Clinical trial NCT05418426
Conditions: Vulvovaginal Atrophy Vasomotor Symptoms
Sponsor: Daré Bioscience, Inc.
Start date: 2020-08-18; Completion date: 2022-01-27
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
An open-label study to assess the PK of estradiol, estrone and progesterone from the DARE-HRT1 intravaginal rings at two different dose strengths.

Detailed description:

Arms: arm 1: 28-day IVR 80/4 arm 2: 28-day IVR 160/8 arm 3: 29 days (estradiol 1mg/progesterone 100 mg oral capsule)
Interventions: intervention 1: IVR Dose 1 intervention 2: IVR Dose 2 intervention 3: Oral Reference
Intervention descriptions: intervention 1: Estradiol 80 ug/progesterone 4 mg intervention 2: Estradiol 160ug/progesterone 8 mg intervention 3: estradiol 1mg/progesterone 100 mg

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
 
 
A Phase 1, Open-Label, Parallel Group Study to Evaluate the 
Pharmacokinetics and Safety of DARE-HRT1 (80μg Estradiol/4mg 
Progesterone and 160μg Estradiol/8mg Progesterone Intravaginal Rings) in 
Healthy Post-Menopausal Women 
 
Protocol Number: DARE-HRT1-001 
 
Final Version 
Date: 06 March 2019 
 
Sponsor: 
Daré Bioscience Australia Pty LTD 
Level 19 HWT Tower, 40 City Road 
Southbank, VIC 3006 
Australia 
Contract Research Organization: ICON Clinical Research, LLC 
820 West Diamond Avenue, Suite 100 
Gaithersburg, MD 20878 USA 
Telephone: (301) 944-6800 
Fax: (215) 699-6288 
 
Confidentiality Statement 
This document and the information contained herein or attached hereto ("Confidential Material") are confidential 
and proprietary to Daré Bioscience Australia Pty LTD. This Confidential Material should be viewed only by those 
individuals or companies that have been given prior authorization to do so by Daré Bioscience Australia Pty LTD 
("Authorized Users"). This Confidential Material should not be made available in any form to any person or 
company, other than the Authorized Users and their respective employees or associates on a need-to-know basis, 
without the prior written consent from Daré Bioscience Australia Pty LTD.


Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-001 
Final Protocol 
 
CONFIDENTIAL 
Date: 06 March 2019 
Page 2 
TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................2 
LIST OF TABLES .........................................................................................................................5 
1 
PROTOCOL SUMMARY............................................................................................6 
LIST OF ABBREVIATIONS .....................................................................................................15 
STUDY ADMINISTRATIVE STRUCTURE ...........................................................................17 
2 
INTRODUCTION AND BACKGROUND ...............................................................19 
2.1 
Introduction ..........................................................................................................19 
2.2 
Investigational Product Background .................................................................20 
2.3 
Summary of Findings to Date .............................................................................20 
2.4 
Study Rationale ....................................................................................................21 
2.4.1 
Dose Rationale .......................................................................................................21 
2.4.2 
Study Design Rationale..........................................................................................23 
2.5 
Hypotheses ............................................................................................................23 
3 
OBJECTIVES .............................................................................................................24 
3.1 
Primary Objective ................................................................................................24 
3.2 
Secondary Objectives...........................................................................................24 
3.3 
Exploratory Objective .........................................................................................24 
4 
STUDY DESIGN .........................................................................................................25 
4.1 
Study Design and Overview ................................................................................25 
4.1.1 
Duration of Study ...................................................................................................27 
4.1.2 
Definition of Study Completion.............................................................................27 
4.1.3 
End of Study ..........................................................................................................27 
5 
SELECTION AND WITHDRAWAL OF SUBJECTS ...........................................28 
5.1 
Inclusion Criteria .................................................................................................28 
5.2 
Exclusion Criteria ................................................................................................28 
5.3 
Subject Re-enrollment .........................................................................................30 
5.4 
Subject Withdrawal .............................................................................................30 
5.5 
Early Termination of Study ................................................................................31 
6 
TREATMENT OF SUBJECTS .................................................................................32 
6.1 
Identity of Study Drugs .......................................................................................32 
6.2 
Treatments Administered ...................................................................................32 
6.3 
Method of Assigning Subjects to Treatment Groups .......................................32 
6.4 
Measurements of Treatment Compliance .........................................................32 
6.5 
Investigational Product Storage, Accountability, and Retention ....................33 
6.5.1 
Storage Conditions .................................................................................................33 


Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-001 
Final Protocol 
 
CONFIDENTIAL 
Date: 06 March 2019 
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6.5.2 
Drug Accountability and Retention .......................................................................33 
6.6 
Packaging and Labeling ......................................................................................33 
6.6.1 
Investigational Product ..........................................................................................33 
6.6.2 
Blinding of Treatment Assignment ........................................................................33 
6.7 
Concomitant Medications and Procedures and Other Restrictions................33 
6.7.1 
Concomitant Medications and Procedures.............................................................33 
6.7.2 
Other Restrictions ..................................................................................................34 
7 
STUDY ASSESSMENTS AND PROCEDURES .....................................................35 
7.1 
Medical and Surgical History .............................................................................35 
7.2 
Demographic Characteristics .............................................................................35 
7.3 
Physical Measurements .......................................................................................35 
7.4 
Pharmacokinetic Assessments ............................................................................35 
7.4.1 
Drug Concentration Measurements .......................................................................35 
7.4.2 
Pharmacokinetic Parameters ..................................................................................35 
7.5 
Safety Assessments ...............................................................................................36 
7.5.1 
Adverse Events ......................................................................................................36 
7.5.2 
Laboratory Tests ....................................................................................................36 
7.5.3 
Other Tests .............................................................................................................38 
7.5.4 
Usability and Tolerability Questionnaire ...............................................................38 
7.5.5 
Vital Signs ..............................................................................................................38 
7.5.6 
Physical Examination.............................................................................................38 
7.5.7 
Electrocardiograms ................................................................................................39 
7.5.8 
Appropriateness of Safety Assessments ................................................................39 
8 
ADVERSE EVENTS ...................................................................................................40 
8.1 
Recording Adverse Events ..................................................................................40 
8.2 
Assessment of Adverse Events ............................................................................40 
8.2.1 
Serious Adverse Events .........................................................................................41 
8.2.2 
Intensity..................................................................................................................41 
8.2.3 
Relationship to Study Drug ....................................................................................42 
8.3 
Discontinuation due to Adverse Events .............................................................42 
8.4 
Reporting Serious Adverse Events .....................................................................42 
9 
STATISTICAL CONSIDERATIONS ......................................................................43 
9.1 
Sample Size Calculation ......................................................................................43 
9.2 
Analysis Populations ............................................................................................43 
9.3 
Randomization .....................................................................................................43 
9.4 
Endpoints ..............................................................................................................43 
9.4.1 
Primary Endpoints .................................................................................................43 
9.4.2 
Secondary Endpoints .............................................................................................43 
9.4.3 
Exploratory Endpoint .............................................................................................44 
9.5 
Pharmacokinetic Statistical Analysis .................................................................44 
9.6 
Safety Analysis .....................................................................................................44 
10 
ACCESS TO SOURCE DATA/DOCUMENTS .......................................................45 


Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-001 
Final Protocol 
 
CONFIDENTIAL 
Date: 06 March 2019 
Page 4 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................46 
11.1 
Conduct of Study..................................................................................................46 
11.1.1 
Protocol Deviations ................................................................................................46 
11.2 
Protocol Amendments .........................................................................................47 
11.3 
Monitoring of Study .............................................................................................47 
12 
ETHICS ........................................................................................................................48 
12.1 
Institutional Review Board/Independent Ethics Committee Approval ..........48 
12.1.1 
Ethics Review Prior to Study .................................................................................48 
12.1.2 
Ethics Review of Other Documents .......................................................................48 
12.2 
Written Informed Consent ..................................................................................48 
13 
DATA HANDLING AND RECORD KEEPING .....................................................49 
13.1 
Data Reporting and Case Report Forms ...........................................................49 
13.1.1 
Case Report Forms .................................................................................................49 
13.1.2 
Laboratory Data .....................................................................................................49 
13.1.3 
Retention of Source Documents ............................................................................49 
13.2 
Retention of Essential Documents ......................................................................49 
14 
ADMINISTRATIVE INFORMATION ....................................................................50 
14.1 
Financing and Insurance .....................................................................................50 
14.2 
Publication Policy.................................................................................................50 
15 
REFERENCES ............................................................................................................51 
APPENDIX A 
USABILITY AND TOLERABILITY QUESTIONNAIRE ........................53 
APPENDIX B 
SUBJECT DAILY DIARY ............................................................................54 
16 
SIGNATURES .............................................................................................................55 
 


Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-001 
Final Protocol 
 
CONFIDENTIAL 
Date: 06 March 2019 
Page 5 
LIST OF TABLES 
Table 1.1 
Schedule of Assessments and Procedures - IVR Treatment Arm............................9 
Table 1.2 
Schedule of Assessments and Procedures - Oral Treatment Arm .........................12 
Table 2.1 
Mean Pharmacokinetic Values for Estradiol .........................................................22 
Table 4.1 
Treatment Allocations ............................................................................................25 
Table 6.1 
Study Drugs ...........................................................................................................32 
Table 7.1 
Clinical Laboratory Tests .......................................................................................37 
 


Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-001 
Final Protocol 
 
CONFIDENTIAL 
Date: 06 March 2019 
Page 6 
1 
PROTOCOL SUMMARY 
Protocol Title: 
A Phase 1, Open-Label, Parallel Group Study to Evaluate the Pharmacokinetics and 
Safety of DARE-HRT1 (80 μg Estradiol/4 mg Progesterone and 160 μg 
Estradiol/8 mg Progesterone Intravaginal Rings) in Healthy Post-Menopausal 
Women  
Study Phase: 
1 
Objectives: 
Primary: 
• 
To describe the pharmacokinetic (PK) parameters over 28 days of two different 
dose combinations of éE-HRT1 intravaginal ring (IVR): 
o 
Estradiol 80 μg/progesterone 4 mg/day IVR 
o 
Estradiol 160 μg/progesterone 8 mg/day IVR 
Secondary: 
• 
To assess the safety and tolerability of DARE-HRT1 
• 
To compare the systemic exposure of estradiol, estrone, and progesterone over 
28 days after administration of DARE-HRT1 IVR and once daily (QD) oral 
Estrace®/Prometrium® 
Exploratory: 
• 
To assess usability and subject tolerability of the DARE-HRT1 IVR 
Hypotheses: 
No formal hypotheses will be tested. 
Endpoints: 
Primary: 
• 
Steady-state concentration (Css) and maximum observed plasma concentration 
(Cmax) for estradiol, estrone, and progesterone for each treatment 
Secondary: 
• 
adverse events 
• 
clinical laboratory findings 
• 
physical examination findings 
• 
vital signs 
• 
pelvic examination findings 
• 
vaginal pH and cytology  
Exploratory: 
• 
responses to Usability and Tolerability questionnaire 


Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-001 
Final Protocol 
 
CONFIDENTIAL 
Date: 06 March 2019 
Page 7 
Study Design: 
This is a randomized, open-label, 3-arm, parallel group study in approximately 
30 healthy postmenopausal women with intact uteri. This study is designed to assess 
the PK of estradiol, estrone, and progesterone from DARE-HRT1 intravaginal rings 
at two dose strengths. Oral estradiol 1 mg/progesterone 100 mg once-daily for 
28 days will serve as an active reference. Upon completion of screening procedures 
and confirmation of eligibility (including an endometrial biopsy, cervical screening 
test, and transvaginal ultrasound), eligible subjects will be admitted to the clinical 
research unit (CRU) on Day -1.  
 
Randomization will occur prior to initiation of treatment and subjects will be 
randomized in a 1:1:1 ratio to the treatment groups below. 
Treatment Group and 
Number of Subjects 
Treatment 
IVR Dose 1 
(n = 10) 
28-day IVR 80/4 (estradiol 80 μg/day + progesterone 
4 mg/day) 
IVR Dose 2 
(n = 10) 
28-day IVR 160/8 (estradiol 160 μg/day + 
progesterone 8 mg/day) 
Oral Reference 
(n = 10) 
Oral Estrace®/Prometrium® QD for 29 days (estradiol 
1 mg/progesterone 100 mg oral capsule) 
 
Day 1 is defined as the first day of treatment, i.e., the day the IVR is self-inserted by 
the subject. The same IVR is to remain intravaginal for 28 days, with removal of 
IVR in the CRU on the morning of Day 29.  
• 
Plasma sampling will occur on Day 1 predose at -1, -0.5, and 0 (immediately; 
within ± 5 minutes) hours prior to insertion of IVR and at 0.5, 1, 2, 4, 8, 12, 24, 
and 48 hours following insertion. Subjects will be discharged from the CRU 
after safety assessments have been completed on Day 3. 
• 
On the morning of Days 8, 11, 15, and 22 subjects will return to the CRU for a 
single PK blood draw and safety assessments.  
• 
Subjects will return to the CRU on Day 28 for a PK blood draw, safety 
assessments, confirmation of IVR placement, and to begin confinement. On the 
morning of Day 29 a PK blood sample will be collected. The IVR will then be 
removed and PK samples will be collected 0.5, 1, 2, 4, 8, 12, and 24 hours 
post-removal. 


Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-001 
Final Protocol 
 
CONFIDENTIAL 
Date: 06 March 2019 
Page 8 
Study Design 
(continued): 
Those enrolled in the oral arm (Estrace/Prometrium) will also begin dosing on 
Day 1, concluding with a last dose on Day 29. Subjects enrolled in the oral arm will 
be directed to self-administer the medication in the morning with a meal and 
approximately 240 mL of water, starting on Day 2 through Day 27. Doses will be 
administered in the CRU each of the mornings of Day 1 and Days 28 and 29 with a 
moderate-fat breakfast.  
• 
Plasma sampling will occur on Day 1 predose at -1, -0.5, and 0 
(immediately: within ± 5 minutes) hours prior to oral dose administration 
and 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose. Subjects will be 
discharged from the CRU and instructed to self-administer the oral 
treatment each morning, with food and approximately 240 mL of water, at 
approximately the same time. 
• 
On Days 8, 15, and 22, subjects will return to the CRU for a single PK 
blood draw and safety assessments.  
• 
Subjects will return on Day 28 and be admitted to consume their oral dose 
with breakfast and begin PK sampling prior to (0 hours) dosing on Day 29 
and the following timepoints post oral dose: 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 
and 24 hours.  
A follow-up phone call will be made from the CRU to each subject to monitor any 
ongoing or emergent AEs approximately 7 days after the last dose of study 
medication or removal of IVR. 
Subject Selection 
Criteria: 
Healthy postmenopausal women with body mass index (BMI) between 18 and 
38 kg/m2, inclusive, normal appearing cervix and vagina based upon pelvic 
examination, intact uterus, acceptable result from endometrial biopsy, normal 
cervical screening test and mammogram, endometrium lining < 4 mm (upon 
transvaginal ultrasound at screening), and without a peanut allergy.  
Study Drug, Dose, and 
Route of 
Administration: 
DARE-HRT1 is an intravaginal ring that delivers estradiol and progesterone and is 
self-administered by intravaginal insertion once and remains in place for 28 days. 
The oral reference is Estrace/Prometrium given by oral capsule QD for 29 days. 
Planned Sample Size: 
Approximately 30 subjects are planned to be enrolled, with 10 subjects randomized 
to each treatment arm. Subjects who terminate early from the trial may be replaced 
to ensure an adequate number of subjects contributing to the PK for each treatment 
arm. 


Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-001 
Final Protocol 
 
CONFIDENTIAL 
Date: 06 March 2019 
Page 9 
Table 1.1 
Schedule of Assessments and Procedures - IVR Treatment Arm 
Study Procedure 
Screening 
Pre-Treatment 
28-Day Treatment Period 
Follow-
Up 
Phone 
Call 
Study Day 
Days -28 
to -2 
Day -1 
Day 1 
Predose 
Days 1, 2, and 3 
Days 8, 11, 
15, and 22 
Day 28 
Day 29 
Day 30 
Time 
 
 
0.5, 1, 2, 4, 8, 12, 
24, and 48 hours 
post insertion 
 
 
 
 
Informed consenta  
X 
 
 
 
 
 
 
 
 
Assign Subject ID  
X 
 
 
 
 
 
 
 
 
Eligibility assessment  
X 
 
X 
 
 
 
 
 
 
Randomization  
 
 
Xb 
 
 
 
 
 
 
Admission to CRU 
 
X 
 
 
 
X 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical and surgical 
history  
 
X 
 
 
 
 
 
 
 
Physical examinationc 
X 
X 
 
 
 
 
 
X 
 
Cervical screening test (if 
needed)  
X 
 
 
 
 
 
 
 
 
Pelvic exam with 
speculum & vaginal 
visual examd 
X 
 
 
 
 
 
 
X 
 
Vaginal cytology and pH  
X 
 
 
 
 
 
 
X 
 
Endometrial biopsy  
X 
 
 
 
 
 
 
 
 
Height (cm), weight (kg), 
and BMI  
X 
X 
 
 
 
 
 
 
 
12-lead ECG  
X 
X 
 
 
 
 
 
 
 
Vital signs (BP and PR), 
RR, oral temp  
X 
X 
X 
 
X 
 
 
X 
 
Hematology & blood 
chemistry  
X 
X 
 
 
X (excluding 
Day 11) 
 
 
X (EOS) 
 


Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-001 
Final Protocol 
 
CONFIDENTIAL 
Date: 06 March 2019 
Page 10 
Table 1.1 
Schedule of Assessments and Procedures - IVR Treatment Arm 
Study Procedure 
Screening 
Pre-Treatment 
28-Day Treatment Period 
Follow-
Up 
Phone 
Call 
Study Day 
Days -28 
to -2 
Day -1 
Day 1 
Predose 
Days 1, 2, and 3 
Days 8, 11, 
15, and 22 
Day 28 
Day 29 
Day 30 
Time 
 
 
0.5, 1, 2, 4, 8, 12, 
24, and 48 hours 
post insertion 
 
 
 
 
FSH  
X 
 
 
 
 
 
 
 
 
Serology testse 
X 
 
 
 
 
 
 
 
 
Drug and alcohol urine 
screen  
X 
X 
 
 
 
 
 
 
 
Transvaginal Ultrasound  
X 
 
 
 
 
 
 
X 
 
Urine dipstick  
X 
X 
 
 
 
 
 
X (EOS) 
 
Dispense test article(s)  
 
 
X 
 
 
 
 
 
 
Training on use of IVR  
X 
 
X 
 
 
 
 
 
 
Usability and Tolerability 
questionnaire  
 
 
 
 
 
 
 
X 
 
Insert Vaginal Ring (after 
predose PK sample)  
 
 
X 
 
 
 
 
 
 
Confirm vaginal ring 
placement  
 
 
 
Xf 
X 
 
X 
 
 
PK blood samples  
X  
X 
X (-1, -0.5, 
and 0 hours 
predose) 
X (once) 
X (once) 
X (once) 
X (0, 0.5, 1, 2, 4, 
8, and 12 hours 
postdose) 
X 
(24 hours 
postdose) 
 
Remove vaginal 
ring/Return test article(s)  
 
 
 
 
 
 
X 
 
 
Review of daily diary 
 
 
 
X 
X 
X 
X 
 
 
Discharge from CRU 
 
 
 
X (Day 3) 
 
 
 
X 
 
Follow-up Phone Callg 
 
 
 
 
 
 
 
 
X 
Adverse events  
 
 
 
AEs collected beginning at IVR placement and in on-going manner, as appropriate 


Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-001 
Final Protocol 
 
CONFIDENTIAL 
Date: 06 March 2019 
Page 11 
Table 1.1 
Schedule of Assessments and Procedures - IVR Treatment Arm 
Study Procedure 
Screening 
Pre-Treatment 
28-Day Treatment Period 
Follow-
Up 
Phone 
Call 
Study Day 
Days -28 
to -2 
Day -1 
Day 1 
Predose 
Days 1, 2, and 3 
Days 8, 11, 
15, and 22 
Day 28 
Day 29 
Day 30 
Time 
 
 
0.5, 1, 2, 4, 8, 12, 
24, and 48 hours 
post insertion 
 
 
 
 
Serious adverse events 
SAEs collected beginning at ICF signing and in on-going manner 
Prior/conmeds  
X 
X 
X 
Conmeds collected in on-going manner, as appropriate 
Abbreviations: AE = adverse event; BP = blood pressure; conmed = concomitant medication; CRU = clinical research unit; ECG = electrocardiogram; EOS = 
end of study; FSH = follicle-stimulating hormone; ID = identification; HRT = hormone replacement therapy; IVR = intravaginal ring; PK = pharmacokinetic; PR 
= pulse rate; RR = respiration rate; SAE = serious adverse event; temp = temperature. 
a. 
Subjects who elect to undergo washout of prior HRT will be asked to sign the informed consent prior to the start of that washout. Washout periods of 
8 weeks will require that Screening not commence until 28 days prior to Day 1. 
b. Randomization will occur after screening procedures are completed and eligibility is verified. 
c. 
Complete physical examination at Screening and Day 30 visit. Symptom-directed examination at all other visits for subjects exhibiting or reporting 
symptoms since their last visit. 
d. The purpose of the pelvic speculum exam is to identify vaginal irritation or abnormalities at baseline so that AEs related to IVR can be associated with IVR 
and not baseline abnormalities. 
e. 
Serology tests include HIV-1 and HIV-2 antibodies, hepatitis B surface antigen, and HCV antibodies.  
f. 
Placement of IVR will be confirmed prior to first post-dose PK collection. 
g. The purpose of the call is to follow up on any ongoing or emergent AEs since discharge from the CRU after the subject’s treatment has been completed 
(approximately 7 days after the last dose of study medication or removal of the IVR). 
 
 


Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-001 
Final Protocol 
 
CONFIDENTIAL 
Date: 06 March 2019 
Page 12 
Table 1.2 
Schedule of Assessments and Procedures - Oral Treatment Arm 
Study Procedure 
Screening 
Pre- Treatment 
Treatment Phase 
Follow-
Up 
Phone 
Call 
 
In-Clinic 
Study Day 
Days -28 
to -2 
Day -1 
Day 1 
Predose 
Days 1 
and 2 
Day 8 
Day 15 
Day 22 
Day 28 
Day 29 
Day 30 
Informed consenta  
X 
 
 
 
 
 
 
 
 
 
 
Assign Subject ID  
X 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment  
X 
 
X 
 
 
 
 
 
 
 
 
Randomization 
 
 
Xb 
 
 
 
 
 
 
 
 
Admission to CRU 
 
X 
 
 
 
 
 
X 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical and surgical 
history  
X 
X 
 
 
 
 
 
 
 
 
 
Physical examinationc 
X 
X 
 
 
 
 
 
 
 
X 
 
Height (cm), weight 
(kg), and BMI 
X 
 
 
 
 
 
 
 
 
 
 
Cervical screening test 
(if needed) 
X 
 
 
 
 
 
 
 
 
 
 
Pelvic exam with 
speculum & vaginal 
visual examd  
X 
 
 
 
 
 
 
 
 
 
 
Vaginal cytology and pH 
X 
 
 
 
 
 
 
 
 
X 
 
Endometrial biopsy 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
X 
 
 
 
 
 
 
 
 
 
Vital signs (BP and PR), 
RR, oral temp  
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
Hematology & blood 
chemistry  
X 
X 
 
 
X 
X 
X 
 
 
X (EOS) 
 
FSH 
X 
 
 
 
 
 
 
 
 
 
 
Serology testse 
X 
 
 
 
 
 
 
 
 
 
 


Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-001 
Final Protocol 
 
CONFIDENTIAL 
Date: 06 March 2019 
Page 13 
Table 1.2 
Schedule of Assessments and Procedures - Oral Treatment Arm 
Study Procedure 
Screening 
Pre- Treatment 
Treatment Phase 
Follow-
Up 
Phone 
Call 
 
In-Clinic 
Study Day 
Days -28 
to -2 
Day -1 
Day 1 
Predose 
Days 1 
and 2 
Day 8 
Day 15 
Day 22 
Day 28 
Day 29 
Day 30 
Drug and alcohol urine 
screen 
X 
X 
 
 
 
 
 
 
 
 
 
Transvaginal Ultrasound 
X 
 
 
 
 
 
 
 
 
X 
 
Urine dipstick  
X 
X 
 
 
 
 
 
 
 
X (EOS) 
 
Administer Treatment 
(Oral HRT)  
 
 
 
X 
X 
X 
X 
X  
X  
 
 
Review of daily diary 
 
 
 
X 
X 
X 
X 
X 
 
 
 
PK blood samples  
X 
X 
X 
(-1.0, -0.5, 
and 
0 hours) 
Xf 
X 
(once) 
X 
(once) 
X 
(once) 
 
X (0, 0.25, 0.5, 
1, 2, 4, 6, 8, 
10, 12 hours 
postdose) 
X 
(24 hours 
postdose) 
 
Discharge from CRU 
 
 
 
Xg 
 
 
 
 
 
X 
 
Follow-up Phone Callh 
 
 
 
 
 
 
 
 
 
 
X 
Adverse events  
 
 
 
AEs collected beginning at first dose and in on-going manner, as appropriate 
Serious adverse events 
SAEs collected beginning at ICF signing and in on-going manner 
Prior/conmeds  
X 
X 
X 
Conmeds collected in on-going manner, as appropriate 
Abbreviations:  AE = adverse events; BP = blood pressure; conmed = concomitant medication; CRU = clinical research unit; ECG = electrocardiogram; EOS = 
end of study; FSH = follicle stimulating hormone; HRT = hormone replacement therapy; ID = identification; IVR = intravaginal ring; PK = pharmacokinetic; PR 
= pulse rate; RR = respiration rate; SAE = serious adverse events; temp = temperature. 
a. 
Subjects who elect to undergo washout of prior HRT will be asked to sign the informed consent prior to the start of that washout. Washout periods of 
8 weeks will require that Screening not commence until 28 days prior to Day 1. 
b. Randomization will occur after screening procedures are completed and eligibility is verified. 
c. 
Complete physical examination at Screening and Day 30 visit. Symptom-directed examination at all other visits for subjects exhibiting or reporting 
symptoms since their last visit. 
d. The purpose of the pelvic speculum exam is to identify vaginal irritation or abnormalities at baseline. 


Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-001 
Final Protocol 
 
CONFIDENTIAL 
Date: 06 March 2019 
Page 14 
e. 
Serology tests include HIV-1 and HIV-2 antibodies, hepatitis B surface antigen, and HCV antibodies 
f. 
Day 1 only at 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose 
g. Discharge on Day 2 following Day 1, 24-hour PK collection 
h. The purpose of the call is to follow up on any ongoing or emergent AEs since discharge from the CRU after the subject’s treatment has been completed 
(approximately 7 days after the last dose of study medication or removal of the IVR). 


Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-001 
Final Protocol 
 
CONFIDENTIAL 
Date: 06 March 2019 
Page 15 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AUC0-24 
area under the plasma concentration-time curve from time 0 to 24 hour; calculated using the 
linear/log trapezoid rule (oral dosing only) 
AUC D1-D30 
area under the plasma concentration-time curve from time 0 (Day 1) to the time of the last 
quantifiable concentration on Day 30; calculated using the linear/log trapezoid rule (IVR 
dosing only) 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
CFR 
Code of Federal Regulations 
Cavg 
time-weighted average observed plasma concentration over 24 hours (Day 29 PK profile for 
oral dosing only) 
Cmax 
maximum observed plasma concentration 
Css 
steady-state concentration (IVR dosing only) 
Ctau 
concentration at the end of the dosing interval (tau) (oral dosing only)  
conmed 
concomitant medication  
CRU 
clinical research unit 
CRO 
contract research organization 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
end-of-study 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
HPV 
human papillomavirus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ID 
identification 
IEC 
independent ethics committee 
IRB 
institutional review board 


Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-001 
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Abbreviation 
Definition 
IVR 
intravaginal ring 
LC/MS/MS 
liquid chromatography/tandem mass spectrometry 
MedDRA 
Medical Dictionary for Regulatory Activities 
OTC 
over-the-counter 
Pap 
Papanicolaou 
PK 
pharmacokinetic(s) 
PR 
pulse rate 
QD 
once daily 
RR 
respiration rate 
SAE 
serious adverse event 
SOP 
standard operating procedure 
SRM 
study reference manual 
SSP 
study-specific procedure 
t½, eff 
effective half-life; calculated using AUC0-24 on Days 1 and 29 (oral dosing only) 
tmax 
time at which the maximum plasma concentration was observed 
temp 
temperature 
ULN 
upper limit of normal 
VMS 
vasomotor symptoms 
VVA 
vulvovaginal atrophy 


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STUDY ADMINISTRATIVE STRUCTURE 
Sponsor: 
Daré Biosciences Inc. 
3655 Nobel Drive, Suite 260  
San Diego, CA 92122 
USA 
Tel: (+1) 858-926-7655 
 
Daré Bioscience Australia Pty LTD 
Level 19 HWT Tower, 40 City Road 
Southbank, VIC 3006 
AUSTRALIA 
Sponsor’s Chief Executive Officer: 
Sabrina Johnson, Daré Biosciences Inc. 
Medical Monitor: 
Jerome Gonzaga, MD, ICON Clinical 
Research, LLC 
Sponsor’s Contact: 
Nadene Zack 
Senior Director, Clinical Operations 
Investigator(s) and Clinical Research Unit(s): 
 
Clinical Research and Development Lead: 
Matthew Medlock, MD, ICON Clinical 
Research, LLC 
Clinical Laboratory(ies): 
 
Bioanalytical Laboratory: 
Agilex Biolabs Pty Ltd 
28 Dalgleish Street 
Thebarton 
SA 5031 
Pharmacokineticist: 
Brian Sadler, PhD, ICON Clinical Research, 
LLC 
Clinical Research Organization: 
ICON Clinical Research, LLC 
820 West Diamond Avenue, Suite 100 
Gaithersburg, MD 20878 
USA 


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ICON Clinical Research Pty Ltd 
Suite 201, Level 2 
2-4 Lyon Park Road 
North Ryde, NSW 2113 
Australia 


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2 
INTRODUCTION AND BACKGROUND 
2.1 
Introduction 
Menopause is defined by the Endocrine Society as the “clinical status after the final menstrual 
period, diagnosed retrospectively after cessation of menses for 12 months in a previously cycling 
woman and reflecting complete or nearly complete permanent cessation of ovarian function and 
fertility” (Stuenkel CA, et al., 2015), and occurs at a median age of 51 years in North America 
(American College of Obstetricians and Gynecologists, 2014). Vasomotor symptoms (VMS), 
including hot flushes and night sweats are the most frequently observed symptoms during 
menopause, although these are not experienced by all women. Additional symptoms may include 
vaginal symptoms such as dryness and dyspareunia, sleep disturbances, and arthralgia (Stuenkel 
CA, et al., 2015). 
The pathophysiology of genitourinary symptoms is caused by a reduction in estrogen levels. 
Lower levels of estrogen cause a thinning of the vaginal epithelium, the elasticity of the vagina is 
reduced, and there is an increase in connective tissue with eventual fibrotic change in some 
women. Decreased estrogen levels are also associated with a reduction in vaginal blood flow and 
in vaginal lubrication (Mac Bride MB, et al., 2010). These physiological changes lead to 
“vulvovaginal atrophy” (VVA) and are responsible for the range of symptoms observed in many 
menopausal women, including vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, 
vaginal pain associated with sexual activity, and vaginal bleeding associated with sexual activity. 
Hormone therapy (HT) is accepted as an effective treatment for the management of both VMS 
and symptomatic VVA, with both local and systemic treatments widely used. The use of 
estrogen for the treatment of symptoms of menopause is advocated by professional medical 
organizations (American College of Obstetricians and Gynecologists, 2014). 
Although estrogen is the most effective treatment for VMS, unopposed treatment (estrogen alone 
without progesterone) is associated with an increased risk of endometrial hyperplasia and 
carcinoma in women with an intact uterus, with a meta-analysis of 30 studies showing a relative 
risk of 2.3 (95% confidence interval [CI]: 2.1-2.5) among women using estrogen and those not 
using it (Grady D, et al., 1995). 
This risk is reduced by the addition of progestogens, with the incidence of endometrial cancer 
under combined treatment being no different from that in untreated women (Anderson GL, et al., 
2003). Furthermore, a Cochrane Review noted a greater effect on reducing hot flash severity 
following treatment with estrogen and progestogens than with estrogen alone (MacLennan AH, 
et al., 2004). 
DARE-HRT1 is an ethylene vinyl acetate (EVA) copolymer intravaginal ring (IVR) containing 
17β-estradiol and progesterone and is being developed for use in the treatment of menopause, 
with the following indications: 


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• Treatment of moderate-to-severe VMS associated with menopause in women with an 
intact uterus. 
• Reduction in the incidence of symptomatic VVA in women requiring treatment for 
VMS due to menopause. 
2.2 
Investigational Product Background 
The DARE-HRT1 IVR is being developed to release 17β-estradiol at an average rate of 80 µg or 
160 µg/day, and progesterone at an average rate of 4 mg or 8 mg/day, for a period of up to 
28 days, as long as the ring is present intravaginally. 
Estradiol and progesterone are the two major steroid reproductive hormones in females and are 
produced by the ovaries. Estradiol is approved for a range of indications, including the treatment 
of VMS of menopause, VVA, postmenopausal osteoporosis prevention, hypoestrogenism, and 
the palliative treatment of breast cancer and androgen-dependent carcinoma of the prostate. Dose 
formulations include oral tablets (10 µg to 2 mg), vaginal cream (0.01%), vaginal inserts 
(0.004 mg to 0.01 mg), transdermal film release (0.025 to 0.1 mg/24 hr), and transdermal spray 
(1.53 mg). Progesterone is also approved for a wide range of indications, including amenorrhea, 
HRT, and infertility as part of assisted reproductive technology treatment. Dose formulations 
include oral capsules (100 mg to 200 mg), vaginal gels (4% to 8%) and inserts (100 mg), and 
injections (50 mg/mL). 
2.3 
Summary of Findings to Date 
The IVR component of DARE-HRT1 is an EVA copolymer ring. Subject exposure to vinyl 
acetate (VA) monomer within the EVA is not expected given the nature of irreversible 
cross-linking of the monomers. The product’s specification for residual VA monomer (100 ppm) 
falls below the qualification limit as detailed in the International Council for Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidance 
Q3B(R2). The safety of the EVA copolymer has been established from nonclinical and clinical 
investigations described in the literature, and IVRs made from EVA have been widely approved 
for use as a vaginal insert for drug delivery, including approvals in the US, the EU, and 
Australia.  
The DARE-HRT1 IVR has been evaluated in a nonclinical study conducted in ovariectomized 
sheep to evaluate the pharmacokinetics (PK) of the 17β-estradiol and progesterone and the safety 
and tolerability of the ring. In this study, IVRs were placed in sheep on Day 1 and remained in 
place through Day 29. The IVRs were well retained over the 28-day period. Pharmacokinetic 
analysis showed sustained release of 17β-estradiol and progesterone over a 28-day period. 
Results of histological assessments of the vagina and cervix showed minimal to mild irritation 
consistent with the expected pharmacodynamic response and a foreign object placement. 
No clinical data are currently available for DARE-HRT1, which has yet to be evaluated in 
humans. A Phase 1 human factors study was conducted with 4 mm and 6 mm cross sectional 


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diameter placebo IVRs. These rings had the same EVA composition as the DARE-HRT1 IVR 
but did not include any active hormone components. In addition to evaluating subjects’ 
comprehension of the instructions for use, subjects were also evaluated on their ability to 
properly insert and remove the rings and were asked to report on the acceptability and 
tolerability of the IVR. The study demonstrated that the placebo IVRs were safe and well 
tolerated, in terms of reported adverse events (AEs) and physicians’ assessments and evaluation 
of the vaginal mucosa, vaginal sections, epithelial integrity, epithelial surface thickness, and 
vaginal color. The most frequently reported AE was vulvovaginal discomfort in 8 of 44 (18.2%) 
treated subjects. Subjects generally found the instructions provided for the IVR easy to 
understand, and 32 of 44 (73.7%) subjects were able to successfully insert and remove the IVR. 
The IVRs were reported to be comfortable by the majority of subjects, with most subjects 
reporting that the IVR was convenient to use and worked with their lifestyle. 
2.4 
Study Rationale 
Daré Biosciences Inc. is developing an intravaginal ring (IVR) to provide local administration of 
17β-estradiol and natural progesterone to treat VMS in women with an intact uterus, while 
aiming to reduce the likelihood of the development of genitourinary symptoms. Non-oral routes 
such as vaginal administration should bypass the first-pass hepatic effect, although this has not 
been demonstrated conclusively. Among the various vaginal dosing treatment modalities, 
evidence suggests a patient preference for the use of IVRs over cream or tablets, with an 
improvement in adherence to treatment (Suckling J, et al., 2006). With low-dose estradiol IVRs 
already approved in the United States for the treatment of VMS due to menopause, and vaginal 
progesterone products also on the market, coadministration of the two hormones together in the 
same IVR is an attractive patient convenience proposition for the treatment of VMS and 
urogenital symptoms of menopause. 
2.4.1 
Dose Rationale 
Estradiol and progesterone have been administered via IVR in previous studies (Hamada et al, 
2003) however, the DARE-HRT1 17β-estradiol and progesterone IVR has not yet been tested in 
human subjects.  
Estradiol – Pharmacokinetics of Vaginal Route 
In a randomized clinical study with a novel vaginal capsule containing solubilised 17β-estradiol, 
the bioavailability and PK of the vaginal capsule in healthy postmenopausal women were 
compared to those of an approved vaginal estradiol tablet (Vagifem®) (Pickar JH, et al., 2016). A 
crossover design was used, with subjects randomized to receive single doses of novel capsule 
then the Vagifem tablet, or the Vagifem tablet followed by the novel capsule. Treatments were 
administered by an investigator. Blood samples were collected at intervals over 24 hours after 
treatment. Two separate studies investigated 10 µg and 25 µg doses. 


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Mean values of PK parameters observed for both estradiol doses following single administration 
of the two treatments are provided in Table 2.1. The Cmax values for estradiol differed 
significantly between the two different formulations, with greater Cmax values observed with the 
Vagifem tablets than the novel capsule. Similarly, AUC0-24 values were greater with the Vagifem 
tablet. This study also showed that the time to reach the highest observed (peak) concentration in 
plasma following administration (tmax) for vaginally administered estradiol is greatly dependent 
on the formulation. 
Table 2.1 
Mean Pharmacokinetic Values for Estradiol 
Dose 
(µg) 
AUC0-24 (pg•h/mL) 
Cmax (pg/mL) 
tmax (h) 
Test 
Vagifem® 
p 
Test 
Vagifem® 
p 
Test 
Vagifem® 
10 
49.62 
132.92 
<0.0001 
14.38 
20.38 
0.0194 
1.75 
9.28 
25 
89.21 
292.1 
<0.0001 
23.08 
42.70 
<0.0001 
1.85 
11.18 
p-values indicate statistical significance at <0.05 between the test products and the Vagifem products. 
Source: Pickar JH, et al., 2016 
Prescribing information for the FDA-approved IVR Femring reports PK data for estradiol 
(FEMRING Package Insert, 2018). Femring is a cured silicone elastomer IVR that releases 
estradiol acetate at two strengths: 0.05 mg/day and 0.10 mg/day, for 3 months. With the 
0.05 mg/day IVR, the reported Cmax was 1129 pg/mL, Cavg was 40.6 pg/mL, and the tmax was 
0.9 hours. With the 0.10 mg/day IVR, the reported Cmax was 1665 pg/mL, Cavg was 76.0 pg/mL, 
and the tmax was 0.7 hours. 
Since the DARE-HRT1 IVR comprises an EVA polymer compared to Femring’s silicone 
elastomer, predictions of PK that might be expected with the DARE-HRT1 based on the Femring 
data should be considered cautiously. Furthermore, the doses of estradiol in the Femring (50 and 
100 μg/day) are not the same as those in the DARE-HRT1 IVR (80 and 160 μg/day). However, 
the estradiol PK results from DARE-HRT1 are expected within the same order of magnitude as 
those reported for Femring. 
Progesterone – Pharmacokinetics of Vaginal Route 
In a study comparing the PK of progesterone from a vaginal progesterone gel (Crinone 8%, 
90 mg) with that of orally administered progesterone (Prometrium 100 mg), 12 healthy 
postmenopausal women were randomized in a 1:1 fashion to receive a single dose of the 
allocated progesterone treatment. The vaginally-administered progesterone had greater 
bioavailability than the oral progesterone in terms of AUC0-24 (1.48 ng•h/mL per mg versus 
0.035 ng•h/mL per mg), with a correspondingly greater Cmax (10.51 ng/mL versus 2.20 ng/mL). 
However, tmax was observed earlier with oral progesterone (1.00 hours) than with the vaginal gel 
(7.67 hours) (Levine H, et al., 2000). 
The PK of vaginally administered progesterone has also been compared to that of intramuscular 
progesterone administration (Miles RA, et al., 1994) in a study with functionally agonadal 
women aged 25 to 54 years. Subjects were randomized to receive a cycle of estrogen and 


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progesterone replacement, comprising oral ethinyl estradiol with either vaginally administered 
micronized progesterone capsules (200 mg every 6 hours) or intramuscular progesterone (50 mg 
twice daily) from Day 15 of the cycle. For the PK assessments, samples were collected for 
6 hours after the first progesterone dose, with samples for steady-state PK collected on Day 21. 
Single-dose exposure was significantly greater with the intramuscular treatment (Cmax 
16.06 ng/mL) than with the vaginal capsule (Cmax 6.64 ng/mL), with a similar difference 
observed in steady-state concentrations (69.80 versus 11.90 ng/mL). Serum concentrations 
increased more rapidly with the intramuscular treatment than with the vaginal treatment. As 
expected, evaluation of progesterone levels in endometrial samples collected on Day 21 showed 
higher progesterone concentrations with vaginal treatment (11.50 ng/mL) than with 
intramuscular treatment (1.40 ng/mL). 
An alternative vaginal progesterone formulation, using an effervescent delivery system rather 
than micronized progesterone capsules, showed similar results. Treatment with the effervescent 
delivery system was able to produce greater endometrial progesterone concentrations than the 
intramuscular treatment, while measured systemic exposure was lower (Paulson RJ, et al., 2014). 
Another study compared progesterone PK following vaginal administration of two different 
formulations, both of which contained 100 mg progesterone. Single administrations of vaginal 
tablets (Endometrin®) and vaginal capsules (Utrogestan®) in postmenopausal women showed 
largely similar results for the two formulations. The AUC was 379.99 nmol/h/L with the tablet 
and 325.89 nmol/h/L with the capsule. A significant difference was observed for Cmax of the 
two formulations, with values of 31.53 nmol/L reported for the tablet and 23.85 nmol/L for the 
capsule. The authors also reported an increase in systemic progesterone levels when subjects 
were “primed” with estrogen (3 mg/day ethinyl estradiol for 2 weeks) before receiving the 
progesterone treatment (Levy T, et al., 2000). 
It is not clear how the PK of progesterone from the treatment modalities described here will 
compare with PK of progesterone released from the EVA ring of DARE-HRT1. It is clear 
though, that administration via the vaginal route should avoid a first-pass effect of liver 
metabolism, (Levy T, et al., 2000), which is supported by the comparison of the oral and vaginal 
routes described by Levine H, et al (2000). 
2.4.2 
Study Design Rationale 
A parallel group study of DARE-HRT1 in healthy postmenopausal women is an appropriate 
design to assess PK and safety. 
2.5 
Hypotheses 
No formal hypotheses will be tested. 


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3 
OBJECTIVES 
3.1 
Primary Objective 
• To describe the PK parameters over 28 days of two different dose combinations of 
DARE-HRT1 intravaginal ring (IVR): 
o Estradiol 80 μg/progesterone 4 mg/day IVR 
o Estradiol 160 μg/progesterone 8 mg/day IVR 
3.2 
Secondary Objectives 
• To assess the safety and tolerability of DARE-HRT1  
• To compare the systemic exposure of estradiol, estrone, and progesterone over 28 days after 
administration of DARE-HRT1 IVR and once daily oral Estrace®/Prometrium® 
3.3 
Exploratory Objective 
• To assess usability and subject tolerability of the DARE-HRT1 IVR 


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4 
STUDY DESIGN 
4.1 
Study Design and Overview 
This is a randomized, open-label, 3-arm, parallel group study in approximately 30 healthy 
postmenopausal women with intact uteri.  
This study is designed to assess the PK of estradiol, estrone, and progesterone from 
DARE-HRT1 intravaginal rings at two dose strengths. Oral estradiol 1 mg/progesterone 100 mg 
once-daily for 28 days will serve as an active reference.  
Three treatment groups will be assessed in this study as shown in Table 4.1. 
Table 4.1 
Treatment Allocations 
Treatment Group and 
Number of Subjects 
Treatment 
IVR Dose 1 
(n=10) 
28-day intravaginal ring 80/4 (estradiol 80 μg/day + progesterone 4 mg/day) 
IVR Dose 2 
(n=10) 
28-day intravaginal ring 160/8 (estradiol 160 μg/day + progesterone 8 mg/day) 
Oral Reference 
(n=10) 
Oral Estrace/Prometrium QD for 29 days (estradiol 1 mg/progesterone 100 mg oral 
capsule) 
Subjects who have been on prior hormone replacement therapy (HRT) therapy will be required 
to have the following washout period prior to randomization (for subjects actively using HRT, 
washout may begin after their informed consent): 
• 4 weeks or longer for prior transdermal estrogen alone or estrogen/progestogen products  
• 8 weeks or longer for prior oral estrogen, oral estrogen/progestogen, or intrauterine 
progestogen therapy 
• 3 months or longer for prior progestogen implants and estrogen alone injectable drug therapy 
• 6 months or longer for prior estrogen pellet therapy or progestogen injectable drug therapy 
Due to study enrollment goals and the length of the required washout period outlined above, 
patients who are currently on either injectable or pellet therapy at the time of presentation for 
screening consideration will not be enrolled. 
Washout periods of 8 weeks will require that Screening not commence until 28 days prior to 
Day 1. 
Upon completion of their screening procedures and confirmation of their eligibility (including an 
endometrial biopsy, cervical screening test [if needed], and transvaginal ultrasound), eligible 
subjects will be admitted to the clinical research unit (CRU) on Day -1. Randomization will 


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occur prior to initiation of treatment. Subjects will be randomized in a 1:1:1 ratio to the treatment 
groups. 
Day 1 is defined as the first day of treatment, i.e., the day the IVR is self-inserted by the subject. 
The same IVR is to remain intravaginal for 28 days, with removal of IVR in the CRU on the 
morning of Day 29. For those randomized to the oral arm (Estrace/Prometrium), dosing will also 
begin on Day 1, concluding with a last dose on Day 29. Subjects in the oral arm will be directed 
to self-administer the medication in the morning with a meal and approximately 240 mL of 
water, starting on Day 2 through Day 27. Doses will be administered in the CRU each of the 
mornings of Day 1 and Days 28 and 29 with a moderate-fat breakfast.  
Safety and tolerability assessments will include monitoring of adverse events and concomitant 
medications, clinical laboratory findings, physical examinations, vital signs, pelvic examinations, 
completion of a Usability and Tolerability questionnaire, and vaginal pH and cytology. Refer to 
the Schedule of Assessments for each treatment arm in Table 1.1 and Table 1.2 for specific 
details. 
IVR Treatment Groups: 
• A single predose blood draw for estradiol, estrone, and progesterone will be obtained at 
screening and Day -1, and -1, -0.5, and 0 (immediately prior to insertion of IVR + 5 min) 
hours on Day 1. Plasma samples for estradiol, estrone, and progesterone will then be 
obtained at 0.5, 1, 2, 4, 8, 12, 24, and 48 hours following administration/insertion. Subjects 
will then be discharged from the CRU after safety assessments have been completed on 
Day 3.  
• Subjects will return on the morning of Days 8, 11, 15, and 22 for a single blood draw as well 
as safety assessments.  
• Subjects will return to the CRU on Day 28 for a PK blood draw, safety assessments, 
confirmation of IVR placement, and to begin confinement. On the morning of Day 29 a PK 
blood sample will be collected. The IVR will then be removed and PK samples will be 
collected 0.5, 1, 2, 4, 8, 12, and 24 hours post-removal. 
Additional details of sampling and safety assessment procedures are presented in the Schedule of 
Assessments and Procedures - IVR Treatment Arm in Table 1.1. 
Oral Treatment Group: 
• A single predose blood draw for estradiol, estrone, and progesterone will be obtained at 
screening and Day -1, and -1.0, -0.5, and 0.0 hours immediately prior to and at 0.25, 0.5, 1, 2, 
4, 6, 8, 10, 12, and 24 hours after the first dose on Day 1. Following the 24-hour PK, subjects 
will be discharged and instructed to self-administer oral estradiol and progesterone 
treatments each morning, with food and approximately 240 mL of water, at approximately 
the same time.  


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• Subjects will return on Days 8, 15, and 22 for a single blood draw as well as safety 
assessments.  
• Subjects will return to the clinic and be admitted on Day 28 to consume their oral dose with 
breakfast. A PK sample will be collected just prior to the last oral dose on the morning of 
Day 29, with additional PK sampling performed at 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 
hours postdose.  
Additional details of sampling and safety assessment procedures are presented in the Schedule of 
Assessments and Procedures - Oral Treatment Arm in Table 1.2. 
4.1.1 
Duration of Study 
Subject participation is expected to last up to 65 days, including a 28-day screening period, a 30-
day on-study period (consisting of a 29-day treatment period and additional sample collections), 
and the follow-up phone call 7 days after the last dose of the investigational product [IP]). 
4.1.2 
Definition of Study Completion 
End-of-study procedures will be performed as specified in the schedule of assessments (Table 
1.1 and Table 1.2). Subjects who terminate from the study early will have EOS procedures 
performed at the time of discontinuation. Subjects with ongoing significant clinical or laboratory 
findings will be followed until the finding is resolved or medically stable. All reasonable 
attempts will be made to follow-up with subjects. The subject’s participation in the study will 
end once all study assessments and follow-up have been completed. 
4.1.3 
End of Study 
The end of the study is defined as the date when the last subject has completed all study 
procedures up to and including the EOS/early termination visit as specified in the schedule of 
assessments (Table 1.1 and Table 1.2). 


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5 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Subjects must meet all the following criteria in order to be enrolled in the study. 
5.1 
Inclusion Criteria 
Subjects must meet all inclusion criteria to be eligible for study participation. 
1. Postmenopausal women with a body mass index (BMI) ≥ 18 and ≤ 38 kg/m2. 
BMI = weight (kg)/(height [m])2 
Postmenopausal is defined as 12-months of spontaneous amenorrhea or 6 months of 
spontaneous amenorrhea with serum FSH levels > 40 mIU/mL or 6 weeks postsurgical 
bilateral oophorectomy with or without hysterectomy (although subjects who have had a 
hysterectomy are not eligible for this study).  
2. Normal cervix and vagina based on pelvic examination with speculum 
3. An intact uterus 
4. An acceptable result from an evaluable screening endometrial biopsy, evaluated by a 
pathologist. Tissue must be read as benign, inactive, or atrophic endometrium by at least one 
pathologist. If no tissue is obtained from the biopsy, the subject will be excluded. 
5. Current on all Australian screening requirements for cervical cancer  
6. Able and willing to correctly and independently complete all study procedures 
7. Able to read, understand, and provide written informed consent after the nature of the study 
has been fully explained and must be willing to comply with all study requirements and 
procedures 
8. Normal mammogram report within 24 months of screening 
5.2 
Exclusion Criteria 
Subjects will not be eligible for study participation if they meet any of the exclusion criteria, or 
will be discontinued at the discretion of the investigator in consultation with the medical monitor 
if they develop any of the exclusion criteria during the study. 
1. Prior abnormal cervical screening test (CST) or Pap result within 2 years of screening. 
Subject can have atypical squamous cells of undetermined significance (ASCUS), if HPV 
negative. 
2. Subjects with any self-reported active sexually transmitted disease and/or evidence of 
infection based on visual vaginal exam by the investigator 
3. Subjects with a UTI during screening as assessed by urine dipstick test with abnormal test 
findings (any positive result for leukocytes AND any positive result for nitrites)  
4. Subjects with > 4 mm endometrium lining at screening (on the transvaginal ultrasound) 


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5. Have a history of endometrial hyperplasia or cervical or uterine carcinoma 
6. Subjects with indwelling catheters or requiring intermittent catheterization 
7. Subjects with multiple or unsuccessful (e.g., still having symptoms) pelvic reconstructive 
surgery, or suffers from pelvic relaxation 
8. Subjects who have had a hysterectomy 
9. Subjects taking any estrogen and/or progesterone products (see Section 4.1 for washout 
requirements) 
10. Subjects with concomitant use of personal lubricants (water-based lubricants are allowed) or 
any intravaginal product or medication, either by prescription or over-the-counter (e.g., 
Femring [estradiol acetate vaginal ring], ESTRING® [estradiol vaginal ring]) with the 
exception of those who agree not to use these products during the IVR use period  
11. Self-reported or observed vaginal irritation; vaginal, vulvar, or cervical lesions, undiagnosed 
vaginal bleeding; or tenderness  
12. Subjects with a finding of clinically significant uterine fibroids at screening 
13. Subjects with a known hypersensitivity to progesterone, estradiol, Femring, or the 
components of the IVR (e.g., ethylene vinyl acetate)  
14. Subjects with known hypersensitivity to peanuts (Prometrium capsules contain peanut oil)  
15. Subjects with prior pelvic malignancies 
16. Subjects with a history of any severe acute or chronic medical or psychiatric condition or 
laboratory abnormality that could increase the risk associated with trial participation or study 
treatment administration or could interfere with the interpretation of trial results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into the trial. 
This includes but is not limited to the following:  
a. Human immunodeficiency virus (HIV) infection (confirmed by medical history/ 
serology testing)  
b. Active chronic hepatitis B or hepatitis C infection including hepatitis B surface 
antigen and hepatitis C antigen positive subjects with or without abnormal liver 
enzymes (confirmed by medical history/serology testing) 
c. Concurrent neurodegenerative disease  
d. Cardiovascular: uncontrolled hypertension, unstable angina, myocardial infarction 
or symptomatic congestive heart failure within the past 6 months, serious 
uncontrolled cardiac arrhythmia, use of Class 1 antiarrhythmic medications, or 
history of venous thromboembolism or stroke  
e. Dementia or significantly altered mental status that would prohibit the 
understanding or rendering of informed consent and compliance with the 
requirements of the protocol  
f. History of gallbladder disease unless gallbladder removed 


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g. Symptomatic bacterial vaginosis  
17. Have fasting triglyceride of > 300 mg/dL and/or total cholesterol of > 300 mg/dL  
18. AST or ALT > 1.5 times the upper limit of normal  
19. Fasting glucose > 125 mg/dL  
20. Evidence of current alcohol or drug abuse in the past 60 days including a positive result from 
the urine drugs of abuse or alcohol screen, or history of drug or alcohol dependence in the 
last two years, as assessed by principal investigator. Alcohol abuse is defined as greater than 
14 standard units/week for females and drug abuse is defined as known psychiatric or 
substance abuse disorder that would interfere with participation with the requirements of this 
study, including current use of any illicit drugs. 
21. Participation in any other investigational drug or device trial in which administration of an 
investigational study drug/device occurred within 30 days or placement of a non-drug eluting 
medical device within 15 days prior to screening.  
5.3 
Subject Re-enrollment 
Subjects who screen fail from the study prior to randomization and study drug administration 
may be re-screened and re-enrolled as long as the subject was not screen failed due to 
noncompliance with the protocol (i.e., positive urine drugs of abuse screen, etc.). The Medical 
Monitor must be consulted prior to re-screening any subject. If the subject is re-screened, the 
subject must be re-consented and the same subject number must be used. 
Screen failure data (date of consent, demographics, reason for screen failure, and adverse events, 
if applicable) will be recorded in the eCRF. 
5.4 
Subject Withdrawal 
Subjects are free to discontinue the study at any time, for any reason, and without prejudice to 
further treatment. The investigator may remove a subject if, in the investigator’s judgment, 
continued participation would pose unacceptable risk to the subject or to the integrity of the 
study data. All procedures for early termination must be completed. Reasons for removal or 
withdrawal may include: 
• Withdrawal of consent 
• Administrative decision by the investigator or sponsor 
• Ineligibility 
• Significant protocol deviation 
• Subject noncompliance 
• Safety concern by the investigator or sponsor 


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• Lost to follow-up 
Subjects who are withdrawn prior to completing all study visits may be replaced. 
In the event of a subject’s withdrawal, the investigator will promptly notify the sponsor and 
medical monitor and will make every effort to complete the EOS assessments. All withdrawn 
subjects with ongoing clinically significant clinical or laboratory findings will be followed until 
the finding is resolved or medically stable; reasonable attempts will be made to follow-up with 
subjects. 
5.5 
Early Termination of Study 
The study may be terminated at any time by the sponsor if serious side effects occur, if potential 
risks to study participants are identified, if the investigator does not adhere to the protocol, or if, 
in the sponsor’s judgment, there are no further benefits to be achieved from the study. In the 
event that the clinical development of the study drug is discontinued, the sponsor shall inform all 
investigators/institutions and regulatory authorities. 


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6 
TREATMENT OF SUBJECTS 
6.1 
Identity of Study Drugs 
A description of the study drugs is presented in Table 6.1. 
Table 6.1 
Study Drugs 
Treatment Group and 
Number of Subjects 
Treatment 
IVR Dose 1 
(n=10) 
28-day IVR 80/4 (estradiol 80 μg/day + progesterone 4 mg/day) 
IVR Dose 2 
(n=10) 
28-day IVR160/8 (estradiol 160 μg/day + progesterone 8 mg/day) 
Oral Reference 
(n=10) 
Oral Estrace/Prometrium QD for 29 days (Estradiol 1 mg/progesterone 100 mg oral 
capsule) 
DARE-HRT1 IVRs will be sourced by Daré Bioscience Australia Pty LTD; oral 
Estrace/Prometrium will be sourced by the CRU. 
6.2 
Treatments Administered 
Each subject will receive either an IVR or daily oral capsule for 28 days.  
The IVR is self-inserted by the subject and is to remain intravaginal for 28 days, with removal of 
IVR in the CRU on the morning of Day 29. If a subject cannot self-insert the IVR, the site 
physician will insert the IVR. 
Those enrolled in the oral arm (Estrace/Prometrium) will also begin dosing on Day 1, with a last 
dose on Day 29. Subjects enrolled in the oral arm will be directed to self-administer the 
medication in the morning with a meal and approximately 240 mL of water, starting on Day 2 
through Day 27. Doses will be administered in the CRU each of the mornings of Days 1, 28, and 
29 with a moderate-fat breakfast. 
6.3 
Method of Assigning Subjects to Treatment Groups 
ICON will prepare the randomization scheme in accordance with its SOPs and the randomization 
plan, which reflect GCP standards. Refer to Section 9.3 for a description of randomization 
methods. Eligible subjects will be assigned to a treatment group according to the list of subject 
randomization assignments. 
6.4 
Measurements of Treatment Compliance 
Treatment compliance of study drug administered by IVR will be confirmed by PK evaluation 
and subject daily diary. Treatment compliance of study drug administered by oral capsule will be 
confirmed during periods of subject confinement to the CRU, and Day 1, as IP will be 
administered by licensed healthcare professionals. Treatment compliance while oral capsule IP is 
self-administered will be confirmed by subject daily diary. Details regarding dosing, including 
the dose administered and the date and time of dosing, will be recorded. Additionally, meal 


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compliance will be confirmed during periods of subject confinement to the CRU (% of meal 
completed, etc. will be recorded). 
6.5 
Investigational Product Storage, Accountability, and Retention 
6.5.1 
Storage Conditions 
The IP is to be stored at refrigerated temperature (2°C to 8°C). The product does not need 
protection from light. Additional information can be found in the Investigator’s Brochure.  
The investigator will ensure that all the study drugs are stored and dispensed in accordance with 
local regulations concerning the storage and administration of investigational drugs. 
6.5.2 
Drug Accountability and Retention 
The investigator must ensure that all study drug supplies are kept in a secure locked area with 
access limited to those authorized by the investigator. The investigator must maintain accurate 
records of the receipt of all study drug shipped by Daré Bioscience Australia Pty LTD or their 
representative, including but not limited to the date received, lot number, expiration date, amount 
received, and the disposition of all study drug. Current dispensing records will also be 
maintained including the date and amount of study drug dispensed and the subject receiving the 
drug. All remaining study drug not required by regulations to be held by the CRU must be 
returned to Daré Bioscience Australia Pty LTD or their representative immediately after the 
study is completed. 
It is the responsibility of Daré Bioscience Australia Pty LTD to ship a sufficient number of 
dosage units to allow the CRU to maintain an appropriate sampling on-site as per applicable 
regulatory requirements. Each reserve sample shall consist of a sufficient quantity to permit the 
local regulatory agency to perform 5 times all of the release tests required in the application or 
supplemental application. 
6.6 
Packaging and Labeling 
6.6.1 
Investigational Product 
Details regarding IP packaging, labeling, and use instructions will be provided in the study 
reference manual. 
6.6.2 
Blinding of Treatment Assignment 
Not applicable. This is an open-label study. 
6.7 
Concomitant Medications and Procedures and Other Restrictions 
6.7.1 
Concomitant Medications and Procedures 
No concomitant medications and personal lubricants (water-based lubricants are allowed) or any 
intravaginal product or medications (prescription, OTC, and herbal), with the exception of 
paracetamol 650 mg/day (not to exceed 2000 mg total in the 7 days prior to administration of the 
study drugs), or vaccinations may be administered during the study unless they are prescribed by 


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the investigator for treatment of specific clinical events. No concomitant procedures will be 
performed during the study unless approved by the investigator. All medications (prescription 
and OTC), vitamin and mineral supplements, and herbs taken during the study will be 
documented on the concomitant medication eCRF. Information recorded will include: start and 
stop dates and times, dose and route of administration, and indication. Medications taken for a 
procedure will also be included, as well as the procedure itself. 
6.7.2 
Other Restrictions 
Subjects will be instructed to adhere to the following restrictions: 
• Strenuous activity (as assessed by the investigator) is prohibited from 48 hours prior to 
admission until final discharge from the CRU. 
• Subjects are not permitted to consume alcohol for 3 days prior to admission to the CRU and 
should refrain from consumption of alcohol until EOS. 
• Subjects are not permitted to consume any food and drink from outside of the CRU while 
residing at the CRU. 
• Subjects must comply with the CRU smoking policy, if applicable. 
• Subjects are not permitted to participate in any other clinical trial or donate blood or plasma 
while participating in this clinical trial. 


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7 
STUDY ASSESSMENTS AND PROCEDURES 
Subjects will undergo study procedures and assessments at time points specified in the schedule 
of assessments (Table 1.1 and Table 1.2). 
7.1 
Medical and Surgical History 
The investigator or designee will collect a complete medical and surgical history at screening. 
Medical and surgical history will be collected at CRU admission to determine if any changes 
have occurred since screening. 
7.2 
Demographic Characteristics 
Demographic characteristics including sex, age, race, and ethnicity will be recorded. 
7.3 
Physical Measurements 
Height (cm) and body weight (kg) without shoes will be recorded.  
7.4 
Pharmacokinetic Assessments 
7.4.1 
Drug Concentration Measurements 
Plasma PK samples will be collected at time points specified in the PK sampling schedule within 
the schedule of assessments (Table 1.1 and Table 1.2). Blood sample collection, processing, and 
shipping details will be outlined in a separate SRM. 
Plasma concentrations of estradiol, estrone, and progesterone will be determined at using a 
validated method.  
7.4.2 
Pharmacokinetic Parameters 
Pharmacokinetic variables will be calculated from the plasma concentration data using 
noncompartmental methods (Phoenix™ WinNonlin®, Version 6.4 or later; Certara LP, Princeton, 
New Jersey, USA) and actual sampling times. 
The following PK parameters will be determined: 
Cavg 
Time-weighted average observed plasma concentration over 24 hours (Day 29 
PK profile for oral dosing only) 
Css 
Steady-state concentration (IVR dosing only) 
Cmax 
Maximum observed plasma concentration 
Ctau 
Concentration at the end of the dosing interval (tau) (oral dosing only)  
tmax 
The time that Cmax was observed 


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AUC0-24 
Area under the plasma concentration-time curve from time 0 to 24 hours; 
calculated using the linear/log trapezoid rule (oral dosing only)  
AUCD1-D30 
Area under the plasma concentration-time curve from time 0 (Day 1) to the 
time of the last quantifiable concentration on Day 30; calculated using the 
linear/log trapezoid rule (IVR dosing only) 
t½,eff 
Effective half-life; calculated using AUC0-24 on Days 1 and 29 (oral dosing 
only) 
Baseline correction, using the average of the three predose concentrations on Day 1, may be 
performed prior to the calculation of PK parameters by noncompartmental methods. Cmax (and 
tmax) will be computed over each 24-hour PK profile (Days 1 and 29) and, for IVR 
administration, over the entire 28-day treatment interval. Additional PK parameters may be 
calculated as appropriate. 
7.5 
Safety Assessments 
7.5.1 
Adverse Events 
Subjects will be monitored for AEs from administration of the first dose (insertion of IVR or first 
oral dose, as applicable) of study drug through the follow-up phone call. Refer to Section 8 for 
additional details. 
7.5.2 
Laboratory Tests 
A certified laboratory will be utilized to process and provide results for the clinical laboratory 
tests listed in Table 7.1. The baseline laboratory test results for clinical assessment for a 
particular test will be defined as the last measurement prior to the first dose of study drug. 
Subjects will fast a minimum of 8 hours prior to clinical laboratory sample collection at 
screening.  
During screening, if a subject has an out-of-range value for a clinical laboratory parameter that 
the investigator believes is not clinically significant or the investigator does not believe is correct 
(e.g., lab or specimen processing error), but the investigator wants to confirm with a repeat 
laboratory test, a single repeat is allowed to confirm the initial result. 
Additional safety laboratory tests may be conducted as needed by the investigator to evaluate 
subject safety. 


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Table 7.1 
Clinical Laboratory Tests 
Hematology 
Chemistry 
Urine Dipstick 
Hematocrit 
Hemoglobin 
Red blood cell count 
White blood cell count 
Neutrophils (absolute) 
Lymphocytes (absolute) 
Monocytes (absolute) 
Basophils (absolute) 
Eosinophils (absolute) 
Platelet count (estimate not 
acceptable) 
 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Gamma glutamyl transferase 
Direct bilirubin 
Total bilirubin 
Lactate dehydrogenase 
Total protein 
Blood urea nitrogen 
Creatinine 
Calcium 
Phosphate 
Sodium 
Potassium 
Carbon dioxide 
Chloride 
Glucose a 
Total cholesterol 
Triglycerides a 
Specific gravity 
Ketones 
pH 
Protein 
Blood 
Glucose 
Leukocyte esterase 
Microscopic analysis (performed if 
blood, leukocytes, or protein are 
present) 
a. 
Fasting 
For any laboratory test value outside the reference range that the investigator considers clinically 
significant during the on-study period (i.e., following dose administration), the investigator will: 
• Repeat the test to verify the out-of-range value and clinical significance. 
• Follow the out-of-range value until the value returns to normal or baseline, or until the value 
is deemed stable and not clinically significant by the investigator. 
• Record as an AE any laboratory test value that is confirmed by repeat and the investigator 
considers clinically significant, requires a subject to be discontinued from the study, requires 
a subject to receive treatment, or requires a change or discontinuation of the study drug (if 
applicable). 


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7.5.3 
Other Tests 
The following tests will be performed: 
• Urine drugs of abuse (at a minimum, cocaine, tetrahydrocannabinol, amphetamines, opiates, 
and phencyclidine), and alcohol screens 
− During the screening period, urine drugs of abuse, and alcohol screens may not be 
repeated for eligibility 
• Serology tests (i.e., HIV-1 and HIV-2 antibodies, hepatitis B surface antigen, and HCV 
antibody, and any confirmatory tests performed at the discretion of the investigator) 
• FSH (screening only; as needed to confirm postmenopausal status) 
• Transvaginal ultrasound 
• Cervical screening test (if needed) 
• Pelvic examination with speculum and vaginal visual examination 
• Vaginal cytology and pH 
• Endometrial biopsy 
7.5.4 
Usability and Tolerability Questionnaire 
A Usability and Tolerability questionnaire will be administered to all IVR subjects at the end of 
the study. 
7.5.5 
Vital Signs 
Vital signs assessments will include oral temperature (C°), respiratory rate (breaths per minute), 
systolic and diastolic blood pressure (mmHg) and pulse rate (bpm). Blood pressure and pulse 
rate will be measured after the subject has been resting quietly in a supine position or in the most 
recumbent position possible for at least 5 minutes. Any clinically significant abnormal vital sign 
assessment requires at least one repeat measurement. 
Vital signs abnormalities that are considered clinically significant initially and on confirmation, 
require a subject to be discontinued from the study, require a subject to receive treatment, or 
require a change or discontinuation from the study drug (if applicable) will be recorded as AEs. 
7.5.6 
Physical Examination 
Comprehensive physical examinations (excluding rectal and breast examinations [unless 
indicated]) will be performed, and abnormal findings will be documented in the subject’s eCRF. 
Pelvic speculum and visual examinations will be conducted to identify vaginal irritation or 
abnormalities at baseline (screening) and for IVR treatment arm subjects on Day 30.  


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An abnormal physical examination finding that is considered clinically significant and requires 
the subject to be discontinued from the study, requires the subject to receive treatment, or 
requires a change or discontinuation of the study drug (if applicable) will be recorded as an AE. 
7.5.7 
Electrocardiograms 
Electrocardiogram assessments will be conducted at screening and Day -1 only for subject 
inclusion/exclusion purposes. 
7.5.8 
Appropriateness of Safety Assessments 
Safety evaluations selected for this study are typical of those for this subject population and 
utilize widely accepted measures. 


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8 
ADVERSE EVENTS 
An AE is defined as any untoward medical occurrence in a subject administered a 
pharmaceutical product during the course of a clinical investigation. An AE can therefore be any 
unfavorable and unintended sign, symptom, or disease temporally associated with the use of a 
study drug, whether or not thought to be related to the study drug. 
Subjects will be monitored throughout the study for AEs, from IVR placement or first oral dose, 
as applicable, through the follow-up phone call. Adverse events that are identified at the last 
assessment visit (or the early termination visit) as specified in the protocol must be recorded on 
the AE eCRF with the status of the AE noted. All events that are ongoing at this time will be 
recorded as ongoing on the eCRF. All (both serious and nonserious) AEs must be followed until 
they are resolved or stabilized, or until reasonable attempts to determine resolution of the event 
are exhausted. The investigator should use his/her discretion in ordering additional tests as 
necessary to monitor the resolution of such events. 
The procedures specified in Section 8.4 are to be followed for reporting SAEs. 
8.1 
Recording Adverse Events 
Adverse events are to be recorded on the AE page of the eCRF. The following information will 
be recorded:  
• Assessment of whether or not the AE is an SAE (Section 8.2.1) 
• Assessment of AE intensity (Section 8.2.2) 
• Assessment of AE relationship to study drug (Section 8.2.3) 
• Action taken - categorized as dose increased, dose not changed, drug interrupted, drug 
withdrawn, not applicable, or unknown, as applicable 
• Outcome - recorded as fatal, not recovered/not resolved, recovered/resolved, 
recovered/resolved with sequelae, recovering/resolving, or unknown, as applicable 
8.2 
Assessment of Adverse Events 
The investigator will assess each AE for seriousness, intensity, and relationship to study drug. 


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8.2.1 
Serious Adverse Events 
The investigator is responsible for determining whether an AE meets the definition of an SAE. 
An SAE is any AE occurring from ICF signing through the follow-up phone call that results in 
any of the following outcomes: 
• Death 
• A life-threatening adverse drug experience 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 
• An important medical event* 
*Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment. 
They may jeopardize the subject and may require medical or surgical intervention to prevent any 
of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
Note: SAEs require immediate reporting to the sponsor and medical monitor. Refer to 
Section 8.4 for details. 
8.2.2 
Intensity 
The intensity of an AE will be graded according to the following definitions: 
• Grade 1: Mild; the subject experiences awareness of signs or symptoms but these are easily 
tolerated or managed without specific treatment. 
• Grade 2: Moderate; the subject experiences discomfort enough to cause interference with 
usual activity, and/or the condition requires specific treatment. 
• Grade 3: Severe; the subject is incapacitated with inability to work or do usual activity, 
and/or the event requires significant treatment measures. 
• Grade 4: Disabling or with life threatening consequences, urgent intervention indicated 
• Grade 5: Death 


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8.2.3 
Relationship to Study Drug 
The relationship of an AE to the study drug should be determined by the investigator according 
to the following criteria: 
• Not related: The event is most likely produced by other factors such as the subject’s clinical 
condition, intercurrent illness, or concomitant drugs, and does not follow a known response 
pattern to the study drug, or the temporal relationship of the event to study drug 
administration makes a causal relationship unlikely 
• Unlikely related: The event is most likely produced by other factors such as the subject’s 
clinical condition, therapeutic interventions, or concomitant drugs administered to the subject 
and it does not follow a known response pattern to the study drug 
• Possibly related: The event follows a reasonable temporal sequence from the time of drug 
administration, and/or follows a known response pattern to the study drug, but could have 
been produced by other factors such as the subject's clinical condition, intercurrent illness, or 
concomitant drugs 
• Related: The event follows a reasonable temporal sequence from the time of drug 
administration, and/or follows a known response pattern to the study drug, and cannot be 
reasonably explained by other factors such as the subject's clinical condition, intercurrent 
illness, or concomitant drugs 
8.3 
Discontinuation due to Adverse Events 
Any subject who experiences an AE may be withdrawn at any time from the study at the 
discretion of the investigator. Subjects withdrawn from the study due to an AE, whether serious 
or nonserious, may be followed by the investigator until the clinical outcome of the AE is 
determined. The AE(s) should be noted on the appropriate eCRFs and the subject’s progress 
should be followed until the AE is resolved or stabilized as determined by the investigator. The 
sponsor and medical monitor must be notified. If the AE relates to overdose of study treatment, 
the Investigator’s Brochure should be consulted for details of any specific actions to be taken. 
8.4 
Reporting Serious Adverse Events 
In the event of any SAE reported or observed during the study, whether or not attributable to the 
study drug, site personnel will report it immediately by telephone to the sponsor, medical 
monitor, and SAE hotline at ICON (ICON plc Pharmacovigilance) in accordance with 
procedures described in the SRM and/or SAE SSP. Site personnel will follow up with a written 
report to the sponsor on the next working day. 
SAE Report Forms will be provided to the CRU to assist in collecting, organizing, and reporting 
SAEs and follow-up information. 
All SAEs should be followed to their resolution, with documentation provided to the sponsor, 
medical monitor, and ICON on a follow-up SAE Report Form. 


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9 
STATISTICAL CONSIDERATIONS 
The statistical analysis will be conducted following the principles as specified in ICH Topic E9 
(CPMP/ICH/363/96). 
All statistical analyses will be described in a separate statistical analysis plan. 
9.1 
Sample Size Calculation 
A total of 30 healthy, postmenopausal female subjects (n = 10 per arm) are planned for inclusion 
in this study. The sample size for this study is based on the desire to accurately assess the PK of 
estrogens and progesterone from the DARE-HRT1 IVR, is empirically derived, and supported by 
the PK data obtained from ovarectomized sheep. Descriptive analyses compared to oral 
estrogen/progesterone therapy will also be performed.  
The sample sizes provided are deemed sufficient to allow for adequate assessment of the PK of 
the IVR (test) formulations. Dropouts may be replaced. Subjects who terminate early from the 
trial may be replaced to ensure an adequate number of subjects contributing to the PK for each 
treatment arm. 
9.2 
Analysis Populations 
Pharmacokinetic Population: all subjects who received a full course of study treatment for their 
dispensed treatment and who have sufficient concentration data for determination of PK 
parameters (primary endpoints); data will be analyzed according to the actual study treatment 
received. 
Safety Population: all enrolled subjects who received active treatment, i.e., inserted an IVR (and 
thus who were exposed to one of the IVRs) or who took at least one dose of the oral reference.  
9.3 
Randomization 
Upon completion of their screening procedures and confirmation of their eligibility (including an 
endometrial biopsy, cervical screening test, and transvaginal ultrasound), eligible subjects will be 
admitted to the CRU on Day -1 and will be randomized. Randomization will occur prior to 
initiation of treatment. Subjects will be randomized in a 1:1:1 ratio to the treatment groups.  
9.4 
Endpoints 
9.4.1 
Primary Endpoints 
• Css and Cmax for estradiol, estrone, and progesterone for each treatment  
9.4.2 
Secondary Endpoints 
• adverse events 
• clinical laboratory findings 
• physical examination findings 
• vital signs 


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• pelvic examination findings 
• vaginal pH and cytology 
9.4.3 
Exploratory Endpoint 
• responses to Usability and Tolerability questionnaire 
9.5 
Pharmacokinetic Statistical Analysis 
The DARE-HRT1 IVR is the test (investigational) product of interest, with two dose 
combinations of estradiol and progesterone being assessed. Thus, comparisons of the estrogen 
and progesterone concentrations will be made for each dose combination as DARE-HRT1 IVR 
versus oral therapy.  
The PK analysis will be performed for each IVR dose and assessed versus the oral reference. 
Graphics will be provided to allow for visual inspection of the mean and individual subject 
concentration-time profiles.  
The PK parameters Cavg, Css, Cmax, Ctau, tmax, AUC0-24, AUCD1-D30, and t½, eff will be determined 
from the plasma concentration-time profiles, where possible. Geometric mean values and 
coefficients of variation (CV%) will be estimated and reported.  
If possible, the dose proportionality for the DARE-HRT1 IVR estradiol and progesterone doses 
will be assessed.  
Other details of the PK analysis will be described in a separate Statistical Analysis Plan.  
9.6 
Safety Analysis 
Adverse events, concomitant medications, clinical laboratory findings, physical examinations, 
pelvic examination with speculum examination and visual vaginal examination findings, 
endometrial biopsy findings, cervical screening test results, and vital signs for each subject will 
be tabulated or summarized descriptively, where appropriate.  
Vital signs data (observed and change from baseline) will be summarized by time point and 
treatment using appropriate descriptive statistics. For the safety population, changes from 
baseline at each post-randomization visit and end of treatment will be compared among 
treatment arms. Qualitative analysis of laboratory tests in terms of abnormality will be 
performed. Findings on physical examination will be reported and compared at the screening and 
end of treatment. 
The number and percentage of subjects reporting any treatment-emergent AE will be tabulated 
by system organ class and preferred term for each treatment (coded using MedDRA). 
Treatment-emergent AEs will be further classified by severity and relationship to treatment. 


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10 
ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator will provide direct access to source data and documents for individuals 
conducting study-related monitoring, audits, IRB/IEC review, and regulatory review. The 
investigator must inform the study subject that his/her study-related records may be reviewed by 
the above individuals without violating the subject’s privacy of personal health information in 
compliance with HIPAA regulations. 
By signing this protocol, the investigator affirms to the sponsor that the investigator will 
maintain, in confidence, information furnished to him or her by the sponsor and will divulge 
such information to the IRB/IEC under an appropriate understanding of confidentiality with such 
board. 


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11 
QUALITY CONTROL AND QUALITY ASSURANCE 
Daré Bioscience Australia Pty LTD / ICON will implement and maintain quality control and 
quality assurance procedures with written SOPs to ensure the study is conducted and data are 
generated, documented, and reported in compliance with the protocol, GCP, and applicable 
regulatory requirements. 
11.1 
Conduct of Study 
This study will be conducted in accordance with the provisions of the Declaration of Helsinki 
and all revisions thereof (Tokyo 2004), and in accordance with the ICH E6 Guidelines on GCPs 
(CPMP/ICH/135/95). Specifically, this study is based on adequately performed laboratory and 
animal experimentation; the study will be conducted under a protocol reviewed by an IRB or 
IEC; the study will be conducted by scientifically and medically qualified persons; the benefits 
of the study are in proportion to the risks; the rights and welfare of the subjects will be respected; 
the physicians conducting the study do not find the hazards to outweigh the potential benefits; 
and each subject will give his or her written, informed consent before any protocol-driven tests 
or evaluations are performed. 
The investigator may not deviate from the protocol without a formal protocol amendment having 
been established and approved by an appropriate IRB/IEC, except when necessary to eliminate 
immediate hazards to the subject or when the change(s) involve only logistical or administrative 
aspects of the study and are approved by the medical monitor and/or Daré Bioscience Australia 
Pty LTD. Any deviation may result in the subject having to be withdrawn from the study, and 
may render that subject nonevaluable. 
11.1.1 
Protocol Deviations 
A protocol deviation is defined as any intentional or unintentional change to, or noncompliance 
with, the approved protocol procedures or requirements. Deviations may result from the action or 
inaction of the subject, investigator, or site staff. Examples of deviations include, but are not 
limited to:  
• Failure to adhere to study exclusion and inclusion criteria 
• Failure to comply with dispensing or dosing requirements 
• Use of medications, food, drink, herbal remedies, or supplements that are specifically 
prohibited in the protocol 
• Missed or out-of-window visits 
• Drug dosing not administered within the time frame specified in the protocol 


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• Failure to adhere to test requirements, including vital signs, laboratory tests, physical 
examinations, PK blood draws, medical history, etc. – either tests not done, incorrect tests 
done, or not done within the time frame specified in the protocol 
• Procedural deviations such as incorrect storage of investigational product, failure to update 
the ICF when new risks become known, failure to obtain IRB approvals for the protocol and 
ICF revisions 
At the outset of the study, a process for defining and handling protocol deviations will be 
established. This will include determining which violations will be designated “key,” requiring 
immediate notification to the medical monitor and Daré Bioscience Australia Pty LTD. The 
investigator is responsible for seeing that any known protocol deviations are recorded and 
handled as agreed. 
11.2 
Protocol Amendments 
Only Daré Bioscience Australia Pty LTD may modify the protocol. Amendments to the protocol 
will be made only after consultation and agreement between Daré Bioscience Australia Pty LTD, 
the medical monitor, and the investigator. All amendments that have an impact on subject risk or 
the study objectives, or require revision of the ICF, must receive approval from the IRB/IEC 
prior to their implementation.  
11.3 
Monitoring of Study 
The investigator will permit the site monitor to review study data as frequently as is deemed 
necessary to ensure data are being recorded in an adequate manner and protocol adherence is 
satisfactory.  
The investigator will provide access to medical records for the monitor to verify eCRF entries. 
The investigator is expected to cooperate with Daré Bioscience Australia Pty LTD/designee in 
ensuring the study adheres to GCP requirements.  
The investigator may not recruit subjects into the study until Daré Bioscience Australia Pty LTD 
or a designee has conducted a visit at the site to conduct a detailed review of the protocol and 
eCRF. With agreement of Daré Bioscience Australia Pty LTD, attendance at an investigator 
meeting may fulfil this requirement. 


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12 
ETHICS 
12.1 
Institutional Review Board/Independent Ethics Committee Approval 
12.1.1 
Ethics Review Prior to Study 
The investigator will ensure that the protocol and consent form are reviewed and approved by the 
appropriate IRB/IEC prior to the start of any study procedures. The IRB/IEC will be 
appropriately constituted and will perform its functions in accordance with ICH GCP guidelines 
and local requirements as applicable. 
12.1.2 
Ethics Review of Other Documents 
In addition, the IRB will approve all protocol amendments (except for Daré Bioscience Australia 
Pty LTD-approved logistical or administrative changes), written informed consent documents 
and document updates, subject recruitment procedures, written information to be provided to the 
subjects, available safety information, information about payment and compensation available to 
subjects, the investigator’s curriculum vitae and/or other evidence of qualifications, and any 
other documents requested by the IRB/IEC and regulatory authority as applicable. 
12.2 
Written Informed Consent 
The nature and purpose of the study will be fully explained to each subject (or the subject’s 
legally responsible guardian). The subjects must be given ample time and opportunity to inquire 
about details of the study, to have questions answered to their satisfaction, and to decide whether 
to participate. Written informed consent must be obtained from each subject (or guardian) prior 
to any study procedures being performed. 


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DATA HANDLING AND RECORD KEEPING 
13.1 
Data Reporting and Case Report Forms 
13.1.1 
Case Report Forms 
The investigator will be provided with eCRFs, and will ensure all data from subject visits are 
promptly entered into the eCRFs in accordance with the specific instructions given. The 
investigator must sign the eCRFs to verify the integrity of the data recorded. 
13.1.2 
Laboratory Data 
All safety samples will be analyzed by the CRU and all bioanalytical samples will be analyzed 
by Agilex Biolabs Pty Ltd, Adelaide, South Australia. A list of the normal ranges for all 
laboratory tests to be undertaken forms part of the documentation to be collated prior to study 
start. The investigator must maintain source documents such as laboratory reports and complete 
history and physical examination reports. 
13.1.3 
Retention of Source Documents 
The investigator must maintain source documents such as laboratory reports, x-rays, ECGs, 
consultation reports, and complete history and physical examination reports. 
13.2 
Retention of Essential Documents 
The study essential documents must be maintained as specified in the ICH guidelines for GCP 
and the applicable regulatory requirements. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents should 
be retained for a longer period; however, if required by the applicable regulatory requirements or 
by an agreement with Daré Bioscience Australia Pty LTD. It is the responsibility of the Daré 
Bioscience Australia Pty LTD to inform the investigator/institution as to when these documents 
no longer need to be retained. 


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14 
ADMINISTRATIVE INFORMATION 
14.1 
Financing and Insurance 
Financing and insurance will be addressed in a separate agreement between Daré Bioscience 
Australia Pty LTD and the investigator. 
14.2 
Publication Policy 
Daré Bioscience Australia Pty LTD will retain ownership of all data. All proposed publications 
based on this study will be subject to Daré Bioscience Australia Pty LTD’s approval 
requirements. 


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15 
REFERENCES 
American College of Obstetricians and Gynecologists (ACOG). ACOG practice bulletin no. 141: 
Management of menopausal symptoms. Obstet Gynecol. 2014;123:202-216. 
Anderson GL, Judd HL, Kaunitz AM, Barad, DH, Beresford SA, Pettinger M, et al. Effects of 
estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the 
Women's Health Initiative randomized trial. JAMA. 2003;290:1739-1748.  
Femring (package insert). Irvine, CA. Allergan USA, Inc.; 2017.  
Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D. Hormone replacement therapy and 
endometrial cancer risk: a meta-analysis. Obstet Gynecol. 1995;85:304-313. 
Hamada AL, Maruo T, Samoto T, Yoshida, S, Nash, H, Spitz, IM, et al. Estradiol/ 
progesterone-releasing vaginal rings for hormone replacement therapy in postmenopausal 
women. Gynecol Endocrinol 2003;17:247-254. 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use; ICH Harmonised Tripartite Guideline; Impurities In New Drug 
Products; Q3B(R2). 02 June 2006.  
Levine H, Watson N. Comparison of the pharmacokinetics of Crinone 8% administered 
vaginally versus Prometrium administered orally in postmenopausal women. Fertil Steril. 
2000;73:516-521. 
Levy T, Yairi Y, Bar-Hava I, Shalev J, Orvieto R, Ben-Rafael Z. Pharmacokinetics of the 
progesterone-containing vaginal tablet and its use in assisted reproduction. Steroids. 
2000;65:645–649. 
Mac Bride MB, Rhodes DJ, Shuster LT. Vulvovaginal atrophy. Mayo Clin Proc. 2010;85:87-94. 
MacLennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/ 
progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev. 
2004;4:CD002978. 
Miles RA, Paulson RJ, Lobo RA, Press MF, Dahmoush L, Sauer MV. Pharmacokinetics and 
endometrial tissue levels of progesterone after administration by intramuscular and vaginal 
routes: a comparative study. Fertil Steril. 1994;62:485-490. 
Paulson RJ, Collins MG, Yankov VI. Progesterone pharmacokinetics and pharmacodynamics 
with 3 dosages and 2 regimens of an effervescent micronized progesterone vaginal insert. J Clin 
Endocrinol Metab. 2014;99:4241-4249. 
Pickar JH, Amadio JM, Bernick BA, Mirkin S. Pharmacokinetic studies of solubilized estradiol 
given vaginally in a novel softgel capsule. Climacteric. 2016;19:181-187. 


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Stuenkel CA, Davis SR, Gompel A, Lumsden MA, Murad, MH, Pinkerton JV, et al. Treatment 
of symptoms of the menopause: An Endocrine Society clinical practice guideline. J Clin 
Endocrinol Metab. 2015;100: 3975-4011. 
Suckling J, Kennedy R, Lethaby A, Roberts H. Local oestrogen for vaginal atrophy in 
postmenopausal women. Cochrane Database Syst Rev. 2006:4:CD001500. 


Daré Bioscience Australia Pty LTD 
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Final Protocol 
 
CONFIDENTIAL 
Date: 06 March 2019 
 
APPENDIX A  
Usability and Tolerability Questionnaire 
 
 
 


Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-001 
Final Protocol 
 
CONFIDENTIAL 
Date: 06 March 2019 
 
APPENDIX B  
Subject Daily Diary 
 
 
 


Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-001 
Final Protocol 
 
CONFIDENTIAL 
Date: 06 March 2019 
 
16 
SIGNATURES 
Protocol Number: DARE-HRT1-001 
Protocol Title: A Phase 1, Open-Label, Parallel Group Study to Evaluate the Pharmacokinetics 
and Safety of DARE-HRT1 (80 μg Estradiol/4 mg Progesterone and 160 μg Estradiol/8 mg 
Progesterone Intravaginal Rings) in Healthy Post-Menopausal Women 
Daré Bioscience Australia Pty LTD Signatures 
This clinical study protocol has been reviewed and approved by Daré Bioscience Australia Pty 
LTD. 
 
 
 
 
 
 
Nadene Zack, MS 
Senior Director, Clinical Operations 
 
Date 
 
March 6, 2019


Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-001 
Final Protocol 
 
CONFIDENTIAL 
Date: 06 March 2019 
 
Protocol Number: DARE-HRT1-001 
Protocol Title: A Phase 1, Open-Label, Parallel Group Study to Evaluate the Pharmacokinetics 
and Safety of DARE-HRT1 (80 μg Estradiol/4 mg Progesterone and 160 μg Estradiol/8 mg 
Progesterone Intravaginal Rings) in Healthy Post-Menopausal Women 
Daré Bioscience Australia Pty LTD Signatures 
This clinical study protocol has been reviewed and approved by Daré Bioscience Australia Pty 
LTD. 
 
 
 
 
 
David Friend, PhD 
Chief Scientific Officer 
 
Date 
 
03/06/2019


Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-001 
Final Protocol 
 
CONFIDENTIAL 
Date: 06 March 2019 
 
Protocol Number: DARE-HRT1-001 
Protocol Title: A Phase 1, Open-Label, Parallel Group Study to Evaluate the Pharmacokinetics 
and Safety of DARE-HRT1 (80 μg Estradiol/4 mg Progesterone and 160 μg Estradiol/8 mg 
Progesterone Intravaginal Rings) in Healthy Post-Menopausal Women 
Investigator Signature 
I agree to conduct the aforementioned study according to the terms and conditions of the 
protocol, GCP guidelines, and all other applicable local and regulatory requirements. All 
information pertaining to the study will be treated in a confidential manner. 
 
 
 
Site Name 
 
 
 
Print Name 
 
 
 
 
 
Signature 
 
Date