p o p ulati o n f or safet y a n d acce pt a bilit y a n al yses. T he 
c orres p o n di n g Tr e ate d A n alysis Set  i ncl u des all baseli ne a n d f oll o w-u p d at a c o ntri b ute d b y 
partici pa nts i n t he Treate d P o p ulati o n. A nal yses will be perf or me d b ase d o n treat me nt recei ve d. 
I n t he e ve nt of ra n d o mizati o n err ors, fail ure t o f oll o w t he i nte nti o n-t o-treat pri nci ple will be 
j ustifie d o n t he gr o u n ds t hat t he st u d y will n ot be use d t o ma ke defi niti ve c o ncl usi o ns re gar di n g 
t he effic ac y of T V-4 6 0 4 6.  
3. 3.  
Pri m ar y E v al u a ble P o p ul ati o n  
T he Pri mar y E val ua bl e P o p ulati o n is a s u bset of t he Treate d P o p ulati o n, e x cl u di n g s u bjects w h o 
ha ve dete cta ble M P A i n t heir baseli ne s peci me n ( m ore t ha n 5 % of t heir i n di vi d ual C ma x ) or f or 
w h o m a maj or pr ot oc ol vi olati o n occ urre d at e nr oll m e nt, i ncl u di n g: t he a bs e nce of a c o nfir me d 
o v ulati o n i n t he pre -treat me nt peri o d; B MI o utsi d e t he eli gi ble ra n ge (wit h t he e x ce pti o n of t he 6 
s u bjects p ur p osef ull y e nr olle d wit h B MI ≥4 0 i n Part 2); or use of dr u gs k n o w n t o i m pact 
o v ulati o n or t he p har mac o k i netics of M P A ( wit h t he e x ce pti o n of selecti ve C O X -2 i n hi bit ors t hat 
are ta k e n f or fe w er t ha n 5 c o nsec uti ve da ys) . T he Pri m ary Ev al u a ble A n alysis Set  i ncl u des all 
ti me c o ntri b ute d b y p artici pa nts i n t he Pri mar y E v al ua ble P o p ulati o n d uri n g w hic h a 
p har mac o ki netic or p har mac o d y na mics o utc o me is assesse d, u p t o t he i nitiati o n of a n y 
me dicati o n k n o w n t o i m pact o v ulat or y f u ncti o n or t he p har mac o ki netics of M P A.  


 
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4.  
G E N E R A L I S S U E S F O R D A T A A N A L Y SI S  
4. 1.  
Ge ner al  
D escri pti ve statistics f or c o nti n u o us  varia bles will i ncl u de t he n u m ber of o bser ve d val u es, t he 
mea n,  sta n dar d de viati o n ( S D), me dia n, mi ni m u m, a n d ma xi m u m val ues. Ge o metric mea n ( G M) 
a n d perce nt c oefficie nt of variati o n ( % C V) will als o be use d t o descri b e c o nti n u o us 
p har mac o ki netic v aria bles. F or cate g orical varia bl es, t he n u m ber a n d p erce nta ge of s u bjects wit h 
a s pecific l e vel of t he v aria ble will be prese nt e d.   
U nless ot her wise s pecifie d, all re p orte d p -v al ues will be assesse d f or statistical si g nifi ca nce at 
t he t w o-si de d 0. 0 5 le vel, a n d all c o nfi de n ce i nter vals ( CIs) f or i n di vi d ual gr o u p para meters will 
be c o m p ute d at t he 9 5 % c o vera ge le vel. Dil uti o n ( Part 1) a n d d ose ( Part 2) gr o u p c o m paris o ns 
will be ma de usi n g 9 0 % CIs f or G M  rati os, wit h n o a dj ust me nt f or m ulti ple testi n g. 
4. 2.  
S pecific ati o n of B aseli ne V al ues  
T he baseli ne v al ue s f or a n y me as ure me nt is t he last val ue o btai ne d pri or t o i njecti o n of st u d y 
dr u g , u nl ess ot her wise n ote d.  
4. 3.  
H a n dli n g Wit h dr a w als a n d Missi n g D at a  
T he pri mar y p har mac o d y na mics o utc o me of ti me t o o v ulati o n, defi ne d as a si n gle ele vate d 
ser u m P ≥ 4. 7 n g/ m L, will be ce ns ore d at m o nt h 1 2 f oll o wi n g treat me nt i nitiati o n. N o i m p utati o n 
of e ve nt ti mes pri or t o m o nt h 1 2 will ta ke place f or t he pri mar y a n al ysis, alt h o u g h se nsiti vit y 
a nal ys es ma y c o nsi der o utc o mes as i nter val -ce ns ore d bet wee n t he dat es of  last P < 4. 7 n g/ m L 
a n d first P ≥ 4. 7 n g/ m L. Missi n g M P A c o nce ntr ati o ns at ke y ti me p oi nts (e g, e n d -ti mes of partial 
A U Cs) will be i m p ute d usi n g met h o ds s pecifi e d i n Secti o n 14  of t he S A P. I nc o m plete A E o nset 
or C M i nitiati o n dates ma y b e i m p ute d t o assess  s afet y or w h e n ce ns ori n g partici pa nts fr o m 
a nal ys es d ue t o e x cl u de d me dicati o n use, as f oll o ws:  
•  If a partici pa nt ca n n ot recall t he da y or m o nt h of o nset/i nitiati o n, t he n t he date will be 
i m p ute d as t he last cli nic visit wit h o ut e vi de nce of t he A E or C M use, or ot h er 
a dj u dicate d date b ase d o n best cli nical j u d g me nt.  
•  If a partici pa nt ca n o nl y recall t he m o nt h of o nset/i nitiati o n, t he n t he date will be 
i m p ute d as t he first da y of t he m o nt h or t he last cli nic visit pri or t o t he A E/ C M, 
w hic he ver is lat er.  
4. 4.  
St u d y  D a ys a n d Visits  
T he start of treat me nt ( da y 0) is defi ne d as t he d ate o n w hic h a s u bject recei ves a d ose of st u d y 
dr u g . T h e st u d y da y o n w hic h a n e ve nt o cc urs or a n o utc o me is assesse d will be calc ulate d as t he 
date of t he e v e nt  or o utc o me , mi n us t he dat e of treat me nt i nitiati o n ; a ne gati ve st u d y da y 
i n dicates a n e v e nt pri or t o st u d y dr u g a d mi nistrati o n. W he n necessar y a n d a p pr o priate, fracti o ns 
of st u d y da ys will be c o m p ute d base d o n t he ti me (i n h o urs a n d mi n utes) of a s u bject’s i njecti o n 
a n d t he ti me o f her e ve nt or o utc o me assess me nt. 
S o me p har mac o ki netic a n d p har mac o d y n a mics data will be assi g n e d t o visit wi n d o ws w he n 
re p orti n g b y-visit s u m maries  (e g, ser u m c o ncertati o n o n da y 1 8 2). I n or der t o ma xi mize t he use 
of a vaila ble d ata, t he wi n d o w peri o ds us e d i n t hes e s u m mar y a nal yses m a y be wi der t ha n 


 
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s pecifie d i n t he st u d y Ma n ual of Pr oce d ures ( M O P) (see Ta bl e  1 , bel o w). If m ulti ple data fall i n 
t he sa me visit wi n d o w, t he n t he val ue cl osest t o t he n o mi nal ti me will be use d. If m ulti ple data i n 
t he sa me visit wi n d o w are e q uall y dista nt t o t he n o mi nal ti me, t he n t he last val ue i n t he visit 
wi n d o w will be use d f or t he a nal ysis.  
T a ble  1 : 
Wi n d o ws use d w he n s u m m arizi n g P h ar m ac o ki neti c a n d P h ar m a c o d y n a mics 
d at a b y st u d y visit  
T ar g et Visit  
Wi n d o w Peri o d 
( M O P) 
Wi n d o w Peri o d 
( A n al ysis) 
Da y s 1 , 2 
 1 h o ur  
+/ - 3  h o urs  
Da ys 3, 5, 7  
 3 h o urs  
+/ - 6 h o urs  
Da ys 1 0, 1 2, 1 4 , 1 8 
 2 4 h o urs  
+/ - 2 4 h o urs  
Da ys 2 1 a n d after  
 4 8 h o urs  
+/ - 8 4 h o urs  
 


 
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5.  
S T U D Y P O P U L A TI O N  
5. 1.  
Ge ner al  
T he st u d y will e nr oll healt h y w o me n 1 8 t o 4 0 years of a ge, i ncl usi ve, w h o are at l o w ris k of  
pre g na nc y (e g, steriliz e d, i n e x cl usi vel y s a me -se x part ners hi p, i n m o n o ga m o us relati o ns hi p wit h 
vasect o miz e d part ner, or usi n g a n o n -h o r m o nal itra uteri ne de vi ce), a n d w h o are c o nfir me d t o 
ha ve o v ulate d d uri n g  t he pre-treat me nt p hase of t he st u d y. 
5. 2.  
S u bject  Dis p ositi o n  
T he n u m bers of p artici pa nts scree ne d a n d e nr olle d i n Part 1 a n d Part 2 of t he st u d y will be 
ta b ulate d b y i n vesti gati o nal ce nter a n d treat me nt gr o u p, a n d p o ole d acr oss ce nters a n d gr o u ps. A 
fl o w dia gra m will be pr o vi de d w hic h pres e nts t he n u m bers a n d perce nta ges of partici pa nts 
c o ntri b uti n g t o t he Treate d a n d Pri mar y E val ua ble P o p ulati o ns; reas o ns f or e x cl usi o n fr o m 
a nal ysis p o p ulati o ns; t otal w o me n -years ( W Y) of f oll o w -u p c o ntri b ute d t o eac h a n al ysis set ( b y 
treat me nt gr o u p); a n d t h e n u m bers a n d perce nta ges of partici pa nts w h o c o m plete t he st u d y, 
disc o nti n ue earl y ( o verall a n d b y reas o n), or w h o are l ost t o f oll o w -u p. S u bjects t hat were 
e x cl u de d fr o m t he vari o us a nal ysis p o p ulati o ns a n d reas o n f or e x cl usi o ns will be liste d.  
5. 3.  
De m o gr a p hics a n d B aseli ne C h ar acteristics  
S u m mar y statistics a p pr o priate t o t he meas ure me nt scale will be use d t o des cri be bas eli ne 
de m o gra p hic, be h a vi oral, a n d c o ntrace pti ve use hist or y dat a. C o nti n u o us varia bles ma y als o be 
descri be d usi n g cate g orical le vels c h ose n b ase d o n pre vi o us e x perie nce wit h si milar st u dies, a n d 
pri or t o u n -bli n di n g of st atisticia ns. Baseli ne d ata will be prese nte d f or t he Scree ne d P o p ulati o n, 
t he Treat e d P o p ulati o n, a n d t he Pri mar y E v al ua ble P o p ulati o n. S u m maries will be pr o vi de d b y 
st u d y Part ( 1 or 2), treat me nt gr o u p, i n vesti gati o nal ce nter, a n d p o ole d acr oss ce nters a n d gr o u ps. 
N o statistical testi n g will be perf or me d t o c o m pare dis tri b uti o ns of baseli ne c haracteristics 
bet wee n dil uti o n or d ose gr o u ps. H o we ver, baseli n e c haracteristics ma y b e c o m pare d b et wee n 
i n vesti gati o nal ce nters  usi n g e x pl orat or y a n al ysis of varia n ce f or c o nti n u o us varia bles or C hi -
S q uare d tests f or cate g ori cal v aria bl es i n or der t o h el p i nter pret a n y a p pare nt differe n ces ( or lac k 
of differe nces) i n p har mac o d y n a mics a n d p har mac o ki netic res p o nses bet w ee n ce nters. 
5. 4.  
Pri or T her a p y a n d Me dic ati o n  use  
Start a n d st o p dates of m e dicati o n or n o n -dr u g t h era p y will be c o m pare d t o t he start date of st u d y 
dr u g d osi n g  t o all o w me dicati o ns/treat me nts t o be classifie d as eit her pri or or c o nc o mit a nt . Pri or 
me dicati o ns i ncl u de  a n y pre vi o us t hera p y, me di cati o n, or pr oce d ure a s u bject has ha d wit hi n  3 0 
da ys b ef ore st u d y dr u g a d mi nistra ti o n. Pri or m e dicati o n use will be d oc u m e nte d, a n d t he 
pre vale n ce of us e will be s u m mariz e d b y t hera pe utic class of me dicati o n a n d cate g or y (c o de d 
usi n g Le xic o m p a n d P D R O nli ne).  
5. 5.  
Me dic al Hist or y  
Pre -e xisti n g me dical hist or y d ata will be c o d e d usi n g t he Me dical Dicti o nar y f or R e g ulat or y 
Acti vities ( Me d D R A)  a n d s u m mariz e d i n ta bles a n d listi n gs b y s yste m or ga n class ( S O C), 
preferre d t er m , a n d hi g hest se verit y, b ot h wit hi n treat me nt gr o u p a n d o v erall. 


 
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5. 6.  
P h ysic al E x a mi n ati o ns  
See Secti o n  8. 5 8  f or des cri pti o n of vital si g ns, b o d y wei g ht, a n d ot her p h ysi cal e xa ms res ults t o 
be prese nt e d i n t he C S R .  
5. 7.  
C hil d be ari n g P ote nti al  a n d Met h o ds  of C o ntr ace pti o n  
In f or mati o n rel ate d t o c hil d beari n g p ot e ntial (i ncl u di n g a v era ge me nstr ual c ycle le n gt h, d ur ati o n 
of me nstr ual blee di n g, et c.)  a n d c o ntrace pti ve met h o d  use d uri n g t h e st u d y will be c ollecte d at 
baseli ne a n d s u m marize d usi n g descri pti ve statistic s. 
5. 8.  
St u d y Pr ot oc ol Vi ol ati o ns  
Data fr o m s u bjects wit h a n y pr ot oc ol vi olati o ns (as rec or de d o n pr ot o c ol vi olati o n case re p ort 
f or ms [C R F s]) d uri n g t he st u d y will be s u m marize d i n fre q ue n c y ta bles. Cate g ori es of de viati o ns 
will i ncl u de vi olati o ns of st u d y e ntr y criteria (e g, use of e x cl u de d me dicati o ns), ra n d o mizati o n 
err ors, vi olati o n of st u d y wit h dra w criteria a n d ot h er vi olati o ns ca pt ure d o n C R Fs.  All pr ot oc ol 
vi olati o ns will be f urt her s u m marize d i n data listi n gs .  


 
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6.  
E F FI C A C Y A N A L Y SI S  
Efficac y will n ot be e val uate d i n t his st u d y.  


 
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7.  
M U L TI P L E C O M P A RI S O N S  A N D M U L TI P LI CI T Y  
N o a dj ust me nts will be ma de f or t he pl a n ne d or u n pla n ne d m ulti ple c o m paris o ns of pri mar y or  
sec o n dar y p h ar mac o ki netic or p har mac o d y na mic e n d p oi nts. 


 
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8.  
S A F E T Y A N A L Y SI S  
8. 1.  
Ge ner al  
Safet y a nal yses will be perf or me d o n t h e Treate d P o p ulati o n. Res ults of all safet y assess me nts, 
i ncl u di n g AE s, I S Rs, del a ye d ret ur n t o o v ulati o n, me n str ual blee di n g patter n c ha n ge, vital si g n 
a n d b o d y wei g ht, a n d use of C Ms  will be s u m marize d wit h descri pti ve statistics b y treat me nt 
gr o u p a n d o verall, a n d/ or prese nte d i n dat a listi n gs.  
8. 2.  
A d verse E ve nts  
All A Es  wi ll be c o de d usi n g Me d D R A b y preferre d ter m a n d S O C. T he n u m ber a n d perce nt a ge 
of  partici pa nts e x perie n ci n g A Es  will be prese nte d b y treat me nt gr o u p: o verall, b y  se v erit y, 
relate d ness t o tr eat me nt, a n d acc or di n g t o w het her or n ot t he e ve nt ha d a n o nset date  wit hi n 7. 5 
m o nt hs of i nitiati o n of treat me nt. Seri o us a d verse e ve nts a n d a d v erse e ve nts lea di n g t o 
wit h dra wal fr o m t he st u d y  will be s u m marize d se p aratel y.  
A listi n g of all A Es will i ncl u de  treat me nt gr o u p, ver bati m A E descri pti o n, preferre d t er m a n d 
S O C , d urati o n, relate d ness t o pr o d uct, seri o us ness, se verit y, o utc o me, a n d w het her wit h dr a wal 
fr o m t he st u d y o cc urre d as a res ult of t he A E . All rele va nt i nf or m ati o n o n a n y deat hs will be 
disc usse d i n t he s u bject n arrati ve i n cl u de d i n t he cli nical st u d y re p or t. 
8. 3.  
Injecti o n Site Re acti o ns  
S u m maries of I S R data (i ncl u di n g nat ur e, ti mi n g a n d w het her or n ot t he I S R was Gra d e 1 or 
hi g her) will be pr o vi de d b y treat me nt gr o u p a n d o verall, a n d t he differe nces i n pr o p orti o ns of 
s u bjects e x perie nci n g I S Rs bet wee n gr o u ps will b e c o m pare d i n Part 2 usi n g Fis her’s e x act tests.  
8. 4.  
Del a ye d Ret ur n t o O v ul ati o n  
T he pr o ba bilit y of ret ur n t o o v ulati o n m ore t ha n 1 2 m o nt hs after treat me nt i nitiati o n will be 
esti mate d usi n g K a pla n -Meier met h o ds a n d prese nte d wit h 9 5 % CIs , b y tr eat me nt g r o u p.  
8. 5.  
Me nstr u al Blee di n g Dist ur b a nce s 
T he perce nta ge of w o me n e x perie nci n g a me n orr hea or ot her me nstr ual blee di n g dist ur ba n ces 
(irre g ular blee di n g or s p otti n g) assess e d m o nt hl y a n d at da y 7,  wee k  1 3 , wee k  3 2, a n d the fi nal 
st u d y visit will be  c o m pare d be t wee n treat me nt gr o u ps usi n g fre q ue nc y t a bles (f or m o nt hl y d ata, 
t he blee di n g hist or y re p ort o btai ne d cl osest i n ti me t o t he tar get m o nt hl y visit - a m o n g visits 
wit hi n 1 4 da ys of t he t ar get - will be use d). T h e n u m ber a n d perce nt a ge of s u bjects e ver 
re p orti n g s p otti n g, irre g ular blee di n g, or u n acce pt a ble blee di n g patter n will als o be ta b ulate d. 
F or Part 2 o nl y, wee kl y diar y d ata w ere di vi de d i nt o 3 0 -da y se g me nts starti n g fr o m t he date of 
t he i njecti o n. F or eac h 3 0-da y peri o d, s u bjects were cate g orize d i nt o o ne of t he f oll o wi n g f o ur 
t y pes: 
1.  N o blee di n g or s p otti n g: n o bl eedi n g or s p otti n g d a ys rec or de d d uri n g t he e ntire 3 0 -da y 
peri o d.  
2.  S p otti n g o nl y: o nl y d a ys wit h s p otti n g rec or de d d uri n g t he 3 0 -da y peri o d  
3.  Blee di n g o nl y: o nl y d a ys wit h blee di n g rec or de d d uri n g  t he 3 0-da y peri o d  


 
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2 1  
4.  Blee di n g a n d s p otti n g: a mi xt ure of blee di n g a n d s p otti n g da ys rec or de d d uri n g t he 3 0 -
da y p eri o d.  
T he perce nta ge of s u bjects e x perie nci n g eac h of t he f o ur blee di n g p atter ns d uri n g m o nt hs 1, 3, 6, 
9, a n d 1 2 will be c o m pare d bet wee n treat m e nt gr o u p s usi n g fre q ue nc y t a bles . 
8. 6.  
Li ver F u ncti o n Tests  
F or Part 2 o nl y, l i ver f u ncti o n tests, i ncl u di n g b ut n ot li mite d t o A L T a n d A S T , will be assesse d 
b y ta b ulati n g a n d gra p hi n g c h a n ge fr o m baseli ne t o wee k  1 3 ( m o nt h  3), wee k  3 2 ( m o nt h  7. 5), 
a n d fi nal s t u d y visit data.  
8. 7.  
M o o d  
F or Part 2 o nl y, m o o d will be assesse d i n fre q ue nc y ta bles at baseli ne a n d at wee k  1 3 ( m o nt h  3), 
wee k  3 2 ( m o nt h  7. 5), a n d fi nal st u d y visits . 
8. 8.  
Vit al Si g ns  a n d B o d y Wei g ht  
P ulse  rate, s yst olic/ diast olic bl o o d press ure, b o d y wei g ht a n d B MI will be s u m marize d i n listi n gs 
a n d ta b ulate d des cri pti ve statistics  b y ce nter, treat me nt gr o u p a n d st u d y visit . Vital si g ns will 
als o be s u m marize d gra p hicall y a n d usi n g s hift-t a bles ( mea n a n d m e dia n c ha n ge fr o m b aseli ne t o 
da y 7, m o nt h 3, a n d m o nt h 7. 5) , b y ce nter a n d treat me nt gr o u p. 
8. 9.  
C o nc o mit a nt Me dic ati o ns or T her a pies  
C o nc o mita nt me dicati o ns i ncl u de me dicati o ns t hat starte d at a n y ti me a n d were  ta ke n at a n y ti me 
d uri n g t he st u d y , u p t o t h e e n d of st u d y as d efi ne d i n t he st u d y pr ot oc ol . T h e use of c o n c o mita nt 
me dicati o ns will be s u m marize d b y t hera pe utic class a n d cat e g or y (c o de d usi n g Le xic o m p a n d 
P D R O nli ne)  wit h descri pti ve statistics.  S u bjects  are c o u nt e d o nl y o n ce i n eac h t hera pe utic class, 
a n d o nl y o n ce i n e ac h preferre d ter m cate g or y.   


 
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2 2  
9.  
A C C E P T A BI LI T Y D A T A  A N A L Y SI S  
Acce pt a bilit y  a nal ys es will be perf or me d o n t he T reate d P o p ulati o n a n d s u m marize d usi n g 
descri pti ve statistics a n d data listi n gs . R es p o nses t o acce pta bilit y q uesti o ns re gar di n g me nstr ual 
patter ns will be assesse d at m o nt hl y a n d fi nal st u d y visits, a n d c o m pare d bet wee n treat me nt 
gr o u ps at m o nt h 7. 5 usi n g Fis her’s e x act tests . Perce pti o ns of pai n at ti me of i njecti o n a n d 
res p o nses o n ot her acce pta bilit y q u esti o n naire ite ms, as well as assess me nt of ease of i njecti o n 
b y  t he st u d y staff, will li ke wise be s u m marize d.   


 
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St u d y T V 4 6 0 4 6 -W H -1 0 0 7 5  
2 3  
1 0.  
P H A R M A C O KI N E TI C S  A N A L Y SI S  
F or b ot h Part 1 a n d Part 2, i n di vi d ual M P A pr ofiles will be dis pla ye d ( b ot h i n t he ori gi nal scale 
a n d usi n g se mi -l o g pl ots) t hr o u g h m o nt h 1 2 f oll o wi n g treat me nt i nitiati o n or earlier date of 
wit h dra wal fr o m t he st u d y usi n g t he Pri mar y Ev al ua ble A nal ysis Set, wit h p ost -baseli ne M P A 
c o nce ntr ati o ns t hat fall bel o w t he li mit of q ua ntificati o n ( L O Q) re place d b y half t h e a p plica bl e 
L O Q.  If 1 2 0 m g/ m L is selecte d as o ne of t he Part 2 d ose  gr o u ps , t he n s u bjects in t hat Part 1 
gr o u p will be i nc or p orat e d i n t he pri mar y Part 2 p har mac o ki netics a nal ysis. Data fr o m t he s u bs et 
of 6 s u bjects ( 2 per d ose gr o u p) wit h e xtre me o besit y ( B MI ≥4 0) i n Part 2, a n d s u bjects wit h 
detecta ble M P A at b aseli ne or w h o use d dr u gs k n o w n t o i nterfere wit h p har mac o ki netics or 
p har mac o d y n a mics of M P A pri or t o ret ur n t o o v ulati o n, will be e x cl u de d fr o m t he pri mar y 
a nal ysis b ut  will be des cri be d se paratel y. S parse d ata c ollecte d after m o nt h 1 2 will li ke wise be 
descri be d se p aratel y f or t he s u bset of s u bjects w h o  ha ve n ot o v ulate d b y m o nt h 1 2.  
T he f oll o wi n g n o n -e x ha usti ve list of p har mac o ki n etic  para m eters a n d m etrics will be esti mate d 
base d o n n o n -c o m p art me ntal a nal ysis  i m ple me nte d usi n g P h oe ni x Wi n N o nli n ® or a vali date d 
S A S ® macr o  (Mat os -Pita  2 0 0 5 ): Cma x , tma x , C9 1, C1 8 2, C2 1 0, A U C0 -9 1, A U C9 1 -1 8 2, A U C0 -1 8 2, A U C0 -
2 1 0, A U C0 -∞, t he ter mi nal p hase rat e c o nsta nt ( λ) a n d t he a p pare nt ter mi nal h alf-life. C o n ve nti o ns 
a n d r ules use d t o esti mat e t hese para meters are detaile d i n S ecti o n 1 4 of t his S A P .  
S u m maries of p har mac o ki netic para met er esti mat es i n eac h tr eat me nt gr o u p will i n cl u de mea ns, 
me dia ns, G Ms, mi ni ma, ma xi ma, S D, % C V , a n d 9 5 % CIs f or G Ms. T he n u m ber a n d perce nt a ge 
of partici pa nts wit h C 1, C9 1, C1 8 2 a n d C 2 1 0 bel o w 0. 1 n g/ m L a n d 0. 2 n g/ m L , a n d t he ti me a b o ve 
0. 1 n g/ m L , will be s u m mariz e d b y gr o u p . T he pre dicte d dr u g acc u m ulati o n after re peat d osi n g  
will be base d o n o bser ve d mea n dr u g c o n ce ntr ati o ns at m o nt hs 6 a n d 1 2 ( w he n r o uti ne P K 
testi n g e n ds). Stea d y st ate c o nc o ntr ati o ns will be pre dicte d  usi n g a n a p pr o priate P K m o del f or 
dr u g c o nce ntrati o ns at m o nt hs 1 8, 2 4, etc., f oll o wi n g eac h s uccessi ve h y p ot hetical d ose gi ve n at 
6 -m o nt h i nter vals . 
T he p har mac o ki netics of M P A will be c o m pare d b et wee n gr o u ps base d o n 9 0 % CIs f or G M 
rati os of Cma x , C1 8 2, C2 1 0, A U C0 -1 8 2, A U C0 -2 1 0, A U C0 -∞, a n d a p pare nt half-life. T he effects of d ose 
gr o u p, i n v esti gati o nal ce nter, B MI, a n d a ge o n Cma x , C1 8 2, A U C0 -1 8 2, a n d half-life i n Part 2 will 
be e x pl ore d gra p hic all y a n d usi n g a n al ysis of c o varia nce o n l o g -tr a nsf or m e d o utc o mes. D ose 
pr o p orti o nalit y of C ma x , C1 8 2, A U C0 -1 8 2, a n d half-life will be e x plore d base d o n d ose -n or malize d 
p har mac o ki netic esti mates. Se nsiti vit y a nal yses will be perf or me d after e x cl u di n g partici pa nts 
deter mi ne d t o be o utliers (e g, d ue t o str o n g s us pici o n of i njecti o n o n or near a bl o o d vessel) or 
w h o fail t o c o m plete 7 . 5 m o nt hs o f f oll o w-u p.  
I n a d diti o n t o n o n-c o m part me ntal a nal yses, n o nli n ear mi x e d effect p har mac o ki netics m o deli n g 
will be perf or me d t o esti mate rates of a bs or pti o n, relati ve bi oa vaila bilit y a n d ot her rele va nt 
p har mac o ki netic p ara m eters. M o deli n g a n d si m ulati o n wil l als o be perf or m e d t o assess t he 
c o ntrace pti ve p ote ntial of a d ose ot her t ha n t h at teste d i n Part 1 or Part 2, i nc or p orati n g hist orical 
data as a v aila ble a n d a p pr o priate. D etails of t he m et h o ds use d f or m o deli n g a n d si m ulati o n 
e x ercises will be descri b e d i n a se parate M o deli n g a n d Si m ulati o n Pla n. 


 
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Statistical A nal ysis Pla n Versi o n 2. 0  
St u d y T V 4 6 0 4 6 -W H -1 0 0 7 5  
2 4  
1 1.  
P H A R M A C O D Y N A MI C S  A N A L Y SI S  
1 1. 1.  
Ge ner al  
T he Pri mar y E val ua bl e Set will be use d f or t he assess me nt of p har mac o d y n a mics  e n d p oi nt s f or 
b ot h Part 1 a n d Part 2 dat a . 
1 1. 2.  
Pri m ar y P h ar m ac o d y n a mics  E n d p oi nt s a n d A n al ysis  
T he pri ma r y p har mac o d y na mics  e n d p oi nt is ti me t o o v ulati o n, defi ne d as a si n gle ele vate d ser u m 
P ≥ 4. 7 n g/ m L. Ti me t o o v ulati o n will be c o m p ute d as t he differe nce i n da ys bet wee n det ecti o n 
of t he first p ost-ra n d o mizati o n ele vate d P a n d t he date of treat me nt i nitiati o n. Beca use 
meas ur e me nt of P will o nl y occ ur at w ee ks 6 1 -6 5 a n d 7 5 -7 8 f or w o me n w h o ha ve n ot o v ulate d 
b y m o nt h 1 2, partici pa nt s w h o d o n ot e x perie nce t h e e n d p oi nt o n or bef ore t heir m o nt h 1 2 visit s 
will ha ve t heir e ve nt ti mes ce ns ore d at m o nt h 1 2 f or p ur p oses of t he pri mar y a n al ysis . H o we ver, 
t hese data ma y b e i ncl u d e d i n sec o n dar y a nal yses t hat acc o u nt f or t he i nter val-ce ns ore d nat ur e of 
e n d p oi nts o bser ve d after m o nt h 1 2 . Alt h o u g h wo me n wit h P ≥ 4. 7 n g/ m L are as k e d t o ret ur n 
wit hi n 5 da ys, c o nfir mati o n of a n ele v ate d P is n ot a c o m p o ne nt of t he pri mar y e n d p oi nt 
defi niti o n. T he p ote ntial f or i nc orrect ti mi n g of e n d p oi nts (e g, if a partici p a nt misse d o ne or m ore 
visits pri or t o first e le vate d P) will be descri be d o n a case-b y -case b asis w he n i nter preti n g t he 
st u d y fi n di n gs or t hr o u g h se nsiti vit y a nal yses. 
If 1 2 0 m g is sel ecte d as o ne of t he d oses i n Part 2, t he n s u bjects assi g n e d t o t hat gr o u p i n Part 1 
will be i nc or p orate d i n t h e a nal y sis of Part 2 dat a . C u m ulati ve pr o ba bilities of ret ur n t o o v ulati o n 
will be esti mate d f or eac h treat me nt gr o u p bas e d o n t he Ka pla n Meier met h o d , wit h  9 5 % CIs 
deri ve d usi n g t he c o m ple me ntar y l o g -l o g tra nsf or mati o n.  
Differe nces i n t he distri b uti o n of ret ur n  t o o v ulati o n bet wee n gr o u ps will be e x pl ore d base d o n 
t w o-si de d l o g-ra n k tests c o n d ucte d at t he 0. 0 5 si g nifica nce l e vel, stratifie d o n i n vesti gati o nal 
ce nter. F or descri pti ve p ur p oses t he me dia n, i nter -q uartile ra n ge, mi ni m u m, a n d ma xi m u m ti me 
t o o v ulati on will be re p orte d b y tr eat me nt gr o u p.  
A n y o utc o m es e x cl u de d fr o m t he Pri mar y E val ua ble A nal ysis Set, a n d t he reas o n(s) f or 
e x cl usi o n (e g, use of e x cl u de d me dicati o ns), will b e descri b e d se paratel y. Data fr o m t he s u bset 
of 6 s u bjects ( 2 per treat me nt gr o u p) wit h e xtre me o besit y ( B MI ≥4 0) will li ke wise be descri be d 
se parat el y. If m ore t h a n 1 0 % of w o me n g o m or e t ha n t w o wee ks ( 1 4 da ys) bet wee n t heir l ast P < 
4. 7 n g/ m L visit a n d t heir first P ≥ 4. 7 n g/ m L visit , t he n se nsiti vit y a nal yses will be perf or me d t o 
esti mate a n d c o m pare c u m ulati ve pr o ba bilities of ret ur n t o o v ulati o n usi n g T ur n b ull’s e xte nsi o n 
of t he Ka pla n -Meier esti mat or f or i nter val ce ns ore d data (T ur n b ull 1 9 7 6 ). 
I n di vi d ual P a n d estr a di ol ( E 2 ) c o nce ntrati o n data will be dis pla ye d gra p hicall y fr o m t he pre -
treat me nt peri o d t hr o u g h ti me of o v ulati o n. Mea n a n d ma xi m u m E 2 c o nce ntrati o ns i n eac h 3 0-
da y f oll o w -u p peri o d will be s u m marize d acr oss s u bjects usi n g mea ns, me dia ns, a n d S D.    
1 1. 3.  
Sec o n d ar y a n d E x pl or at or y  P h ar m ac o d y n a mi cs A n al yses  
N o nli near mi x e d effects p har mac o ki netic a n d p har mac o d y na mics m o deli n g a n d si m ulati o n ma y 
be use d t o assess t he relati o ns hi p bet wee n i n di vi d ual ser u m M P A c o nce ntr ati o ns a n d d urati o n of 
o v ulati o n s u p pressi o n, wit h e m p hasis o n c haracterizi n g t he d istri b uti o n of a n y a p p are nt 


 
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Statistical A nal ysis Pla n Versi o n 2. 0  
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2 5  
o v ulat or y s u p pressi o n t hr es h ol d a n d t he l o west d ose w hic h ma y relia bl y i n hi bit o v ulati o n f or 6 
m o nt hs.  
 
 
 
 
 
 


 
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2 6  
1 2.  
S T A TI S TI C A L S O F T W A R E  
All data listi n gs, s u m maries, a n d statistical a nal ys es will be ge nerate d usi n g P h oe ni x 
Wi n N o nli n ®  a n d/ or S A S ®  versi o n 9. 4  or later. 


 
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2 7  
1 3.  
C H A N G E S T O A N A L Y S E S S P E CI FI E D I N P R O T O C O L  V 1. 0  
1 3. 1.  
C h a n ges fr o m V 1. 0 of pr ot oc ol, Pri or t o St u d y I niti ati o n 
T he pr ot oc ol was a me n d e d t wice pri or t o  st u d y i nitiati o n ( ori gi nal pr ot oc ol: 0 1 Ma y 2 0 1 6; 
a me n d me nt 1: 2 9 Ma y 2 0 1 6 ; a me n d me nt 2: 0 4 N o ve m ber 2 0 1 6). T his secti o n descri be d c h a n ges 
t o pla n ne d statistical a nal ys es b ase d o n a m e n d me nt s 1 a n d 2 , w hic h were i n c or p orat e d i n V 1. 0 of 
t he S A P. 
•  A d dresse d a me n d me nt 0 1 of pr ot oc ol re gar di n g ti mi n g of me nstr ual blee di n g a n d 
relate d acce pta bilit y data. 
•  S pecifie d t hat o nl y p artici pa nts wit h baseli ne M P A e x cee di n g 5 % of t heir i n di vi d ual 
C ma x  will be e x cl u de d fr o m t he Pri mar y E v al u ble P o p ulati o n.  T his c ha n ge was m a de 
c orres p o n di n g t o t he c h a n ge i n Pr ot oc ol A me n d m e nt 2, Secti o n 8. 2. 3 ( Pri mar y 
E val ua ble P o p ulati o n).  
•  S pecifie d sele cti ve C o x -2 i n hi bit ors (e g, Mel o xica m or Celec o xi b) t hat are ta ke n f or 
fe wer t ha n 5 c o ns ec uti ve da ys will n ot lea d t o e x cl usi o n fr o m t he Pr i mar y E vala u ble 
P o p ulati o n or A nal ysis Set . T his c ha n ge was ma d e i n res p o n di n g t o t he c h a n ge i n 
Pr ot oc ol A me n d me nt 2, Secti o n 5. 3 ( Pri or a n d C o nc o mita nt Me dicati o n or 
Treat me nt)  
1 3. 2.  
C h a n ges fr o m V 1. 0 of S A P, After I niti ati o n of P art 1 (2 6  Oct o ber 
2 0 1 6) b ut Pri or t o A v ail a bilit y of a n y P K/ P D d at a , i ncl u di n g c h a n ges 
m a de i n a ntici p ati o n of Pr ot oc ol A me n d me nt 3 ( 2 7 M arc h 2 0 1 7)  
•  C ha n ge d m et h o d f or esti mati n g M P A acc u m ulati o n f oll o wi n g 2 or m or e h y p ot hetical 
d oses deli vere d at 6-m o nt h i nter vals . T he met h o d s pecifie d i n V 1. 0 of S A P ass u me d a 
o ne -c o m part me ntal E V -m o del o be yi n g m o n o p hasic deca y w hi c h ma y or ma y n ot 
a p pl y f or T V -4 6 0 4 6. R e vise d met h o d is base d o n o bser ve d mea n dr u g c o n ce ntrati o ns 
at m o nt h 6 a n d m o nt h 1 2 ( w he n re g ular P K sam pli n g e n ds), a n d a n a p pr o p riate m o del 
f or pre dicti n g dr u g c on c en trati o ns at s u bse q ue nt 6-m o nt h i nter vals .  
•  C ha n ge d pla ns f or descri pti ve a nal ys es of E 2 d ata . T his c ha n ge was ma de t o clarif y 
t he a nal yses of E 2 d escri be d i n S A P V 1. 0. 
•  Pr ot oc ol A me n de me nt 3 i ncl u de d la n g ua ge t o t he effect t hat fe wer t ha n 3 d oses c o ul d 
be selecte d f or Part 2, as well as ne w safet y meas ures f or Part 2 , i ncl u di n g: m o o d a n d 
li ver f u ncti o n testi n g at t he wee k 1 3, wee k 3 2, a n d fi nals st u d y visit; w ee kl y 
electr o nic diar y data ; me nstr ual blee di n g patter n .  
1 3. 3.  
C h a n ges fr o m V 1. 0 of S A P, After i niti al I nteri m Re vie w of P K/ P D 
d at a  (2 7 M arc h 2 0 1 7 ) 
•  Clarifie d visit wi n d o w f or m o nt hl y me ns utr ual blee di n g d ata  
•  A d de d a n e x pl orat or y ass ess me nt of t he n u m ber a n d perce nt a ge of w o me n e ver 
re p orti n g irre g ul ar blee di n g, s p otti n g, or u nacce pt a ble blee di n g patter ns.  


 
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Statistical A nal ysis Pla n Versi o n 2. 0  
St u d y T V 4 6 0 4 6 -W H -1 0 0 7 5  
2 8  
•  Alt h o u g h t he p har mac o ki netic pr ofile of t he c urre nt T V -4 6 0 4 6 i n vesti gati o n al 
pr o d uct was f o u n d t o b e fa v ora bl e i n Part 1 of t he st u d y, a d ecisi o n was ma de n ot t o 
c o nti n ue t o Part 2 of t he st u d y d ue t o c halle n ges wit h t he sta bilit y, s yri n gea bilit y, a n d 
ma n ufact uri n g of t h e c urre nt f or m ulati o n. As s uc h, a nal ys es pla n ne d  f or Part 2 of 
st u d y are n ot rele v a nt, si nce Part 2 was n e ver i m ple me nte d.  


 
 P har mac o ki netics  St u d y – C o ntrace pti o n  
Statistical A nal ysis Pla n Versi o n 2. 0  
St u d y T V 4 6 0 4 6 -W H -1 0 0 7 5  
2 9  
1 4.  
C O N V E N TI O N U S E D W H E N  E S TI M A TI N G I N DI VI D U A L 
P H A R M A C O KI N E TI C P A R A M E T E R S  
•  C ma x  a n d tma x  will n ot be re p orte d f or partici p a nts w h o disc o nti n ue t he st u d y wit h o ut 
pr o vi di n g at least o ne M P A s peci me n after t he ti me of t heir ma xi m u m o bser ve d M P A 
c o nce ntr ati o n.  
•  T he ter mi nal p hase rate c o nsta nt (λ ) w ill be esti mate d as mi n us t he sl o pe of t he 
ter mi nal p hase, bas e d o n t he last t hree or m ore l o g-tra nsf or me d M P A c o nce ntrati o ns 
re gress e d o n ti me.2 T his re gressi o n will e x cl u de s peci me ns o btai ne d o n or after t he 
first occ urre nce of a b el o w L O Q val ue or mo nt h 1 2, w hic he ver is earlier, as well as 
s peci me ns c ollect e d bef ore tma x . If t he esti mate d sl o pe is n ot ne gati ve, or if t here are 
fe wer t ha n t hree ti me p oi nts a vaila ble f or esti mati n g λ, t he n n o val ue will b e re p ort e d 
f or t hat partici pa nt.  
•  Partial A U Cs w ill be c o m p ute d usi n g a li near/l o g-tra pez oi dal r ule, wit h 
c o nce ntr ati o ns at e n d -ti mes i m p ute d if n o s peci me n was c ollecte d o n t h e a p plica ble 
da y(s), as f oll o ws: if a partici pa nt disc o nti n ue d or ha d her first L O Q meas ure me nt 
pri or t o reac hi n g a partial A U C e n d ti me, t he n t he missi n g c o nce ntr ati o n will be 
i m p ute d usi n g λ. If t he e n d-ti me occ urs wit hi n t he ra n ge of t he partici pa nts’ e val ua ble 
data, t he n t he c o n ce ntr ati o n will be esti mate d usi n g li near ( u p t o C ma x ) or l o garit h mic 
re gressi o n ( o n or aft er Cma x ), based o n t he t w o s p eci me ns c ollect e d cl osest i n ti me t o 
t he tar get date. 
•  A U C 0 -∞ will be c o m p ute d as A U C 0 -last + C last/ λ, w here ‘last’ is t he last da y use d t o 
c o m p ute λ as pr e vi o usl y defi ne d.  
                                                 
2 T he act ual n u m ber of ti me p oi nts use d t o c o m p ute λ  will be c h ose n base d o n t he re gressi o n wit h lar gest a dj uste d 
R 2 (see Mat os -Pita a n d Mi g uel Lill o, 2 0 0 5 ). 


 
 P har mac o ki netics  St u d y – C o ntrace pti o n  
Statistical A nal ysis Pla n Versi o n 2. 0  
St u d y T V 4 6 0 4 6 -W H -1 0 0 7 5  
3 0  
1 5.  
R E F E R E N C E S  
Mat os -Pita, A S a n d Mi g uel Lill o, B.  N o nc o m part me ntal P har mac o ki netics a n d B i oe q ui val e nce 
A nal ysis. Pr ocee di n g of P har ma S U G 2 0 0 5, P h oe ni x, A Z. S P 0 7.  
T ur n b ull, B W. T he e m pirical distri b uti o n f u ncti o n wit h ar bitraril y gr o u pe d, ce ns ore d, a n d 
tr u ncate d dat a. J o ur nal of t he R o yal Statistical S ociet y, Series B 1 9 7 6; 3 8 : 2 9 0-2 9 5.