A Phase 1/2,, Open-label, Parallel Group Study to Evaluate the Safety and Pharmacokinetics of DARE-HRT1 (80ug Estradiol/4 mg Progesterone and 160ug Estradiol/8 mg Progesterone Intravaginal Rings) Over 12 Weeks in Healthy Postmenopausal Women
Phase: PHASE1
Conditions: Vulvovaginal Atrophy, Vasomotor Symptoms
Sponsor: Daré Bioscience, Inc.

Clinical Study Protocol 
 
 
A Phase 1/2, Open-label, Parallel Group Study to Evaluate the Safety and 
Pharmacokinetics of DARE-HRT1 (80 μg Estradiol/4 mg Progesterone and 
160 μg Estradiol/8 mg Progesterone Intravaginal Rings) Over 12 Weeks in 
Healthy Postmenopausal Women 
 
Protocol Number: DARE-HRT1-002 
 
 
Sponsor: 
Daré Bioscience Australia Pty LTD 
Level 19 HWT Tower,  
40 City Road 
Southbank, VIC 3006 
Australia 
 
 
Contract Research 
Organization: 
ICON Clinical Research, Pty Limited 
Suite 201, Level 2 
2-4 Lyon Park Road 
North Ryde, NSW 2113 
Australia 
Telephone: +61 (0)2 9859 3900 
Fax: +61 (0)2 9859 3999 
 
 
Protocol Version: 
Version 1.0 
 
Date: 06 January 2022 
 
 
 
 
 
 
 
 
 
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.

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Protocol Number: DARE-HRT1-002 
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CONFIDENTIAL 
Protocol Number: DARE-HRT1-002 
Page 2  
TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................2 
LIST OF TABLES .........................................................................................................................5 
LIST OF FIGURES .......................................................................................................................5 
1 
PROTOCOL SUMMARY ...........................................................................................6 
LIST OF ABBREVIATIONS .....................................................................................................12 
STUDY ADMINISTRATIVE STRUCTURE ...........................................................................14 
2 
INTRODUCTION AND BACKGROUND ...............................................................15 
2.1 
Introduction ..........................................................................................................15 
2.2 
Investigational Product Background .................................................................16 
2.3 
Summary of Findings to Date .............................................................................16 
2.3.1 
Phase 1 Study: DARE-HRT1.................................................................................17 
2.4 
Study Rationale ....................................................................................................21 
2.4.1 
Dose Rationale .......................................................................................................21 
2.4.2 
Study Design Rationale ..........................................................................................24 
3 
OBJECTIVES .............................................................................................................26 
3.1 
Primary Objectives ..............................................................................................26 
3.2 
Exploratory Objectives ........................................................................................26 
4 
STUDY DESIGN .........................................................................................................27 
4.1 
Study Design and Overview ................................................................................27 
4.1.1 
Duration of Study ...................................................................................................29 
4.1.2 
Definition of Study Completion .............................................................................29 
4.1.3 
End of Study ..........................................................................................................29 
5 
SELECTION AND WITHDRAWAL OF PARTICIPANTS ..................................30 
5.1 
Inclusion Criteria .................................................................................................30 
5.2 
Exclusion Criteria ................................................................................................31 
5.3 
Participant Re-enrollment...................................................................................33 
5.4 
Participant Withdrawal ......................................................................................33 
5.5 
Early Termination of Study ................................................................................33 
6 
TREATMENT OF PARTICIPANTS .......................................................................34 
6.1 
Identity of Study Products ..................................................................................34 
6.2 
Treatments Administered ...................................................................................34 
6.3 
Method of Assigning Participants to Treatment Groups .................................34 
6.4 
Measurements of Treatment Compliance .........................................................34 
6.5 
Investigational Product Storage, Accountability, and Retention ....................35 
6.5.1 
Storage Conditions .................................................................................................35 

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6.5.2 
Study Product Accountability and Retention .........................................................35 
6.6 
Packaging and Labeling ......................................................................................35 
6.6.1 
Investigational Product ..........................................................................................35 
6.6.2 
Blinding of Treatment Assignment ........................................................................35 
6.7 
Concomitant Medications and Procedures and Other Restrictions ................35 
6.7.1 
Concomitant Medications and Procedures .............................................................35 
6.7.2 
Other Restrictions ..................................................................................................36 
7 
STUDY ASSESSMENTS AND PROCEDURES .....................................................37 
7.1 
Medical and Surgical History .............................................................................37 
7.2 
Demographic Characteristics .............................................................................37 
7.3 
Physical Measurements .......................................................................................37 
7.4 
Daily Diary ............................................................................................................37 
7.5 
Training ................................................................................................................37 
7.6 
Pharmacokinetic Assessments ............................................................................37 
7.6.1 
Drug Concentration Measurements .......................................................................37 
7.6.2 
Pharmacokinetic Parameters ..................................................................................37 
7.7 
Safety Assessments ...............................................................................................38 
7.7.1 
Adverse Events ......................................................................................................38 
7.7.2 
Laboratory Tests ....................................................................................................38 
7.7.3 
Other Assessments .................................................................................................40 
7.7.4 
Vital Signs ..............................................................................................................40 
7.7.5 
Physical Examination.............................................................................................40 
7.7.6 
Electrocardiograms ................................................................................................41 
7.7.7 
Appropriateness of Safety Assessments ................................................................41 
7.8 
Exploratory Assessments.....................................................................................41 
7.8.1 
Usability and Tolerability Questionnaire ...............................................................41 
7.8.2 
Vaginal Cytology ...................................................................................................41 
7.8.3 
Vaginal pH .............................................................................................................41 
7.8.4 
Most Bothersome Symptom ..................................................................................41 
7.8.5 
Menopause-specific Quality of Life ......................................................................42 
8 
ADVERSE EVENTS ...................................................................................................43 
8.1 
Recording Adverse Events ..................................................................................43 
8.2 
Assessment of Adverse Events ............................................................................43 
8.2.1 
Serious Adverse Events .........................................................................................44 
8.2.2 
Intensity..................................................................................................................44 
8.2.3 
Relationship to Study Product ...............................................................................45 
8.3 
Discontinuation due to Adverse Events .............................................................45 
8.4 
Reporting Serious Adverse Events .....................................................................45 
9 
STATISTICAL CONSIDERATIONS ......................................................................47 
9.1 
Sample Size Calculation ......................................................................................47 
9.2 
Analysis Populations ............................................................................................47 
9.3 
Randomization .....................................................................................................47 
9.4 
Endpoints ..............................................................................................................48 

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9.4.1 
Primary Endpoints .................................................................................................48 
9.4.2 
Exploratory Endpoints ...........................................................................................48 
9.5 
Pharmacokinetic Statistical Analysis .................................................................48 
9.6 
Safety Analysis .....................................................................................................49 
10 
ACCESS TO SOURCE DATA/DOCUMENTS .......................................................50 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................51 
11.1 
Conduct of Study..................................................................................................51 
11.1.1 
Protocol Deviations ................................................................................................51 
11.2 
Protocol Amendments .........................................................................................52 
11.3 
Monitoring of Study .............................................................................................52 
12 
ETHICS ........................................................................................................................53 
12.1 
Human Research Ethics Committee Approval .................................................53 
12.1.1 
Ethics Review Prior to Study .................................................................................53 
12.1.2 
Ethics Review of Other Documents .......................................................................53 
12.2 
Written Informed Consent ..................................................................................53 
13 
DATA HANDLING AND RECORD KEEPING .....................................................54 
13.1 
Data Reporting and Case Report Forms ...........................................................54 
13.1.1 
Case Report Forms .................................................................................................54 
13.1.2 
Laboratory Data .....................................................................................................54 
13.1.3 
Retention of Source Documents ............................................................................54 
13.2 
Retention of Essential Documents ......................................................................54 
14 
ADMINISTRATIVE INFORMATION ....................................................................55 
14.1 
Financing and Insurance .....................................................................................55 
14.2 
Publication Policy.................................................................................................55 
15 
REFERENCES ............................................................................................................56 
16 
SIGNATURES .............................................................................................................58 
17 
APPENDICES .............................................................................................................61 
APPENDIX A 
USABILITY AND TOLERABILITY QUESTIONNAIRE ........................61 
APPENDIX B 
MENQOL INSTRUMENT ............................................................................63 
APPENDIX C 
PARTICIPANT DAILY DIARY ..................................................................71 
 

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LIST OF TABLES 
Table 1-1: 
Schedule of Events ...................................................................................................9 
Table 2-1: 
Summary of Plasma Pharmacokinetic Parameters by IVR 
Treatment Arm .......................................................................................................19 
Table 2-2: 
Summary of Plasma Pharmacokinetic Parameters for Oral 
Treatment Arm .......................................................................................................20 
Table 2-3 
Mean Pharmacokinetic Values for Estradiol .........................................................22 
Table 2-4: 
Estradiol Pharmacokinetics: Femring Versus DARE-HRT1 .................................23 
Table 2-5: 
Progesterone Pharmacokinetics: Endometrin and Utrogestan 
Versus DARE-HRT1 .............................................................................................24 
Table 4-1: 
Treatment Allocations ............................................................................................27 
Table 6-1: 
Study Products .......................................................................................................34 
Table 7-1: 
Clinical Laboratory Tests .......................................................................................39 
Table 7-2: 
Assessment of Most Bothersome Symptom ..........................................................42 
 
LIST OF FIGURES 
Figure 2-1: 
Mean (±SD) Unadjusted Plasma Concentrations (pg/mL) Over 
Time by Treatment Arm ........................................................................................18 
 
 
 

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1 
PROTOCOL SUMMARY 
Protocol Title: 
A Phase 1/2, Open-label, Parallel Group Study to Evaluate the Safety and 
Pharmacokinetics of DARE-HRT1 (80 μg Estradiol/4 mg Progesterone and 160 μg 
Estradiol/8 mg Progesterone Intravaginal Rings) Over 12 Weeks in Healthy 
Postmenopausal Women  
Product Name/Number 
DARE-HRT1 
Protocol Number 
DARE-HRT1-002 
Study Phase: 
1/2 
Objectives: 
Primary: 
• 
To assess the safety and tolerability of DARE-HRT1 intravaginal rings (IVRs) 
over 12 weeks of use 
• 
To describe the pharmacokinetic (PK) parameters of 2 different dose 
combinations of DARE-HRT1 over 12 weeks: 
o 
Estradiol 80 μg/progesterone 4 mg/day IVR 
o 
Estradiol 160 μg/progesterone 8 mg/day IVR 
Exploratory: 
• 
To assess usability and participant tolerability of the DARE-HRT1 IVR 
• 
To conduct a preliminary evaluation of the effect of the DARE-HRT1 IVR on 
vasomotor symptoms (VMS) and on vulvovaginal atrophy (VVA) signs and 
symptoms of menopause  
Endpoints: 
Primary: 
• 
Incidence and severity of adverse events 
• 
Changes from baseline in clinical laboratory findings 
• 
Changes from baseline in physical examination findings 
• 
Changes from baseline in vital signs results 
• 
Changes from baseline in speculum examination findings 
• 
Changes from baseline in transvaginal ultrasound findings 
• 
Steady-state concentration (Css) and maximum observed plasma concentration 
(Cmax) in each cycle for estradiol, estrone, and progesterone 
Exploratory: 
• 
Responses to the Usability and Tolerability questionnaire  
• 
Change from baseline to Week 12 in responses to the Menopause-specific 
Quality of Life (MENQOL) questionnaire  
• 
Mean change from baseline to Week 12 in severity of the participant’s VVA 
signs and symptoms  
• 
Mean change from baseline to Week 12 in the severity of the participant’s most 
bothersome VVA symptom 
• 
Mean change from baseline to Week 12 in vaginal pH  
• 
Mean change from baseline to Week 12 in vaginal maturation index (parabasal, 
intermediate, and superficial cells) 

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Study Design: 
This is a randomized, open-label, 2-arm, parallel group study in approximately 20 
healthy postmenopausal women with an intact uterus. This study is designed to 
assess the safety of DARE-HRT1 IVRs at two dose strengths, and the PK of 
progesterone, estradiol, and its metabolite estrone, from the IVRs. A preliminary 
assessment of the effect of DARE-HRT1 on VMS and on VVA signs and symptoms 
of menopause will be included. Screening procedures will ensure that participants 
are eligible, and will include a transvaginal ultrasound and, if needed, an endometrial 
biopsy and/or cervical screening test. Eligible participants with ongoing hormone 
replacement therapy at study entry will be required to undergo an appropriate 
washout period. 
Randomization will occur prior to initiation of treatment and participants will be 
randomized in a 1:1 ratio to the following treatment groups. 
Treatment Group and 
Number of Participants 
Treatment 
IVR Dose 1 
(N = 10) 
12-week IVR 80/4 (estradiol 80 μg/day + 
progesterone 4 mg/day), replaced every 28 days 
IVR Dose 2 
(N = 10) 
12-week IVR 160/8 (estradiol 160 μg/day + 
progesterone 8 mg/day), replaced every 28 days 
 
Participants will use DARE-HRT1 IVRs for 12 weeks, across three 28-day cycles, 
with a new IVR administered on Day 1 of each cycle. For each cycle, Day 1 is 
defined as the first day of treatment, i.e., the day the IVR is self-administered by the 
participant. Correct placement of the IVR will be confirmed by the study staff. The 
same IVR is to remain in position for 28 days, with removal of the IVR by the 
participant in the clinical research unit (CRU) on the morning of Day 1 of the next 
cycle. Participants will use a paper diary to document insertion and removal of the 
IVR and any instances of the IVR falling out, as well as any concomitant medication 
use. 
In Cycle 1: 
• 
Baseline PK sampling will occur predose on Day 1 at -1, -0.5 and 0 (within 
10 minutes) hours prior to insertion of the first IVR. Repeated blood sampling 
for PK will occur at 0.5, 1, 2, 4, and 8 hours following insertion. 
In Cycles 2 and 3:  
• 
Participants will return to the CRU on Day 1. During that visit, the IVR will be 
removed, blood will be drawn for PK (0 hours), and a new IVR inserted 
immediately (within 10 minutes) after blood was drawn. Repeated blood 
sampling for PK will occur at 0.5, 1, 2, 4, and 8 hours following insertion. 
In Cycles 1, 2, and 3: 
• 
On the mornings of Days 2 and 3, participants will return to the CRU for a 
single PK blood draw (24 and 48 hours following IVR insertion, respectively) 
• 
On the morning of Days 8, 15, and 22, participants will return to the CRU for a 
single PK blood draw and safety assessments 
In Cycle 3 only: 
• 
On the morning of Cycle 3, Day 29 (EOS), participants will return to the CRU 
for removal of the IVR. Repeated blood sampling will be performed before 
removal of the IVR (0 hours), and at 0.5, 1, 2, 4, and 8 hours after removal  
• 
Participants will return to the CRU the following day (Day 30) to provide a 
single PK blood sample 24 hours after IVR removal  

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A follow-up telephone call will be made from the CRU to each participant to 
monitor any ongoing or emergent AEs approximately 7 days after the removal of the 
third IVR. 
Participant Selection 
Criteria: 
Healthy postmenopausal women with body mass index between 18 and 38 kg/m2, 
inclusive, normal cervix, vagina, uterus, and adnexa, based upon pelvic examination 
(speculum and bimanual), normal transvaginal ultrasound and acceptable result from 
endometrial biopsy if needed at screening, normal cervical screening test and normal 
mammogram within 24 months before screening.  
Study Product, Dose, 
and Route of 
Administration: 
DARE-HRT1 is an IVR that delivers estradiol and progesterone. It is self-
administered by intravaginal insertion once and remains in place for 28 days. 
Two formulations will be studied, providing different doses: 
• 
Estradiol 80 μg/progesterone 4 mg/day IVR 
• 
Estradiol 160 μg/progesterone 8 mg/day IVR  
Participants will self-administer DARE-HRT1 in the CRU on Cycle 1, Day 1. A 
replacement IVR will be self-administered every 28 days, on Day 1 of Cycles 2 
and 3. 
Planned Study Sites 
Approximately two study sites in Australia. 
Planned Sample Size: 
Approximately 20 participants are planned to be enrolled, with 10 participants 
randomly allocated to each treatment arm. Participants who terminate early from the 
trial may be replaced to ensure an adequate number of participants contributing to 
the PK analysis in each treatment arm. 

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Table 1-1: 
Schedule of Events 
Study Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
EOS / 
ET 
Follow-
Up 
Phone 
Call 
Study Day 
Days -28 to -2 
1 
2, 3 
8, 15, 22 
1 
2, 3 
8 
15 
22 
1 
2, 3 
8, 15, 22 
29 
30 
+7 
Informed consenta  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assign Participant ID  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical history  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Cervical screening test 
(if needed)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Speculum examinationc 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Bimanual examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaginal pH  
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Vaginal cytology 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Transvaginal ultrasoundd  
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Endometrial biopsyd  
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height (cm), weight (kg), and 
BMIf  
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
12-lead ECG  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (BP and PR), RR, 
oral temperature 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
 
 
Hematology and blood 
chemistry  
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
 
 
Urine dipstick 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
FSH  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
EOS / 
ET 
Follow-
Up 
Phone 
Call 
Study Day 
Days -28 to -2 
1 
2, 3 
8, 15, 22 
1 
2, 3 
8 
15 
22 
1 
2, 3 
8, 15, 22 
29 
30 
+7 
Serology testsg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug and alcohol urine screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Training on use of IVR  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense IVR(s)  
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
Insert new IVR (after predose 
PK sample)i  
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
Remove used vaginal 
ring/return IVR(s)  
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Confirm IVR placement  
 
Xj 
X 
X 
Xj 
X 
X 
X 
X 
Xj 
X 
X 
 
 
 
PK blood samplesk 
X 
Xl 
X 
X 
Xl 
X 
X 
X 
X 
Xl 
X 
X 
Xm 
Xm 
 
Usability and Tolerability 
questionnaire  
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Vulvovaginal atrophy 
symptoms including most 
bothersome symptom 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
MENQOL questionnaire  
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Dispensing / Review of daily 
diary 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Adverse events, including 
serious adverse events 
Adverse events and serious adverse events collected beginning at ICF signing and in an ongoing manner  
TEAEs 
 
TEAEs collected beginning at IVR placement and in an ongoing manner as appropriate 
Prior/concomitant 
medications  
X 
Concomitant medications collected in ongoing manner, as appropriate 
Follow-up telephone calln 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: AE = adverse event; BMI = body mass index; BP = blood pressure; ECG = electrocardiogram; EOS = end of study; ET = early termination; 
FSH = follicle-stimulating hormone; HCV = hepatitis C virus; HIV = human immunodeficiency virus; ICF = informed consent form; ID = identification; 

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IVR = intravaginal ring; MENQOL = Menopause-specific Quality of Life; PK = pharmacokinetic; PR = pulse rate; RR = respiratory rate; SAE = serious adverse 
event; TEAE = treatment-emergent adverse events; temp = temperature. 
a. 
Participants undergoing washout of prior hormone replacement therapy will be required to sign the ICF before starting washout. Where washout of HRT will 
take approximately 8 weeks, screening procedures should not commence until 28 days prior to Cycle 1, Day 1.  
b. Complete physical examination at Screening and EOS/ET visit. Additional symptom-directed examinations can be performed at all other visits for 
participants exhibiting signs or reporting symptoms since their last visit. 
c. 
The purpose of the speculum examination on Cycle 1 Day 1 is to identify vaginal abnormalities at baseline, to allow differentiation of baseline abnormalities 
from AEs related to the IVR. 
d. In addition to scheduled transvaginal ultrasounds, any participant experiencing postmenopausal bleeding during study will undergo a transvaginal ultrasound 
and possible endometrial biopsy as an unscheduled visit, to have this evaluated histologically.  
e. 
Upon transvaginal ultrasound:  
• 
if endometrial thickness is ≤ 4.0 mm in a participant without postmenopausal vaginal bleeding, an endometrial biopsy is not indicated for the 
purposes of screening  
• 
if endometrial thickness is > 4.0 mm ≤ 6.0 mm in a participant without postmenopausal vaginal bleeding, an acceptable result from an evaluable 
screening endometrial biopsy, evaluated by a pathologist, is required for inclusion into the study. Tissue must be read as benign, inactive, or 
atrophic endometrium by at least 1 pathologist 
f. 
Height will be measured at Screening only. 
g. Serology tests include HIV-1 and HIV-2 antibodies, hepatitis B surface antigen, and HCV antibodies. 
h. Randomization will occur after screening procedures are completed and eligibility is verified. 
i. 
Participants will self-administer the IVR in the clinical research unit on Day 1 of each cycle. Insertion should take place after the 0-hour PK sample has been 
collected. At the end of each cycle, participants will remove their own IVR. 
j. 
In each cycle, investigators will confirm correct placement of the IVR prior to the first postdose PK sample collection. 
k. Repeated blood sampling for PK will be performed on Day 1 of each cycle, with single samples collected on Day 2 (24 hours postdose), Day 3 (48 hours 
postdose), and on Days 8, 15, and 22 of each cycle. 
l. 
On Day 1 of each cycle, repeated blood sampling for PK will be performed, with samples collected at the following time points: 0 (within 10 minutes) hours 
prior to insertion of the IVR, then after insertion of the IVR at 0.5, 1, 2, 4, and 8 hours following insertion. On Day 1 of Cycle 1, baseline sampling will 
occur predose at -1, -0.5, and 0 (within 10 minutes) hours prior to insertion of the first IVR. 
m. Repeated blood sampling for PK will be performed on Day 29 of Cycle 3, with samples collected at the following time points: before removal of the IVR 
(0 hours), then after removal of the IVR at times 0.5, 1, 2, 4, and 8 hours, with a final sample on Day 30 of Cycle 3, 24 hours after removal of the IVR.  
n. The purpose of the call is to follow up on any ongoing or emergent AEs after the participant’s treatment has been completed (approximately 7 days after 
removal of the third IVR. 
 
 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AUC D1-D29 
area under the plasma concentration-time curve from time 0 (Day 1) to the time of the last 
quantifiable concentration on Day 29; calculated using the linear/log trapezoid rule 
BMI 
body mass index 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed plasma concentration 
Css 
steady-state concentration 
CRU 
clinical research unit 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
end-of-study 
EVA 
ethylene vinyl acetate 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HREC 
Human Research Ethics Committee 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ID 
identification 
IP 
investigational product 
IVR 
intravaginal ring 
mITT 
modified intent-to-treat (population) 
OTC 
over-the-counter 
PK 
pharmacokinetic(s) 
PR 
pulse rate 
RR 
respiration rate 
SAE 
serious adverse event 
SOP 
standard operating procedure 
SRM 
study reference manual 

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Abbreviation 
Definition 
tmax 
time at which the maximum plasma concentration was observed 
TEAE 
treatment-emergent adverse event 
temp 
temperature 
VMS 
vasomotor symptoms 
VA 
vinyl acetate 
VVA 
vulvovaginal atrophy 

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STUDY ADMINISTRATIVE STRUCTURE 
Sponsor: 
Daré Bioscience, 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 Bioscience, Inc. 
Medical Monitor: 
To be determined 
Sponsor’s Contact: 
Nadene Zack 
Vice President, Clinical Operations 
Bioanalytical Laboratory: 
Agilex Biolabs Pty Ltd 
28 Dalgleish Street 
Thebarton 
Adelaide, SA 5031 
Australia 
Pharmacokineticist: 
Brian Sadler, PhD, ICON Clinical Research, 
LLC 
Clinical Research Organization: 
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 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: 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. It 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, 
hormone replacement therapy (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 the vinyl 
acetate (VA) monomer within the EVA is not expected due to the extremely low amount of 
residual VA in the EVA. The product’s specification for residual vinyl acetate 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 
United States, the European Union, 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. 
A Phase 1 human factors study was conducted with 4 mm and 6 mm cross sectional diameter 
placebo IVRs. These rings had the same EVA composition as the DARE-HRT1 IVR but did not 

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include any active hormone components. In addition to evaluating participants’ comprehension 
of the instructions for use, participants 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 participants. Subjects 
generally found the instructions provided for the IVR easy to understand, and 32 of 44 (73.7%) 
participants were able to successfully insert and remove the IVR. The IVRs were reported to be 
comfortable by the majority of participants, with most participants reporting that the IVR was 
convenient to use and worked with their lifestyle. 
2.3.1 
Phase 1 Study: DARE-HRT1 
A Phase 1 open-label study of DARE-HRT1 has been conducted to evaluate the PK and safety of 
the two DARE-HRT1 formulations in healthy post-menopausal women. Participants were 
randomized in a 1:1:1 ratio to receive DARE-HRT1 Dose 1 (80 µg estradiol/4 mg progesterone), 
DARE-HRT1 Dose 2 (160 µg/8 mg), or oral treatment with daily estradiol 1 mg tablet and a 
progesterone 100 mg capsule. Participants in the DARE-HRT1 groups used an IVR for 28 days, 
while those in the oral group received treatment every day for 29 days. In addition to PK 
sampling, participants underwent similar assessments to those conducted in the present study, 
including speculum examination, transvaginal ultrasounds, safety laboratory tests, and vital 
signs; participants also completed a Usability and Tolerability questionnaire at the end of the 
study. 
A total of 34 women were randomized to treatment, and 33 received the allocated treatment: 
10 participants received DARE-HRT1 Dose 1, 12 received Dose 2, and 11 received oral 
treatment. Of these, all 10 participants in the Dose 1 group completed the scheduled treatment, 
10 participants (83.3%) in the Dose 2 group completed treatment, and all 11 participants 
receiving oral estradiol/progesterone completed treatment. 
2.3.1.1 
Pharmacokinetics 
Following the insertion of the IVR on Day 1, plasma concentrations of estradiol, estrone, and 
progesterone followed a similar pattern: an initial increase in concentrations, peaking within 
1-2 days after IVR insertion, followed by a decline in concentrations up to approximately Day 8 
(192 hours), after which concentrations were maintained until the removal of the IVR on the 
morning of Day 29 (Figure 2-1). Post-removal of the IVR, concentrations declined towards 
baseline levels. Concentrations of estradiol, estrone, and progesterone were generally higher for 
IVR Dose 2 compared to IVR Dose 1, consistent with the increased dose of both estradiol and 
progesterone in IVR Dose 2, with the exception of the steady-state concentrations of estrone that 
were very similar between Day 8 and the morning of Day 29 for both Dose 1 and Dose 2.  

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For the oral arm, there was the expected increase in estradiol, estrone, and progesterone 
concentrations on both Day 1 and Day 30, that had returned close to baseline/predose levels within 
24 hours (Figure 2-1). For both estrone and progesterone, steady-state concentrations appeared to 
have been achieved by Day 8 and were maintained for the duration of the 29 days of dosing. 
Trough concentrations of estrone were more variable than either estradiol or progesterone, with 
steady-state appearing to have been achieved between Days 8 and 15. 
Figure 2-1: 
Mean (±SD) Unadjusted Plasma Concentrations (pg/mL) Over Time by 
Treatment Arm 
Estradiol 
Progesterone 
Estrone 
0
90
180
270
360
450
540
630
700
Time (h)
1
10
100
1000
Plasma Concentrations (pg/mL
IVR Dose 2
IVR Dose 1
0
90
180
270
360
450
540
630
700
Time (h)
1
10
100
1000
Plasma Concentrations (pg/mL
Oral Reference
0
90
180
270
360
450
540
630
700
Time (h)
10
100
1000
10000
100000
Plasma Concentrations (pg/mL
IVR Dose 2
IVR Dose 1
0
90
180
270
360
450
540
630
700
Time (h)
10
100
1000
10000
100000
Plasma Concentrations (pg/mL
Oral Reference
0
90
180
270
360
450
540
630
700
Time (h)
10
100
1000
Plasma Concentrations (pg/mL
IVR Dose 2
IVR Dose 1
0
90
180
270
360
450
540
630
700
Time (h)
10
100
1000
Plasma Concentrations (pg/mL
Oral Reference

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Selected summary PK parameters are shown for the IVR treatments in Table 2-1 and for the oral 
treatment group in Table 2-2.  
IVR Treatment Arms: For all 3 analytes, there was an increase in exposure associated with IVR 
Dose 2 compared to IVR Dose 1 for baseline-adjusted (and unadjusted, data not shown) Cmax and 
AUCD1-D30, although the increase for estrone was generally less than the 2-fold increase in the 
amount of both estradiol and progesterone in Dose 2 compared to Dose 1 (Table 2-1). For both 
estradiol and progesterone, higher Css was also associated with Dose 2 but for estrone, Css was 
more similar for Dose 1 and Dose 2. 
For both estradiol and progesterone, peak concentrations (tmax) were observed within 24 hours of 
insertion, whereas peak estrone concentrations were observed 48 hours after insertion. 
For both unadjusted and baseline-corrected estradiol Cmax and Css, there was a less than 
dose-proportional increase, as indicated by slope estimates being less than 1. For uncorrected and 
baseline-corrected progesterone Cmax, the slope estimate was closer to 1 and the 90% CI for the 
estimate contained 1, indicating an approximate dose-proportional increase in exposure after 
treatment by IVR. There was a less than dose-proportional increase in both unadjusted and 
baseline-corrected progesterone Css. 
Table 2-1: 
Summary of Plasma Pharmacokinetic Parameters by IVR Treatment Arm 
 
Estradiol 
Progesterone 
Estrone 
Parameter (unit) 
Statistic 
IVR Dose 1 
N = 10 
IVR Dose 2 
N = 11 
IVR Dose 1 
N = 10 
IVR Dose 2 
N = 11 
IVR Dose 1 
N = 10 
IVR Dose 2 
N = 11 
Cmax (pg/mL or ng/mL)a 
Baseline-adjusted conc. 
Mean 
143.655 
294.154 
4.527 
8.984 
57.213 
82.961 
tmax (h) 
Baseline-adjusted conc. Median 
12.000 
8.000 
18.015 
8.000 
47.990 
48.000 
AUCD1-D30  
(h*pg/mL or h*ng/mL)a 
Baseline-adjusted conc. 
Mean 
20793.725 
37263.109 
1142.290 
1884.718 
16942.583 
22085.960 
Css (pg/mL or ng/mL)a 
Baseline-adjusted conc. 
Mean 
20.379 
30.920 
1.322 
2.084 
22.148 
25.248 
Abbreviations: 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; Cmax = maximum observed 
plasma concentration; conc. = concentration, Css = steady-state concentration; h = hour(s); IVR = intravaginal ring; 
N = number of participants; tmax = time at which the maximum plasma concentration was observed 
a. 
Estradiol and estrone parameters reported in pg/mL; progesterone parameters reported in ng/mL. 
 
Oral Treatment Arm: For both unadjusted and baseline-corrected estradiol and estrone, both peak 
and overall exposure were higher on Day 29 compared to Day 1 of oral treatment (Table 2-2). 
Unadjusted and baseline-corrected progesterone exposures were also higher on Day 29 compared 
to Day 1, but not to the same extent as for either estradiol or estrone. On both Day 1 and Day 29, 

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peak progesterone levels occurred earlier than for either estradiol or estrone. The estimated 
effective t1/2 on Day 29 for both estradiol and estrone was much longer than the corresponding 
estimate for progesterone. 
 
Table 2-2: 
Summary of Plasma Pharmacokinetic Parameters for Oral Treatment Arm 
 
Estradiol 
Progesterone 
Estrone 
Parameter (unit) 
Statistic 
Day 1 
N = 11 
Day 29 
N = 11 
Day 1 
N = 11 
Day 29 
N = 11 
Day 1 
N = 11 
Day 29 
N = 11 
Cmax (pg/mL or ng/mL)a 
Baseline-adjusted conc. 
Mean 
18.903 
47.848 
10.217 
13.209 
167.878 
296.424 
tmax (h) 
Baseline-adjusted conc. Median 
10.000 
6.000 
2.000 
1.020 
6.000 
4.000 
AUC0-24H  
(h*pg/mL or h*ng/mL)a 
Baseline-adjusted conc. 
Mean 
366.453 
849.479 
17.245 
19.010 
2568.370 
5012.178 
Cavg (pg/mL or ng/mL)a 
Baseline-adjusted conc. 
Mean 
NA 
35.4 
NA 
0.792 
NA 
209 
t1/2, eff (h) 
Baseline-adjusted conc. Median 
NA 
30.775 
NA 
5.736 
NA 
22.672 
Abbreviations: AUC0-24H = area under the plasma concentration-time curve from time 0 (Day 1) to the time of the 
last quantifiable concentration 24 hours; calculated using the linear/log trapezoid rule; Cavg = time-weighted average 
observed plasma concentration over 24 hours; Cmax = maximum observed plasma concentration; 
conc. = concentration, h = hour(s); IVR = intravaginal ring; N = number of participants; NA = not applicable; 
t1/2, eff = effective half-life 
a. 
Estradiol and estrone parameters reported in pg/mL; progesterone parameters reported in ng/mL. 
 
2.3.1.2 
Safety 
Adverse events (AEs) in the DARE-HRT1-001 study were assessed by the investigator regarding 
the relationship to study product but no distinction was made regarding AEs that may have been 
related to the IVR device itself rather than the drugs released from the IVR. Therefore, it is 
possible that some AEs were related to the intravaginal presence of an EVA copolymer ring 
rather than either combination of hormones released from the IVR. 
No serious AEs (SAEs) were reported, 1 treatment-emergent AE (TEAE) led to the 
discontinuation of 1 participant in the Dose 2 group (upper respiratory tract infection, unrelated, 
participant completed treatment), and all TEAEs were mild or moderate in severity.  
Product-related TEAEs were reported in 70% of participants in the Dose 1 group (18 events), 
58.3% of participants in the Dose 2 group (37 events), and 45.5% of participants in the oral 
reference arm (8 events). The most frequent TEAEs were recorded in the SOC of reproductive 
systems and breast disorders: 60% of participants in the Dose 1 group experienced 14 TEAEs, 

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58.3% of participants in the Dose 2 group experienced 24 TEAEs, and 45.5% of participants in 
the oral reference group experienced 6 TEAEs. The most frequently experienced TEAEs (> 10% 
of participants in at least 1 dosage group) included abdominal pain, vaginal hemorrhage, 
vulvovaginal pruritus, vulvovaginal burning sensation, vaginal discharge, vulvovaginal 
candidiasis, pelvic discomfort, breast tenderness, and headache. 
There were no clinically meaningful abnormalities or trends identified in observed values or 
changes from baseline in clinical laboratory data, vital signs, physical examination findings, 
ECGs, speculum examination findings, or transvaginal ultrasound results. 
There was a minimally increased incidence in positive ultrasound results at Day 30 compared to 
screening in both IVR treatment groups but not the oral reference group. New onset positive 
ultrasound results were reported for 2 participants in each IVR dose group and included 
hydrosalpinx, increased endometrial thickness (8 mm), 2 small fibroids, and a small cyst. 
Abnormal postdose endometrial biopsy results showed no evidence of plasma cells, endometritis, 
atypia, hyperplasia, or malignancy. 
The majority of participants in both IVR treatment groups responded favorably for each category 
related to ease of insertion/removal, comfort when wearing, convenience to use, fit with lifestyle, 
and likelihood to use an IVR for future health conditions. 
2.4 
Study Rationale 
Daré Biosciences Inc. is developing an IVR to provide local administration of bioidentical 
17β-estradiol and 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 a 
convenient 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 AL, et 
al., 2003). The DARE-HRT1 17β-estradiol and progesterone IVR has been investigated in a 
recently completed first-in-human study in approximately 34 healthy postmenopausal women 
with an intact uterus. Study DARE-HRT1-001 was a 28-day study designed to assess the PK and 
safety of progesterone, estradiol, and its metabolite estrone, from DARE-HRT1 IVRs at two dose 
strengths, and included a treatment group receiving oral estradiol 1 mg/progesterone 100 mg as 
an active reference (see Section 2.3.1). Treatment with the two IVR dose strengths was 

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considered to be safe and well tolerated, and suitable for further investigation. The estradiol and 
progesterone doses in the present study are the same as those used in DARE-HRT1-001.  
The rationale for the initial selection of these doses is provided here. In the present study, the 
treatment period will be 12 weeks, to allow evaluation of safety and tolerability of DARE-HRT1 
over a longer period, since treatment is intended to be for longer than 28 days. In addition, the 
longer treatment period will allow a preliminary evaluation of the effect of the DARE-HRT1 
IVR on VMS and on VVA signs and symptoms of menopause. 
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 participants randomized to receive a single dose of the 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. 
Mean values of PK parameters observed for both estradiol doses following single administration 
of the two treatments are provided in Table 2-3. 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 2-3 
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, differences in the kinetics of drug release might be expected; thus the reported Cmax 

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and tmax values for Femring are very different from those observed for DARE-HRT1 in the 
previous Phase 1 study (see Section 2.3.1.1). 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 in the Phase 1 study showed that Css 
concentrations were comparable to the Cavg reported for Femring (Table 2-4). 
Table 2-4: 
Estradiol Pharmacokinetics: Femring Versus DARE-HRT1 
Parameter 
Femring 
0.05 mg/day 
Femring 
0.10 mg/day 
DARE Dose 1a 
Estradiol 80 μg/day / 
Progesterone 4 mg/day 
DARE Dose 2a 
Estradiol 160 μg/day / 
Progesterone 8 mg/day 
Cmax 
1129 pg/mL 
1665 pg/mL 
144 pg/mL 
294 pg/mL 
Cavg 
40.6 pg/mL 
76.0 pg/mL 
Css = 20.4 pg/mL 
Css = 30.9 pg/mL 
tmax 
0.9 h 
0.7 h 
12.0 h 
8.0 h 
Abbreviations: Cavg = time-weighted average observed plasma concentration over 24 hours; Cmax = maximum 
observed plasma concentration; Css = steady-state concentration; tmax = time at which the maximum plasma 
concentration was observed 
a 
Values for DARE-HRT1 Dose 1 and Dose 2 are baseline-adjusted values. 
Source: FEMRING Package Insert, 2018 
 
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 
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 

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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 (Table 2-5). The authors also reported an increase in systemic progesterone levels when 
participants were “primed” with estrogen (3 mg/day ethinyl estradiol for 2 weeks) before 
receiving the progesterone treatment (Levy T, et al., 2000). 
Table 2-5: 
Progesterone Pharmacokinetics: Endometrin and Utrogestan Versus 
DARE-HRT1 
Parameter 
Endometrin 
100 mg Tablets 
Utrogestan 
100 mg Capsules 
DARE Dose 1a 
Estradiol 80 μg/day / 
Progesterone 4 mg/day 
DARE Dose 2a 
Estradiol 160 μg/day / 
Progesterone 8 mg/day 
AUC 
380 nmol/h/L 
326 nmol/h/L 
NA 
NA 
Cmax 
31.53 nmol/L 
(9.915 ng/mL) 
23.85 nmol/L 
(7.500 ng/mL) 
4.527 ng/mL 
8.984 ng/mL 
Abbreviations: AUC = area under the plasma concentration-time curve; Cavg = time-weighted average observed 
plasma concentration over 24 hours; Cmax = maximum observed plasma concentration; Css = steady-state 
concentration; NA = not applicable 
a 
Values for DARE-HRT1 Dose 1 and Dose 2 are baseline-adjusted values. 
Source: Levy T et al, 2000 
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). Based on the PK findings from DARE-HRT1-001, the 
baseline-adjusted progesterone Css concentrations associated with both IVR dose 1 and IVR 
dose 2 should be sufficient to suppress estrogen-induced endometrial hyperplasia. 
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 over an extended treatment period of 12 weeks. No control group 
is included; in the first-in-human study, DARE-HRT1-001, an oral treatment group was included 

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to allow a comparison of the PK of estradiol and progesterone by the 2 different administration 
routes; it is not considered necessary to duplicate this comparison here. The present study will 
include an evaluation of the effect of DARE-HRT1 on VVA signs and symptoms (based on 
vaginal pH, vaginal cytology, and most bothersome symptom) and VMS (based on relevant 
Menopause-specific Quality of Life [MENQOL] questions). However, the present study is not 
designed to demonstrate the efficacy of the investigational product (IP) compared to a placebo 
control or active comparator. 

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3 
OBJECTIVES 
3.1 
Primary Objectives 
• To assess the safety and tolerability of DARE-HRT1 IVRs over 12 weeks of use 
• To describe the PK parameters of two different dose combinations of DARE-HRT1 over 
12 weeks: 
o Estradiol 80 μg/progesterone 4 mg/day IVR 
o Estradiol 160 μg/progesterone 8 mg/day IVR 
3.2 
Exploratory Objectives 
• To assess usability and participant tolerability of the DARE-HRT1 IVR  
• To conduct a preliminary evaluation of the effect of the DARE-HRT1 IVR on VMS and on 
VVA signs and symptoms of menopause 

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4 
STUDY DESIGN 
4.1 
Study Design and Overview 
This is a randomized, open-label, 2-arm, parallel group study in approximately 20 healthy 
postmenopausal women with an intact uterus.  
This study is designed to assess the safety and tolerability of DARE-HRT1 IVRs at two dose 
strengths over 12 weeks of use, and to evaluate the PK of progesterone, estradiol, and its 
metabolite estrone, from the IVRs over this extended period. The study also includes a 
preliminary evaluation of the effect of DARE-HRT1 on VVA signs and symptoms (based on 
vaginal pH, vaginal cytology, and most bothersome symptom) and VMS (based on VMS 
questions in MENQOL). In addition, usability and tolerability will be assessed via a 
questionnaire. 
Two treatment groups will be assessed in this study as shown in Table 4-1. 
Table 4-1: 
Treatment Allocations 
Treatment Group 
Number of 
Participants 
Treatment 
IVR Dose 1 
10 
12-week IVR 80/4 (estradiol 80 μg/day + progesterone 4 mg/day),  
replaced every 28 days 
IVR Dose 2 
10 
12-week IVR 160/8 (estradiol 160 μg/day + progesterone 8 mg/day),  
replaced every 28 days 
Participants who have been on prior HRT therapy will be required to complete the following 
washout period prior to randomization (for participants actively using HRT, washout may begin 
only after they have provided 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 
Due to study enrollment goals and the length of the required washout periods, patients who are 
currently on progestogen implants or estrogen alone injectable drug therapy (requiring 3 months’ 
washout) or estrogen pellet therapy or progestogen injectable drug therapy (requiring 6 months’ 
washout) at the time of screening will not be enrolled. 
Where washout of HRT will take approximately 8 weeks, screening procedures should not 
commence until 28 days prior to Day 1. 
Upon completion of their screening procedures and confirmation of their eligibility, eligible 
participants will attend the clinical research unit (CRU) on the morning of Day 1.  
Randomization will occur prior to initiation of treatment. Participants will be randomized in a 
1:1 ratio to the two treatment groups (Table 4-1). 

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Participants will use DARE-HRT1 IVRs for 12 weeks, across three 28-day cycles, with a new 
IVR administered on Day 1 of each cycle. For each cycle, Day 1 is defined as the first day of 
treatment, i.e., the day the IVR is self-administered by the participant. Correct placement of the 
IVR will be confirmed by the study staff. The same IVR is to remain in position for 28 days, 
with removal of the IVR by the participant in the CRU on the morning of Day 1 of the next 
cycle. Participants will use a paper diary to document insertion and removal of the IVR and any 
instances of the IVR falling out, as well as any concomitant medication use. 
In Cycle 1: 
• Baseline PK sampling will occur predose on Day 1 at -1, -0.5 and 0 (within 10 minutes) 
hours prior to insertion of the first IVR. Repeated blood sampling for PK will occur at 0.5, 1, 
2, 4, and 8 hours following insertion. 
In Cycles 2 and 3: 
• Participants will return to the CRU on Day 1. During that visit, the IVR will be removed, 
blood will be drawn for PK (0 hours), and a new IVR inserted immediately (within 
10 minutes) after blood was drawn. Repeated blood sampling for PK will occur at 0.5, 1, 2, 
4, and 8 hours following insertion.  
In Cycles 1, 2, and 3: 
• On the mornings of Days 2 and 3, participants will return to the CRU for a single PK blood 
draw (24 and 48 hours following IVR insertion, respectively). 
• On the morning of Days 8, 15, and 22, participants will return to the CRU for a single PK 
blood draw and safety assessments. 
In Cycle 3 only: 
• On the morning of Cycle 3, Day 29 (EOS), participants will return to the CRU for safety 
assessments, to complete study questionnaires, and for removal of the IVR. Repeated blood 
sampling will be performed before removal of the IVR (0 hours), and at 0.5, 1, 2, 4, and 
8 hours after removal  
• Participants will return to the CRU the following day (Day 30) to provide a single PK blood 
sample 24 hours after IVR removal  
A follow-up telephone call will be made from the CRU to each participant to monitor any 
ongoing or emergent AEs approximately 7 days after the removal of the third IVR. 
Safety assessments will include monitoring of AEs and concomitant medications, clinical 
laboratory findings, physical examinations, vital signs, speculum examinations, and transvaginal 
ultrasounds (and endometrial biopsies, if required).  
Exploratory assessments will include completion of a Usability and Tolerability questionnaire. 
Exploratory assessments will also be conducted to evaluate VVA signs and symptoms (including 

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vaginal cytology, vaginal pH, and most bothersome symptom) and VMS (based on relevant 
MENQOL questions).  
Refer to the schedule of events in Table 1-1 for specific details. 
4.1.1 
Duration of Study 
Participant participation is expected to last up to 121 days, including a 28-day screening period, 
an 86-day on-study period (consisting of an 84-day treatment period and additional sample 
collections), and a follow-up telephone call 7 days after the removal of the third IP). 
4.1.2 
Definition of Study Completion 
End-of-study procedures will be performed as specified in the schedule of events (Table 1-1). 
Participants who terminate from the study early will undergo the same procedures at the time of 
discontinuation as those scheduled for EOS (early termination assessments). Participants with 
ongoing significant clinical or laboratory findings at the time of EOS/early termination will be 
followed until the finding is resolved or medically stable. All reasonable attempts will be made 
to follow-up with participants. 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 participant has completed all study 
procedures up to and including the EOS/early termination visit as specified in the schedule of 
events (Table 1-1). 

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5 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
Participants must meet all the following criteria in order to be enrolled in the study. 
5.1 
Inclusion Criteria 
Participants 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 follicle-stimulating hormone (FSH) levels 
> 40 mIU/mL or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy 
(although participants who have had a hysterectomy are not eligible for this study).  
The investigator will need to determine if a participant’s BMI falling within the obese-
severely obese range could potentially interfere with the protocol-required procedures, 
specifically the pelvic examinations described in Inclusion Criterion #2. Any participant 
whose BMI is determined to fall into this category should be excluded from trial 
participation. 
2. Normal cervix, vagina, uterus, and adnexa based on speculum examination and bimanual 
examination. 
3. Normal transvaginal ultrasound, and endometrial biopsy results as follows:  
• If endometrial thickness is ≤ 4.0 mm in a participant without postmenopausal vaginal 
bleeding, an endometrial biopsy is not indicated for the purposes of screening,  
• If endometrial thickness is > 4.0 mm ≤ 6.0 mm in a participant without 
postmenopausal vaginal bleeding, an acceptable result from an evaluable screening 
endometrial biopsy, evaluated by a pathologist, is required for inclusion into the 
study. Tissue must be read as benign, inactive, or atrophic endometrium by at least 1 
pathologist,  
4. Current on all Australian screening requirements for cervical cancer. 
5. Able and willing to correctly and independently complete all study procedures.  
6. Able and willing to stop any ongoing HRT in accordance with the appropriate washout 
periods (see Section 4.1 for washout requirements). Participants who are using HRT that 
requires more than 8 weeks to wash out (e.g., progestogen implants or progestogen injectable 
drug therapy, estrogen alone injectable drug therapy or estrogen pellet therapy) will not be 
eligible. 

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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 
Participants 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 or Papanicolaou result within 2 years of screening. 
Participant can have atypical squamous cells of undetermined significance, if human 
papillomavirus negative. 
2. Participants with any self-reported active sexually transmitted disease and/or evidence of 
infection based on vaginal visual examination by the investigator. 
3. Participants with a urinary tract infection during screening as assessed by urine dipstick test 
with abnormal test findings (any positive result for leukocytes AND any positive result for 
nitrites). 
4. Have a history of endometrial hyperplasia or cervical or uterine carcinoma. 
5. Participants with indwelling catheters or requiring intermittent catheterization. 
6. Participants with multiple or unsuccessful (e.g., still having symptoms) pelvic reconstructive 
surgery, or who suffer from pelvic relaxation. 
7. Participants who have had a hysterectomy. 
8. Participants taking any estrogen and/or progesterone products who are not willing to stop this 
treatment during their participation in this trial (see Section 4.1 for washout requirements). 
Participants who are using HRT that requires more than 8 weeks to wash out 
(e.g., progestogen implants or progestogen injectable drug therapy, estrogen alone injectable 
drug therapy or estrogen pellet therapy) will not be eligible. 
9. Participants with concomitant use of personal lubricants (water-based lubricants are allowed) 
or any intravaginal product or medication, either by prescription or over-the-counter (OTC) 
(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. 
10. Self-reported or observed vaginal irritation unrelated to VVA; vaginal, vulvar, or cervical 
lesions, undiagnosed vaginal bleeding; or tenderness. 
11. Participants with a finding of clinically significant uterine fibroids at screening. 

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12. Participants with a known hypersensitivity to progesterone, estradiol, Femring, or the 
components of the IVR (e.g., ethylene vinyl acetate). 
13. Participants with prior pelvic malignancies. 
14. Participants 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 participant 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 antibody positive participants 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. Participants with known thrombophilias may not participate in this study because 
estrogen-based products are contraindicated for them, 
g. Symptomatic bacterial vaginosis. 
15. Fasting triglyceride of > 3.39 mmol/L and/or total cholesterol of > 7.77 mmol/L. 
16. Aspartate aminotransferase or alanine aminotransferase > 1.5 times the upper limit of normal. 
17. Fasting glucose > 6.94 mmol/L. 
18. 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 2 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. Use of medical cannabis is not exclusionary. 
19. 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.  

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5.3 
Participant Re-enrollment 
Participants who screen-fail from the study prior to randomization and study product 
administration may be rescreened and re-enrolled as long as the participant 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 rescreening any participant. If the participant is 
rescreened, she must be reconsented and a new participant number must be used. 
5.4 
Participant Withdrawal 
Participants are free to discontinue the study at any time, for any reason, and without prejudice to 
further treatment. The investigator may remove a participant if, in the investigator’s judgment, 
continued participation would pose unacceptable risk to the participant 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 
• Participant noncompliance 
• Safety concern by the investigator or sponsor 
• Lost to follow-up 
Participants who are withdrawn prior to completing all study visits may be replaced. 
In the event of a participant’s withdrawal, the investigator will promptly notify the sponsor and 
medical monitor and will make every effort to complete the EOS assessments. All withdrawn 
participants 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 participants. 
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 product is discontinued, the sponsor shall inform 
all investigators/institutions and regulatory authorities. 

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6 
TREATMENT OF PARTICIPANTS 
6.1 
Identity of Study Products 
A description of the study products is presented in Table 6-1. 
Table 6-1: 
Study Products 
Treatment Group and 
Number of Participants 
Treatment 
IVR Dose 1 
(N=10) 
12-week IVR 80/4 (estradiol 80 μg/day + progesterone 4 mg/day), 
replaced every 28 days 
IVR Dose 2 
(N=10) 
12-week IVR 160/8 (estradiol 160 μg/day + progesterone 8 mg/day), 
replaced every 28 days 
DARE-HRT1 IVRs will be sourced by Daré Bioscience Australia Pty LTD. 
6.2 
Treatments Administered 
Each participant will be assigned to receive an IVR (Dose 1 or Dose 2) for 12 weeks, across 
three 28-day cycles, with a new IVR administered on Day 1 of each cycle. In Cycles 2 and 3, the 
new IVR should be self-administered as soon as possible after the previous IVR has been 
removed. 
For each cycle, Day 1 is defined as the first day of treatment, i.e., the day the IVR is self-
administered by the participant. Correct placement of the IVR will be confirmed by the study 
staff. The same IVR is to remain in position for 28 days, with removal of the IVR by the 
participant in the CRU on the morning of Day 1 of the next cycle. 
If a participant cannot self-insert the IVR, the site physician will insert the IVR. 
At the end of each cycle, participants will remove their own IVR. 
6.3 
Method of Assigning Participants to Treatment Groups 
ICON will prepare the randomization scheme in accordance with its standard operating 
procedures (SOPs) and the randomization plan, which reflect Good Clinical Practice (GCP) 
standards. Refer to Section 9.3 for a description of randomization methods. Eligible participants 
will be assigned to a treatment group according to the list of participant randomization 
assignments. 
6.4 
Measurements of Treatment Compliance 
Treatment compliance of study product administration will be confirmed by PK evaluation and 
participant daily diary. 

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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 products are stored and dispensed in accordance 
with local regulations concerning the storage and administration of investigational drugs. 
6.5.2 
Study Product Accountability and Retention 
The investigator must ensure that all study product 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 products 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 products. Current dispensing records will also 
be maintained including the date and number of study products dispensed and the participant 
receiving the product. All remaining study products 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 a separate 
Study Reference Manual (SRM). 
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 (prescription, OTC, and herbal), with the exception of paracetamol 
up to 650 mg/day (not to exceed 2000 mg total in the 7 days before the first treatment with 
DARE-HRT1), no personal lubricants (with the exception of water-based lubricants), or 
intravaginal products may be administered during the study unless they are prescribed by the 
investigator for treatment of specific clinical events. No concomitant procedures will be 
performed during the study unless approved by the investigator. No vaccinations are allowed 

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other than for coronavirus disease 2019 (COVID-19) unless approved by the investigator. All 
medications (prescription and OTC), vitamin and mineral supplements, and herbal remedies 
taken during the study will be documented on the concomitant medication electronic case report 
form (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 
Participants will be instructed to adhere to the following restrictions: 
• Participants must comply with the CRU smoking policy, if applicable 
• Participants 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 
Participants will undergo study procedures and assessments at time points specified in the 
schedule of events (Table 1-1). 
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 on Cycle 1 Day 1 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 and BMI will be calculated. 
7.4 
Daily Diary 
Participants will use a paper diary to document insertion and removal of the IVR and any 
instances of the IVR falling out, as well as any concomitant medication use (see Appendix C ). 
Diaries will be dispensed at screening, and participants should bring the diary to study visits in 
accordance with the schedule of events (Table 1-1) for review. 
7.5 
Training 
Participants will be trained how to use the IP in accordance with the schedule of events 
(Table 1-1). 
7.6 
Pharmacokinetic Assessments 
7.6.1 
Drug Concentration Measurements 
Plasma PK samples will be collected at time points specified in the PK sampling schedule within 
the schedule of events (Table 1-1). Blood sample collection, processing, and shipping details will 
be outlined in a separate SRM. 
Plasma concentrations of estradiol, estrone, and progesterone will be determined using a 
validated method.  
7.6.2 
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: 
Css 
Steady-state concentration 

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Cmax 
Maximum observed plasma concentration 
tmax 
The time that Cmax was observed 
AUCD1-D29 
Area under the plasma concentration-time curve from time 0 (Day 1) to the 
time of the last quantifiable concentration on Day 29; calculated using the 
linear/log trapezoid rule 
Baseline correction, using the average of the 3 predose concentrations on Day 1, may be 
performed prior to the calculation of PK parameters by noncompartmental methods. The Cmax 
(and tmax) will be computed over each 24-hour PK profile (Day 1 of each cycle) and over the 
entire 28-day treatment interval. Additional PK parameters may be calculated as appropriate. 
7.7 
Safety Assessments 
7.7.1 
Adverse Events 
Participants will be monitored for AEs from the time of consent. Treatment-emergent AEs 
(TEAEs) will be those with an onset after insertion of the first IVR through the follow-up 
telephone call. Serious adverse events will be collected beginning at ICF signing and in an 
ongoing manner through the follow-up telephone call. Refer to Section 8 for additional details. 
7.7.2 
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 administration of study 
product. 
Participants will fast for a minimum of 8 hours prior to clinical laboratory sample collection at 
screening. For subsequent clinical laboratory sample collections, participants will not be required 
to be fasted. 
During screening, if a participant 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., laboratory 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 
participant 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 
Bicarbonate 
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) 
Nitrites 
a. 
Fasting, at screening visit 
For any laboratory test value outside the reference range that the investigator considers to be 
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 which: 
o the investigator considers clinically significant 
o requires a participant to be discontinued from the study 
o requires a participant to receive treatment, or  
o requires a change or discontinuation of the study product (if applicable) 

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7.7.3 
Other Assessments 
The following assessments will be performed: 
• Urine drugs of abuse according to the local standard, including (at a minimum, cocaine, 
tetrahydrocannabinol, amphetamines and opiates), and alcohol screens via urinalysis or a 
commercially available urine dipstick. 
o During the screening period, urine drugs of abuse, and alcohol screens may not be 
repeated for eligibility unless the investigator believes that a positive result is possibly 
attributable to a concomitant medication; a repeat test will be allowed under this 
circumstance.  
• 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 (as needed to confirm postmenopausal status) 
• Transvaginal ultrasound 
• Cervical screening test (if needed) 
• Speculum examination to identify vaginal abnormalities, with a bimanual examination at 
Screening  
• Endometrial biopsy (if needed): any participant experiencing bleeding during the study will 
undergo a transvaginal ultrasound and possible endometrial biopsy. 
• Record prior and concomitant medications (Section 6.7) 
7.7.4 
Vital Signs 
Vital signs assessments will include oral temperature (°C), respiratory rate (breaths per minute), 
systolic and diastolic blood pressure (mmHg) and pulse rate (beats per minute). Blood pressure 
and pulse rate will be measured after the participant 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 participant to be discontinued from the study, require a participant to receive treatment, 
or require a change or discontinuation from the study product (if applicable) will be recorded as 
AEs. 
7.7.5 
Physical Examination 
Comprehensive physical examinations (excluding rectal and breast examinations [unless 
indicated]) will be performed, and abnormal findings will be documented in the participant’s 
eCRF as shown in the schedule of events (Table 1-1). Additional symptom-directed 

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examinations can be performed at all other visits for participants exhibiting signs or reporting 
symptoms since their last visit. 
An abnormal physical examination finding that is considered clinically significant and requires 
the participant to be discontinued from the study, requires the participant to receive treatment, or 
requires a change or discontinuation of the study product (if applicable) will be recorded as an 
AE. 
7.7.6 
Electrocardiograms 
Electrocardiogram assessments will be conducted as a standard check to ensure overall stable 
health prior to trial entry. 
7.7.7 
Appropriateness of Safety Assessments 
Safety evaluations selected for this study are typical of those for this participant population and 
utilize widely accepted measures. 
7.8 
Exploratory Assessments 
7.8.1 
Usability and Tolerability Questionnaire 
A Usability and Tolerability questionnaire (see Appendix A ) will be administered to all 
participants in accordance with the schedule of events (Table 1-1). 
7.8.2 
Vaginal Cytology 
Samples for vaginal cytology will be collected at the time points specified in the schedule of 
events (Table 1-1) to determine the maturation index. Investigators should collect a swab of the 
lateral vaginal wall to be submitted for determination of the vaginal maturation index. 
The maturation index is determined by categorizing the ratio of the 3 types of vaginal epithelial 
cell (parabasal, intermediate, and superficial). 
7.8.3 
Vaginal pH 
Vaginal swabs for determination of pH will be collected in accordance with the schedule of 
events (Table 1-1). The pH of vaginal secretions will be measured using pH paper. Additional 
details and instructions will be provided in the SRM. 
7.8.4 
Most Bothersome Symptom 
At the Cycle 1 Day 1 Visit, participants will rate the first 4 items in the list of VVA symptoms in 
Table 7-2 as either not present (none), mild, moderate, or severe, and will indicate whether 
vaginal bleeding associated with vaginal activity is present or absent. They will then select 1 of 
the 5 symptoms as their most bothersome symptom. All 5 symptoms will be evaluated again 
during later study visits (see Table 1-1), and the change in severity from baseline will be 
determined. Changes from baseline in each participant’s most bothersome symptom will be 
evaluated. 

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Table 7-2: 
Assessment of Most Bothersome Symptom 
Symptom 
Assessment 
Vaginal dryness 
None, mild, moderate, or severe 
Vaginal and/or vulvar irritation/itching 
None, mild, moderate, or severe 
Dysuria 
None, mild, moderate, or severe 
Vaginal pain associated with sexual activity 
(dyspareunia)  
None, mild, moderate, or severe 
Vaginal bleeding associated with sexual activity 
Presence versus absence 
 
7.8.5 
Menopause-specific Quality of Life 
Participants will complete the MENQOL questionnaire (see Appendix B ) on Cycle 1 Day 1 and 
at the end of the study (see Table 1-1). Developed in 1996, the MENQOL is a self-administered, 
29-item questionnaire with 4 domains: vasomotor, physical, psychosocial, and sexual. 
Participants record whether they have experienced the listed problems in the past month, and rate 
the severity on a Likert scale from 0 (Not at all bothered) to 6 (Extremely bothered) (Hilditch JR, 
et al., 1996; Lewis JE, et al., 2005).  
Assessment of the severity of VMS at baseline and at the end of the study will be based on the 
relevant questions from MENQOL. 
 

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8 
ADVERSE EVENTS 
An AE is defined as any untoward medical occurrence in a participant 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/product, whether or not thought to be related to the study drug/product. 
Participants will be monitored for AEs throughout the study from the time of consent. 
Treatment-emergent AEs (TEAEs) will be those with an onset after insertion of the first IVR 
through the follow-up telephone 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 product (Section 8.2.3) 
• Action taken - categorized as dose increased, dose not changed, treatment interrupted, 
treatment 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 product. 

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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 telephone 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 participant 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 participant experiences awareness of signs or symptoms but these are 
easily tolerated or managed without specific treatment 
• Grade 2: Moderate; the participant experiences discomfort enough to cause interference with 
usual activity, and/or the condition requires specific treatment 
• Grade 3: Severe; the participant 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 Product 
The relationship of an AE to the study product 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 participant’s 
clinical condition, intercurrent illness, or concomitant drugs, and does not follow a known 
response pattern to the study product, or the temporal relationship of the event to study 
product administration makes a causal relationship unlikely 
• Unlikely related: The event is most likely produced by other factors such as the participant’s 
clinical condition, therapeutic interventions, or concomitant drugs administered to the 
participant and it does not follow a known response pattern to the study product 
• Possibly related: The event follows a reasonable temporal sequence from the time of study 
product administration, and/or follows a known response pattern to the study product, but 
could have been produced by other factors such as the participant's clinical condition, 
intercurrent illness, or concomitant drugs 
• Related: The event follows a reasonable temporal sequence from the time of study product 
administration, and/or follows a known response pattern to the study product, and cannot be 
reasonably explained by other factors such as the participant's clinical condition, intercurrent 
illness, or concomitant drugs 
8.3 
Discontinuation due to Adverse Events 
Any participant who experiences an AE may be withdrawn at any time from the study at the 
discretion of the investigator. Participants 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 participant’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 
Serious adverse events will be collected beginning at ICF signing and in an ongoing manner 
through the follow-up telephone call. In the event of any SAE reported or observed during the 
study, whether or not attributable to the study product, 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 study-
specific procedure. 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. 

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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 20 healthy, postmenopausal female participants (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 safety, tolerability, and PK of the DARE-HRT1 IVR over a 12-week period. The sample 
sizes provided are deemed sufficient to allow for adequate assessment of the IVR. Dropouts may 
be replaced. Participants who terminate early from the trial may be replaced to ensure an 
adequate number of participants contributing safety data from extended treatment with the IVR 
for each treatment arm. 
9.2 
Analysis Populations 
Safety Population: all enrolled participants who received active treatment, i.e., inserted an IVR 
(and thus who were exposed to one of the IVRs). 
All safety analyses (primary endpoints) will be conducted in the Safety Population. 
Pharmacokinetic Population: all participants who received a full course of study treatment for 
their dispensed treatment and who have sufficient concentration data for determination of PK 
parameters (primary endpoint); data will be analyzed according to the actual study treatment 
received. 
All PK analyses will be conducted in the Pharmacokinetic Population. 
Modified Intent-to-treat (mITT) Population: all enrolled participants who received active 
treatment and who underwent a baseline assessment and at least 1 post-treatment assessment of 
at least 1 of the following exploratory assessments: Usability and Tolerability questionnaire, 
vaginal cytology, vaginal pH, most bothersome symptom, or VMS (MENQOL) 
All exploratory analyses will be conducted in the mITT population. 
9.3 
Randomization 
Upon completion of their screening procedures and confirmation of their eligibility (including a 
transvaginal ultrasound and, if needed, an endometrial biopsy and/or cervical screening test), 
eligible participants will return to the CRU on Cycle 1 Day 1 and will be randomized. 
Randomization will occur prior to initiation of treatment. Participants will be randomized in a 
1:1 ratio to the two treatment groups.  

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9.4 
Endpoints 
9.4.1 
Primary Endpoints 
The primary endpoints are as follows: 
• Incidence and severity of AEs 
• Changes from baseline in clinical laboratory findings 
• Changes from baseline in physical examination findings 
• Changes from baseline in vital signs results 
• Changes from baseline in speculum examination findings 
• Changes from baseline in transvaginal ultrasound findings 
• Steady-state concentration (Css) and maximum observed plasma concentration (Cmax) in each 
cycle for estradiol, estrone, and progesterone 
9.4.2 
Exploratory Endpoints 
Exploratory endpoints are as follows: 
• Responses to the Usability and Tolerability questionnaire 
• Change from baseline to Week 12 in responses to the MENQOL questionnaire  
• Mean change from baseline to Week 12 in the severity of the participant’s VVA signs and 
symptoms 
• Mean change from baseline to Week 12 in the severity of the participant’s most bothersome 
VVA symptom 
• Mean change from baseline to Week 12 in vaginal pH  
• Mean change from baseline to Week 12 in vaginal maturation index (parabasal, intermediate, 
and superficial cells) 
9.5 
Pharmacokinetic Statistical Analysis 
The PK analysis will be performed for each IVR dose. Graphics will be provided to allow for 
visual inspection of the mean and individual participant concentration-time profiles.  
The PK parameters Css, Cmax, tmax, and AUCD1-D29 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.  

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9.6 
Safety Analysis 
Adverse events, concomitant medications, clinical laboratory findings, physical examinations, 
speculum examination findings, transvaginal ultrasound results (and endometrial biopsy findings 
if required), and vital signs for each participant 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. Using the safety population, changes from 
baseline at each post-randomization visit and end of treatment will be compared between 
treatment arms. Qualitative analysis of laboratory tests in terms of abnormality will be 
performed. Findings on physical examination at screening and end of treatment will be reported 
and compared. 
The number and percentage of participants reporting any TEAE will be tabulated by system 
organ class and preferred term for each treatment (coded using Medical Dictionary for 
Regulatory Activities [MedDRA] version 24.1 or later). All TEAEs 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, Human Research Ethics Committee (HREC) 
review, and regulatory review. The investigator must inform the study participant that their 
study-related records may be reviewed by the above individuals without violating the 
participant’s privacy of personal health information in compliance with the Australian Privacy 
Act 1988 regulations. 
By signing this protocol, the investigator affirms to the sponsor that the investigator will 
maintain, in confidence, information furnished to them by the sponsor and will divulge such 
information to the HREC under an appropriate understanding of confidentiality with such 
committee. 

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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 GCP 
(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 HREC; 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 participants will be respected; 
the physicians conducting the study do not find the hazards to outweigh the potential benefits; 
and each participant will give their 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 HREC, except when necessary to eliminate 
immediate hazards to the participant 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 participant having to be 
withdrawn from the study, and may render that participant 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 participant, 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 
• Study product 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 tests not done within the time frame specified in the protocol 
• Procedural deviations such as incorrect storage of IP, failure to update the ICF when new 
risks become known, failure to obtain HREC 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 participant 
risk or the study objectives, or require revision of the ICF, must receive approval from the HREC 
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 participants 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 
Human Research 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 HREC prior to the start of any study procedures. The HREC 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 HREC will approve all protocol amendments (except for Daré Bioscience 
Australia Pty LTD-approved logistical or administrative changes), written informed consent 
documents and document updates, participant recruitment procedures, written information to be 
provided to the participants, available safety information, information about payment and 
compensation available to participants, the investigator’s curriculum vitae and/or other evidence 
of qualifications, and any other documents requested by the HREC and regulatory authority as 
applicable. 
12.2 
Written Informed Consent 
The nature and purpose of the study will be fully explained to each participant (or the 
participant’s legally responsible guardian). The participants 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 
participant (or guardian) prior to any study procedures being performed. 

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13 
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 participant 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 IP. 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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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. 
Hilditch JR, Lewis J, Peter A, et al. A menopause-specific quality of life questionnaire: 
development and psychometric properties. Maturitas. 1996;24(3):161-175. 
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. 
Lewis JE, Hilditch JR, Wong CJ. Further psychometric property development of the Menopause-
Specific Quality of Life questionnaire and development of a modified version, MENQOL-
Intervention questionnaire. Maturitas. 2005;50(3):209-221. 
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. 

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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. 
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, Lethaby A, Kennedy R. Local oestrogen for vaginal atrophy in postmenopausal 
women. Cochrane Database Syst Rev. 2006:4:CD001500. 

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16 
SIGNATURES 
Protocol Number: DARE-HRT1-002 
Protocol Title: A Phase 1/2, Open-label, Parallel Group Study to Evaluate the Safety and 
Pharmacokinetics of DARE-HRT1 (80 μg Estradiol/4 mg Progesterone and 160 μg Estradiol/ 
8 mg Progesterone Intravaginal Rings) Over 12 Weeks in Healthy Postmenopausal Women 
Daré Bioscience Australia Pty LTD Signatures 
This clinical study Protocol Version 1.0, dated 06 January 2022, has been reviewed and 
approved by Daré Bioscience Australia Pty LTD. 
 
 
 
 
 
 
Nadene Zack, MS 
Vice President, Clinical Operations 
 
Date 
 

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Protocol Number: DARE-HRT1-002 
Protocol Title: A Phase 1/2, Open-label, Parallel Group Study to Evaluate the Safety and 
Pharmacokinetics of DARE-HRT1 (80 μg Estradiol/4 mg Progesterone and 160 μg Estradiol/ 
8 mg Progesterone Intravaginal Rings) Over 12 Weeks in Healthy Postmenopausal Women 
Daré Bioscience Australia Pty LTD Signatures 
This clinical study Protocol Version 1.0, dated 06 January 2022, has been reviewed and 
approved by Daré Bioscience Australia Pty LTD. 
 
 
 
 
 
David Friend, PhD 
Chief Scientific Officer 
 
Date 
 

Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-002 
Protocol Version 1.0 
 
CONFIDENTIAL 
Protocol Number: DARE-HRT1-002 
Page 60  
Protocol Number: DARE-HRT1-002 
Protocol Title: A Phase 1/2, Open-label, Parallel Group Study to Evaluate the Safety and 
Pharmacokinetics of DARE-HRT1 (80 μg Estradiol/4 mg Progesterone and 160 μg Estradiol/ 
8 mg Progesterone Intravaginal Rings) Over 12 Weeks in Healthy Postmenopausal Women 
 
Version 1.0: 06 January 2022 
 
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 
 
 
 

Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-002 
Protocol Version 1.0 
 
CONFIDENTIAL 
Protocol Number: DARE-HRT1-002 
Page 61  
17 
APPENDICES 
APPENDIX A  
Usability and Tolerability Questionnaire 
“Usability and Tolerability Questionnaire for Subjects Assigned to an Intravaginal Ring (IVR)” 
(Version 1, 18 December 2021) is provided here. 
 
 
 
 
 
 
 
 
 

Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-002 
Protocol Version 1.0 
 
CONFIDENTIAL 
Protocol Number: DARE-HRT1-002 
Page 62  
Usability and Tolerability Questionnaire for Subjects Assigned to an 
Intravaginal Ring (IVR) 
EASE OF USE 
 
1 
2 
3 
4 
5 
 
Very easy 
Somewhat 
easy 
Neutral; not 
easy or 
difficult 
Somewhat 
difficult 
Very 
difficult 
Ease of insertion 
 
 
 
 
 
Ease of removal 
 
 
 
 
 
 
COMFORT AND CONVENIENCE 
 
1 
2 
3 
4 
5 
 
Strongly 
agree 
Agree 
Neither agree 
or disagree 
Disagree 
Strongly 
disagree 
IVR is comfortable 
when worn 
 
 
 
 
 
IVR is convenient to 
use 
 
 
 
 
 
IVR works with my 
lifestyle 
 
 
 
 
 
 
Please rate the overall comfort of the IVR (circle one): 
1 
2 
3 
4 
5 
Very 
Comfortable 
Comfortable 
Neither 
Comfortable nor 
Uncomfortable 
Uncomfortable 
Very 
Uncomfortable 
 
Question (circle the number that 
best represents how you feel) 
Very 
likely 
Somewhat 
likely 
Neither 
likely nor 
unlikely 
Somewhat 
unlikely 
Very 
Unlikely 
How likely would you be to use 
the intravaginal ring for a 
condition or disease that is 
related to women’s health (e.g., 
hormone replacement, 
overactive bladder, uterine 
fibroids)? 
1 
2 
3 
4 
5 
How likely would you be to use 
the intravaginal ring for a 
condition or disease that is not 
related to women’s health (e.g., 
high blood pressure, diabetes)? 
1 
2 
3 
4 
5 

Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-002 
Protocol Version 1.0 
 
CONFIDENTIAL 
Protocol Number: DARE-HRT1-002 
Page 63  
APPENDIX B  
MENQOL Instrument 
The 1-month recall MENQOL questionnaire is provided here. 
 
 

Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-002 
Protocol Version 1.0 
 
CONFIDENTIAL 
Protocol Number: DARE-HRT1-002 
Page 64  
 
1 
 
 

Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-002 
Protocol Version 1.0 
 
CONFIDENTIAL 
Protocol Number: DARE-HRT1-002 
Page 65  
 
 
2 
 
 

Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-002 
Protocol Version 1.0 
 
CONFIDENTIAL 
Protocol Number: DARE-HRT1-002 
Page 66  
 
 
3 
 
 

Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-002 
Protocol Version 1.0 
 
CONFIDENTIAL 
Protocol Number: DARE-HRT1-002 
Page 67  
 
 
4 
 
 

Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-002 
Protocol Version 1.0 
 
CONFIDENTIAL 
Protocol Number: DARE-HRT1-002 
Page 68  
 
 
5 
 
 

Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-002 
Protocol Version 1.0 
 
CONFIDENTIAL 
Protocol Number: DARE-HRT1-002 
Page 69  
 
 
6 
 
 

Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-002 
Protocol Version 1.0 
 
CONFIDENTIAL 
Protocol Number: DARE-HRT1-002 
Page 70  
 
 
7 
 
 

Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-002 
Protocol Version 1.0 
 
CONFIDENTIAL 
Protocol Number: DARE-HRT1-002 
Page 71  
APPENDIX C  
Participant Daily Diary 
“Daily Diary Questions for Subjects Assigned to an Intravaginal Ring (IVR)” (Version 1, 
18 December 2021) is provided here. 
 
 
 
 
 
 
 
 
 

Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-002 
Protocol Version 1.0 
 
CONFIDENTIAL 
Protocol Number: DARE-HRT1-002 
Page 72  
Daily Diary Questions for Subjects Assigned to an Intravaginal Ring (IVR) 
Date: _______________________ 
Did you take any medications today? 
YES 
 
NO 
<circle one> 
If yes, record medication name, time, reason, and dose below. If no, continue to next question. 
Medication Name 
Time Taken 
Reason Taken 
Dose 
1. 
 
 
 
2. 
 
 
 
3. 
 
 
 
4. 
 
 
 
5. 
 
 
 
 
Did the ring fall out today?  
YES 
 
NO 
<circle one>   
Complete one line for EACH time the ring falls out: 
If yes, time ring fell out:                            Time of reinsertion: ____________              
Activity at time ring fell out (running, walking, lifting, restroom use, sitting, sleeping, 
other, <specify>):__________________________________________ 
If yes, time ring fell out:                            Time of reinsertion: ____________              
Activity at time ring fell out (running, walking, lifting, restroom use, sitting, sleeping, 
other, <specify>):__________________________________________ 
If yes, time ring fell out:                            Time of reinsertion: ____________              
Activity at time ring fell out (running, walking, lifting, restroom use, sitting, sleeping, 
other, <specify>):__________________________________________ 
Did you remove the ring today? 
 
YES 
 
NO 
<circle one>   
Complete one line for EACH time the ring was removed: 
If yes, time ring removed:                            Time of reinsertion: ___________              
Removal reason (discomfort, other, <specify>):_______________________________ 
If yes, time ring removed:                            Time of reinsertion: ___________              
Removal reason (discomfort, other, <specify>):_______________________________ 

Daré Bioscience Australia Pty LTD 
Protocol Number: DARE-HRT1-002 
Protocol Version 1.0 
 
CONFIDENTIAL 
Protocol Number: DARE-HRT1-002 
Page 73  
If yes, time ring removed:                            Time of reinsertion: ___________              
Removal reason (discomfort, other, <specify>):_______________________________ 
Did you experience any of the following today?  
Circle one per question 
Vaginal pain 
Yes 
No 
Vaginal burning 
Yes 
No 
Vaginal itching 
Yes 
No 
Discomfort during physical activity 
Yes 
No 
Discomfort while sitting 
Yes 
No 
Discomfort while standing 
Yes 
No 
Discomfort while lifting an object 
Yes 
No 
Discomfort while using the restroom 
Yes 
No 
Discomfort during sexual activity 
Yes 
No 
Intravaginal ring didn’t feel like it was in the right place 
Yes 
No 
Intravaginal ring felt like it was slipping out 
Yes 
No