Clinical trial NCT05378269
Conditions: Vulvar Atrophy
Sponsor: Daré Bioscience, Inc.
Start date: 2021-11-22; Completion date: 2023-03-01
Enrollment: 17 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to study the safety, PK and PD of Intravaginal Tamoxifen on postmenopausal women with vulvar vaginal atrophy.

Detailed description:

Arms: arm 1: Vaginal insert arm 2: vaginal insert arm 3: vaginal insert arm 4: vaginal insert arm 5: vaginal insert
Interventions: intervention 1: Tamoxifen intervention 2: Placebo
Intervention descriptions: intervention 1: Tamoxifen vaginal insert intervention 2: Placebo vaginal insert

Protocol documents:
Prot_SAP_000.pdf: 
 
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Page 1 of 84 
PROTOCOL AMENDMENT 
 
PRODUCT NAME/NUMBER: 
DARE-VVA1 (Intravaginal Tamoxifen) 
PROTOCOL NUMBER: 
DARE-VVA-001 
IND NUMBER: 
n/a 
NCT NUMBER:  
n/a 
DEVELOPMENT PHASE: 
1/2 
PROTOCOL TITLE: 
Phase 1/2 Study of Intravaginal Tamoxifen 
(DARE-VVA1): Randomized, Double-blind, 
Placebo-controlled Study of Safety, Pharmacokinetics and 
Pharmacodynamics in Postmenopausal Participants with 
Moderate to Severe Vulvar and Vaginal Atrophy 
PROTOCOL DATE: 
Version 1.0, 29-Jun-2021 
AMENDMENT 1 DATE: 
AMENDMENT 2 DATE: 
Version 2.0, 15-Mar-2022 
Version 3.0, 04-Apr-2022 
SPONSORED BY: 
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 
 
This study will be performed in compliance with ICH Good Clinical Practices and applicable 
regulatory requirements, including the archiving of essential documents. Information contained in 
this protocol is confidential in nature, and may not be used, divulged, published, or otherwise 
disclosed to others except to the extent necessary to obtain approval of the institutional review 
board or independent ethics committee, or as required by law. Persons to whom this information 
is disclosed should be informed that it is confidential and may not be further disclosed without the 
express permission of Daré Bioscience Inc. 
 


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1. APPROVAL SIGNATURES 
PROTOCOL NUMBER: 
DARE-VVA1-001 
PROTOCOL TITLE: 
Phase 1/2 Study of Intravaginal Tamoxifen (DARE-VVA1): 
Randomized, Double-blind, Placebo-controlled Study of Safety, 
Pharmacokinetics and Pharmacodynamics in Postmenopausal 
Participants with Moderate to Severe Vulvar and Vaginal Atrophy 
AMENDMENT 1 DATE: 
AMENDMENT 2 DATE: 
Version 2.0, 15-Mar-2022 
Version 3.0, 04-Apr-2022 
I, the undersigned, have read this protocol and confirm that to the best of my knowledge it 
accurately describes the planned conduct of the study. 
SIGNATURE 
 
DATE: 
 
 
 
 
 
 
 
Christine Mauck, MD, MPH 
Medical Director  
Daré Bioscience, Inc. 
 
 
 
 
 
 
 
David Friend, PhD 
Chief Scientific Officer 
Daré Bioscience, Inc. 
 
 
 
 
 
 
 
 
 
 
 


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2. PROTOCOL SUMMARY 
2.1. Synopsis 
 
PRODUCT 
NAME/NUMBER 
Tamoxifen vaginal insert / DARE-VVA1: 1, 5, 10, 20 mg 
PROTOCOL 
NUMBER 
DARE-VVA-001 
DEVELOPMENT 
PHASE 
Phase 1/2 
PROTOCOL TITLE 
Phase 1/2 Study of Intravaginal Tamoxifen (DARE-VVA1): Randomized, Double-blind, 
Placebo-controlled Study of Safety, Pharmacokinetics and Pharmacodynamics in 
Postmenopausal Participants with Moderate to Severe Vulvar and Vaginal Atrophy 
INDICATION 
Moderate to severe vulvar and vaginal atrophy (VVA) 
OBJECTIVES 
Primary:  
• 
To evaluate the safety and tolerability of DARE-VVA1 by intravaginal 
administration 
• 
To determine the plasma pharmacokinetics (PK) of DARE-VVA1 after 
intravaginal application 
Secondary:  
• 
To evaluate preliminary efficacy and pharmacodynamics (PD) of DARE-VVA1 
in terms of most bothersome symptom, dyspareunia, and changes in vaginal 
cytology and pH 
Exploratory: 
• 
To evaluate the impact of DARE-VVA1 on quality of life using a 
menopause-specific instrument 
• 
To assess the usability and acceptability of DARE-VVA1 
RATIONALE 
The use of estrogen-containing products for the treatment of VVA is contraindicated in 
women with hormone receptor-positive (HR+) breast cancer due to their capacity to 
promote tumor growth. There remains a large unmet need for a novel nonhormonal VVA 
treatment for this subset of cancer patients and survivors, and other women who require 
or prefer a treatment option that does not contain estrogen. An exploratory study of 
intravaginal tamoxifen has demonstrated the potential for this selective estrogen receptor 
modulator (SERM), which acts as an estrogen receptor agonist in the vagina and as an 
antagonist in breast tissue, to improve VVA symptoms. The present study will evaluate 
different doses of DARE-VVA1, a tamoxifen vaginal insert, in postmenopausal women 
with VVA, including women with a history of breast cancer, to evaluate safety and 
tolerability, PK, initial responses to treatment, and PD. 
STUDY DESIGN 
This is a randomized, multi-center, double-blind, parallel-arm, placebo-controlled, 
dose-ranging study to evaluate the safety, tolerability, PK, and PD of DARE-VVA1, a 
novel intravaginal tamoxifen product. The investigational product (IP) will be evaluated 
at 4 dose levels (1 mg, 5 mg, 10 mg, and 20 mg) and compared to a placebo vaginal 
insert. The IP will be administered intravaginally for 56 days according to the following 
treatment schedule: once daily for 2 weeks then twice a week for 6 weeks.  
Approximately 40 postmenopausal women with VVA will be enrolled, 20 who have 
undergone hysterectomy and 20 who have not. After signing informed consent, eligible 


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participants will be randomly allocated as follows: the 20 hysterectomized women will 
be allocated to 1 of the 5 treatment groups, and the 20 non-hysterectomized women will 
be randomly allocated to one of the same 5 treatment groups, such that each treatment 
group ends up with 4 hysterectomized women and 4 non-hysterectomized women, for a 
total of 8 women. In each treatment group, participants will have serial blood sampling 
for PK analysis and undergo safety evaluations and preliminary assessments of 
effectiveness. 
Following the completion of treatment, participants will attend a follow-up visit on 
Day 63. 
PLANNED NUMBER 
OF PARTICIPANTS 
A sufficient number of participants will be screened to randomize 40 participants 
(8 participants per group) to the following planned treatment groups:  
Dose 
Level 
Treatment 
Number of  
 Participants  
Placebo 
One placebo insert 
N=8 
1 mg 
One DARE-VVA1 1 mg insert 
N=8 
5 mg 
One DARE-VVA1 5 mg insert 
N=8 
10 mg 
One DARE-VVA1 10 mg insert 
N=8 
20 mg 
One DARE-VVA1 20 mg insert 
N=8 
STUDY ENTRY 
CRITERIA 
This study will enroll healthy postmenopausal females with moderate to severe VVA. 
Participants must meet all inclusion criteria to be eligible for enrollment into the study. 
Participants will not be eligible for entry into this study if they meet any of the exclusion 
criteria and 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. 
Inclusion criteria: 
1. 
Women aged 40-75 (inclusive). 
2. 
Postmenopausal women with a body mass index between 18 and 38 kg/m2, 
inclusive. 
3. 
Postmenopausal, defined as: 
a. 
For non-hysterectomized women, 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. 
b. For hysterectomized women, serum follicle-stimulating hormone 
(FSH) levels > 40 mIU/mL or 6 weeks postsurgical bilateral 
oophorectomy. 
4. 
Have moderate to severe VVA as determined by self-assessment of the 
following symptoms: vaginal dryness, vaginal and/or vulvar irritation/itching, 
dysuria, vaginal pain with sexual activity (dyspareunia) (all self-assessed as 
none, mild, moderate, or severe), or vaginal bleeding associated with sexual 
activity (self-assessed as presence versus absence). To be eligible, at least 1 of 
the first 4 symptoms must be reported as moderate or severe, or vaginal bleeding 
associated with sexual activity must be present. 
5. 
Women who currently have vaginal intercourse or other sexual activity 
(masturbation, etc.) at least once a month (with or without a partner), or who 
had intercourse or other sexual activity at least once a month in the past, but later 
decreased sexual activity due to excessive pain or va ginal dryness. Participants 
must be willing to engage in vaginal intercourse or other sexual activity 
(masturbation, etc.) at least 1 time between Days 49-56 of the clinical study. 


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6. 
Participants, upon pelvic examination with speculum examination, must have a 
normal-appearing vulva other than atrophic changes and normal-appearing 
vagina (without erosions, ulcerations, scarring, or evidence of dermatoses) other 
than atrophic changes (loss of rugae, mucosal pallor, mucosal dryness, mucosal 
petechiae). Women without a cervix must have a normal-appearing vaginal cuff. 
7. 
Women who have not undergone hysterectomy must have: 
a. 
No prior history of endometrial ablation. 
b. Endometrial thickness ≤ 4 mm on transvaginal ultrasound. 
8. 
Women with a cervix must: 
a. 
Have a normal-appearing cervix other than atrophic changes (i.e., 
cervical stenosis and/or flushness with the vaginal wall). 
b. Be current on all recommended screening and management 
requirements for cervical cancer. 
9. 
Vaginal cellular cytology with ≤ 5% superficial cells. 
10. Vaginal pH > 5 at Screening Visit. 
11. Normal mammogram report within 2 years of screening. 
12. Normal manual breast examination by investigator at baseline. 
13. Baseline hematology, clinical chemistry, urinalysis, coagulation, and viral 
serologies for human immunodeficiency virus (HIV), hepatitis C virus (HCV), 
and hepatitis B surface antigen (HBsAg) all within normal limits OR accepted 
by the investigator and medical monitor as not clinically significant. 
14. Normal 12-lead electrocardiogram (ECG).  
15. Able to read, understand, and provide written informed consent and applicable 
data protection authorization after the nature of the study has been fully 
explained, and must be willing to comply with all study requirements. 
16. Willing and able to correctly and independently complete all study procedures. 
Exclusion criteria: 
1. 
A history of or physical examination finding for any significant cardiovascular, 
renal, pulmonary, neurological and hepatic diseases preventing compliance with 
this study. 
2. 
A medical history of or use of anticoagulant drugs to treat or prevent 
coagulopathies, thrombophilia or thromboembolic disease (deep vein 
thrombosis, pulmonary or systemic embolism, stroke, or transient ischemic 
attack). 
3. 
Uncontrolled 
hypertension (either 
systolic 
> 180 mmHg or diastolic 
> 105 mmHg), treatment with Class 1 antiarrhythmics or digitalis, history of 
congestive heart failure (New York Heart Association [NYHA] > Class I), or 
myocardial infarction within 12 months. 
4. 
Women with a cervix cannot have had an abnormal cervical screening test 
within 2 years of screening. Participants can have atypical squamous cells of 
undetermined significance if human papilloma virus-negative. 
5. 
Women who have not undergone hysterectomy cannot have a history of or 
current endometrial pathology: hyperplasia, carcinoma and/or polyp (prior 
history of a benign endometrial polyp with no current evidence of polyp is 
acceptable). 


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6. 
A medical history of breast cancer within 5 years of screening. 
Participants with a history of breast cancer more than 5 years prior to screening 
are considered eligible if their disease was node-negative, nonmetastatic, and if 
all treatment with aromatase inhibitors (AIs) or SERMs was completed at least 
6 months prior to screening. 
7. 
A medical history of malignant melanoma. 
8. 
Any cancer (except nonmelanomatous skin cancer) diagnosed less than 5 years 
prior to the Screening Visit. 
9. 
A medical history of undiagnosed vaginal bleeding. 
10. A known or suspected estrogen-dependent neoplasia. 
11. Previous radiation treatment to the pelvis. 
12. Women who have previously reported an unsatisfactory outcome from a vaginal 
hormone therapy for VVA. 
13. Known hypersensitivity to any ingredients in DARE-VVA1. 
14. Use of vaginal hormonal products (rings, creams, gels, tablets, capsules) within 
4 weeks prior to Day 1. 
15. Use of transdermal estrogen products within 4 weeks prior to Day 1. 
16. Use of oral estrogen therapy within 8 weeks prior to Day 1. 
17. Use of estrogen-alone injectable drug therapy within 12 weeks prior to Day 1. 
18. Administration of estrogen pellet therapy within 6 months prior to Day 1. 
19. Use of thyroid hormone replacement therapy unless the participant is on a stable 
dose for > 6 months, and participant is euthyroid based on a normal, sensitive 
immunoassay for thyroid-stimulating hormone (TSH). 
20. Use of SERMs or AIs within 6 months prior to screening. 
21. Use of anabolic or other steroids (including hormonal creams such as 
testosterone) within 4 weeks prior to Day 1. 
22. Use of corticosteroids, > 5 mg/day prednisone or equivalent, for more than 
4 weeks within 4 weeks prior to Day 1. 
23. Participants with any self-reported active sexually transmitted disease and/or 
evidence of infection (including bacterial vaginosis) on vaginal examination by 
the investigator. 
24. 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). 
25. Women who have not undergone hysterectomy cannot have clinically 
significant uterine fibroids. 
26. 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 the 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. 


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27. 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 the 
Screening Visit (Visit 1). 
28. In the opinion of the investigator, participant has any disorder or finding that 
might interfere with the conduct of the study. 
TEST PRODUCT 
Name: DARE-VVA1 (tamoxifen vaginal insert) 1, 5, 10, and 20 mg 
Dose, route: 1, 5, 10, and 20 mg; vaginal administration by self-placement 
CONTROL 
PRODUCT 
Name: Matching placebo vaginal insert 
Dose, route: vaginal administration by self-placement 
TREATMENT 
REGIMENS 
DARE-VVA1 and placebo inserts will be self-administered by participants for 56 days 
(Days 1 to 56). The IP will be inserted intravaginally in the morning, at approximately 
the same time. Treatment will be administered once a day for the first 2 weeks, followed 
by twice weekly treatment for 6 weeks. The first twice-weekly dose will be administered 
on Day 18 during a study visit. 
PLANNED STUDY 
SITES 
Approximately 3 study sites in Australia. 
CRITERIA FOR 
EVALUATION 
Pharmacokinetics: 
After baseline evaluations including the time 0 venous plasma sample, the Day 1 
DARE-VVA1 dose or matching placebo will be administered. Serial peripheral venous 
samples will be drawn from an indwelling line at 0.5, 1, 2, 4, 5, 8, 12, and 24 hours. The 
same sampling schedule will be used for PK analysis with administration of the Day 56 
vaginal insert. Trough samples will be collected before administration of inserts on 
Days 4, 7, 10, 18, 28, and 42, and a final sample will be collected at follow-up on Day 63. 
Samples will be analyzed using validated methods to determine plasma concentrations of 
tamoxifen and 3 metabolites: 4-hydroxytamoxifen, N-desmethyltamoxifen, and 
N-desmethyl-4-hydroxytamoxifen (endoxifen). 
Safety: 
Observations of safety (self-reported or by examination) will be recorded on an ongoing 
basis. Any irritation, discharge or pain will be reported as an adverse event (AE) using 
standardized Medical Dictionary for Regulatory Activities (MedDRA) codes and graded 
for severity. 
Visual examination by vaginal speculum and full pelvic examination for any vaginal 
inflammation will be conducted at screening, pretreatment (Day 1), during treatment, and 
1 week after treatment. 
Clinical laboratory measurements including full hematology and biochemistry panels will 
be recorded at screening, at baseline, on Days 7, 18, 28, and 57, and 1 week after 
treatment.  
Dipstick urinalysis of a void sample will be reported at screening, at baseline, on Days 7, 
18, 28, and 57, and 1 week after treatment. If abnormal, the sample will be centrifuged 
for microscopic description of cellular elements. 
Vital signs, including pulse rate, respiratory rate, and supine blood pressure, will be 
recorded in a supine position at screening, during the administration period, and 1 week 
after treatment. 
Standard 12-lead ECGs will be recorded at screening, prior to dose on Days 1, 7, 18, 28, 
and 56, at 4 hours postdose on Days 1 and 56, on Day 57, and 1 week after treatment. 


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A complete physical examination (excluding rectal examinations) will be performed at 
screening and will include a manual breast examination. Subsequent physical 
examinations will be abbreviated and will be directed based on signs and symptoms 
exhibited by the participant. 
Pelvic speculum and visual examinations will be conducted to identify vaginal 
abnormalities. Clinically significant abnormal findings from the speculum examination 
will be reported as an AE. Investigators will also conduct an assessment of local irritation; 
erythema and edema will be rated from 0 (none) to 3 (severe). 
Women who have not undergone hysterectomy will have a transvaginal ultrasound to 
determine endometrial thickness. 
Pharmacodynamics and Efficacy:  
Estrogenic effect measurements will include vaginal cytology (maturation index; 
percentage of basal and superficial cells) and vaginal pH at screening and baseline, every 
2 weeks during treatment, and 1 week after treatment. 
Pharmacodynamics will be assessed by correlating the dose administered to exposure of 
tamoxifen in plasma, and then by relating the exposure to local vaginal changes in 
cytology and pH as well as to the reported symptomatology over 56 days. 
Exploratory: 
Menopause-specific Quality of Life (MENQOL) questionnaires will be completed prior 
to dosing on Day 1, and after treatment on Day 57. 
Details of the analysis of the responses to the Usability and Acceptability questionnaire 
will be outlined in the statistical analysis plan. 
STATISTICAL 
METHODS 
General: 
For the purpose of all safety, efficacy, and other analyses where applicable, baseline is 
defined as the last measurement before the start of study drug administration. 
Continuous endpoints will be summarized with number (n), mean, standard deviation, 
median, minimum, and maximum. In addition, change from baseline values will be 
calculated at each time point and summarized descriptively. For categorical endpoints, 
descriptive summaries will include counts and percentages. 
Analysis Populations:  
The ITT population, defined as all randomized participants, will be used to summarize 
participant disposition, demographics and baseline characteristic summaries, efficacy 
endpoints, and exploratory endpoints.  
Efficacy evaluations include changes in vaginal pH, changes in va ginal cytology 
(maturation index; percentage of basal and superficial cells), change in dyspareunia, and 
change in most bothersome symptom. These will be summarized using the ITT 
population. For the analysis the exploratory endpoints, results from the MENQOL 
questionnaire and the Usability and Acceptability questionnaire will be summarized over 
time from baseline in the ITT population. 
An analysis of covariance (ANCOVA) model will be used to assess treatment differences 
in change from baseline for vaginal pH, vaginal cytology, and most bothersome 
symptom, using baseline score as a covariate. With no formal testing planned for this 
study, the P values will be informational. 
The Safety population, defined all participants who are enrolled and receive any amount 
of planned IP, will summarize the recorded AEs, clinical laboratory safety tests, vital 
signs, ECG results, physical examination findings, and any other parameter relevant for 
safety assessment. 


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The PK population consists of all participants who receive at least 1 dose of IP and 
provide at least 1 quantifiable PK plasma sample. This population will be used to 
summarize PK concentrations and parameters over time.  
Pharmacokinetic parameter estimates will be calculated by a standard noncompartmental 
method of analysis; these may include (but are not limited to) measures of the extent of 
absorption using estimates of the area under the plasma concentration-time curve (AUC), 
the maximum observed drug concentration (Cmax), and the time to reach maximum drug 
concentration (Tmax). Other parameters may be included at the discretion of the 
pharmacokineticist and as data permit. 
Participant listings will be provided for all the CRF data. 
SAMPLE SIZE 
DETERMINATION 
This dose ranging study is not powered for statistical significance. A sample size of 
8 participants in each treatment group is considered sufficient to provide information on 
safety, PK, and PD effects, to guide the design of future studies with DARE-VVA1. A 
total of 40 participants is planned for this study. 
STUDY AND 
TREATMENT 
DURATION 
The sequence and maximum duration of the study periods will be as follows: 
1. 
Screening: 21 days 
2. 
Treatment: 56 days 
3. 
Follow-up: 7 days 
The maximum treatment duration for each participant is 56 days. 
The maximum study duration for each participant is approximately 12 weeks. 
 


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2.2. Schedule of Events 
Table 2-1: 
Schedule of Events 
Screening 
Administration Period 
ET 
FU 
Day(s) 
-21 to -1 
1-2a 
4b 
7a,b 
10b 
18b 
28b 
42b 
56-57a 
 
63 
Window 
- 
- 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
- 
±1 
Time from Admin. (hr.) 
 
Pre-dose 
0 
4 
10 
24c 
 
 
 
 
 
 
Pre-dose 
0 
4 
10 
24c 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
Physical examd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vaginal speculum exame 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
Mammogramf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cervical screening testg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsh 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
12-Lead ECGi 
X 
X 
 
X 
 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Serum biochemistry 
X 
X 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
X 
X 
X 
Hematology 
X 
X 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
X 
X 
X 
Coagulation panel 
X 
X 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
X 
 
X 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSHj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drugs of abusek 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral serologyl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaginal pHm 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
Vaginal cytology 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
Transvaginal ultrasound 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Assessment of VVA 
symptomso 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
Diary administration and 
reviewp 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
 
Study drug administrationq 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
MENQOL 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Usability and Acceptability 
questionnaire 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
PK blood samplesr 
 
X 
0.5, 1, 2, 4, 5, 8, 
12 (hr.) 
X 
X 
X 
X 
X 
X 
X 
X 
0.5, 1, 2, 4, 5, 8, 
12 (hr.) 
X 
 
X 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE = adverse event; ECG = electrocardiogram; ET = early termination; FSH = follicle-stimulating hormone: FU = follow-up; HBsAg = hepatitis 
B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; hr. = hour; IP = investigational product; MENQOL = Menopause-specific 
Quality of Life; PK = pharmacokinetics; TSH = thyroid-stimulating hormone; VVA = vulvar vaginal atrophy  


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a. 
Multiple non-PK assessments scheduled for the same time point should be performed on the same day as dosing. PK blood sample procedures should 
follow the defined window, if applicable. 
b. Samples for PK trough levels should be obtained prior to DARE-VVA1 insertion on Days 4, 7, 10, 18, 28, and 42. Administration of DARE-VVA1 will 
take place at site on the day of these visits, after collecting the trough PK sample. 
c. 
Participants will be discharged from the site after all 24-hour assessments have been completed. Day 1-2 only: Administration of DARE-VVA1 should 
be the final activity before discharge, following completion of all 24-hour assessments. 
d. A complete physical examination (excluding rectal examinations) will be performed at screening and will include a manual breast examination. Subsequent 
physical examinations will be abbreviated and will be directed based on signs and symptoms exhibited by the participant. 
e. 
Vaginal speculum examinations will include assessment of local irritation (scoring of erythema and edema), and a full pelvic examination.  
f. 
Mammograms should be conducted ONLY in those participants who have not had one within the last 2 years. 
g. Cervical screen testing should be conducted ONLY in those participants who have a cervix and have not had cervical screening within the last 5 years. 
h. Vital signs assessments will include pulse rate, respiratory rate, and supine blood pressure. Assessments will be performed after the participant has been 
in a supine position for at least 5 minutes. Temperature will also be measured. 
i. 
12-lead ECGs will be performed after the participant has been supine for at least 5 minutes. 
j. 
FSH will be assessed in all hysterectomized women who have not undergone bilateral oophorectomy, and in  non-hysterectomized women who have not 
undergone bilateral oophorectomy and have experienced spontaneous amenorrhea for ≥ 6 months but < 12 months, to confirm postmenopausal status. 
k. Drugs of abuse will be measured at screening by local laboratories via urinalysis and alcohol screens versus a commercially available urine dipstick.  
l. 
Viral serology: a blood sample will be collected for the determination of HIV, HCV, and HBsAg. 
m. Vaginal pH will be evaluated using commercially available pH strips. 
n. Transvaginal ultrasound will be performed on women who have not undergone a hysterectomy. During screening, the pelvic examination, with assessment 
of local irritation and cervical screening (if needed), should be performed prior to the transvaginal ultrasound. 
o. Participants will be required to engage in vaginal intercourse or other sexual activity (masturbation, etc.) at least 1 time between Days 49-56, and complete 
an assessment of VVA symptoms in their diary.  
p. Diaries will be provided to participants at screening, and participants will be trained on their completion. Participants will record their administration of 
DARE-VVA1 in the diary, including the time of placement. Study staff should instruct participants to bring their diaries to all site visits for review. 
q. On Days 4, 7, 10, 18, 28, and 42, participants should not self-administer the IP at home; blood samples for trough PK assessments should be collected at 
site before the IP is administered. 
r. 
Permissible windows for PK sampling are as follows: 0.5 hours and 1 hours = ±10 minutes; 2, 4, 5, 8, 12, and 24 hours = ±15 minutes. Trough samples 
collected on Days 4, 7, 10, 18, 28, and 42 should be collected within 30 minutes before IP administration. 
s. 
Adverse event information will be collected at the specified time points, as well as at any time when a clinical research unit staff member becomes aware 
of an AE during the administration period. 
 


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3. TABLE OF CONTENTS 
1. 
APPROVAL SIGNATURES .................................................................................................. 2 
2. 
PROTOCOL SUMMARY....................................................................................................... 3 
2.1. Synopsis ......................................................................................................................... 3 
2.2. Schedule of Events ....................................................................................................... 10 
3. 
TABLE OF CONTENTS ...................................................................................................... 12 
3.1. List of In-text Tables .................................................................................................... 16 
3.2. List of In-text Figures................................................................................................... 16 
AMENDED PROTOCOL ............................................................................................................ 17 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................... 18 
5. 
INTRODUCTION ................................................................................................................. 20 
5.1. Background and Rationale ........................................................................................... 20 
5.2. Nonclinical Experience ................................................................................................ 21 
5.3. Clinical Experience ...................................................................................................... 21 
5.4. Summary of Potential Risks and Benefits.................................................................... 22 
6. 
OBJECTIVES ........................................................................................................................ 24 
6.1. Primary Objective ........................................................................................................ 24 
6.2. Secondary Objectives ................................................................................................... 24 
6.3. Exploratory Objectives................................................................................................. 24 
6.4. Objectives and Endpoints ............................................................................................. 24 
7. 
STUDY DESIGN .................................................................................................................. 26 
7.1. Overall Study Design and Plan .................................................................................... 26 
7.2. Rationale and Discussion of Study Design .................................................................. 27 
7.3. Selection of Doses in the Study.................................................................................... 28 
7.4. Study Sites .................................................................................................................... 28 
7.5. End of Study Definition ............................................................................................... 28 
8. 
PARTICIPANT POPULATION ........................................................................................... 29 
8.1. Selection of Study Population and Diagnosis .............................................................. 29 
8.2. Study Entry Criteria ..................................................................................................... 29 
8.2.1 Inclusion Criteria .............................................................................................. 29 
8.2.2 Exclusion Criteria ............................................................................................. 30 
8.3. Premature Participant Withdrawal ............................................................................... 32 
8.4. Discontinuation of Investigational Product.................................................................. 32 
8.5. Participant Discontinuation/Withdrawal from the Study ............................................. 32 
9. 
TREATMENTS ..................................................................................................................... 34 
9.1. Identification of Investigational Products .................................................................... 34 
9.2. Selection of Timing of Dose for Each Participant ....................................................... 34 
9.3. Dose Adjustment Criteria ............................................................................................. 34 


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9.4. Treatment Compliance ................................................................................................. 34 
9.5. Method of Assigning Participants to Treatment Groups.............................................. 35 
9.6. Blinding and Unblinding Treatment Assignment ........................................................ 35 
9.7. Permitted and Prohibited Therapies ............................................................................. 36 
9.7.1 Permitted Therapies .......................................................................................... 36 
9.7.2 Prohibited Therapies......................................................................................... 36 
9.7.3 Restrictions ....................................................................................................... 37 
9.8. Treatment After End of Study ...................................................................................... 37 
9.9. Dispensing and Storage ................................................................................................ 37 
9.10. Drug Accountability ..................................................................................................... 38 
9.11. Labeling and Packaging ............................................................................................... 38 
10. STUDY PROCEDURES ....................................................................................................... 39 
10.1. Study Duration ............................................................................................................. 39 
10.1.1 Overall Study Schedule .................................................................................... 39 
10.2. Study Periods and Visits .............................................................................................. 39 
10.2.1 Screening .......................................................................................................... 39 
10.2.2 Double-blind Treatment Period ........................................................................ 39 
10.2.2.1 Day 1 to 2 ............................................................................................. 39 
10.2.2.2 Days 4, 7, 10, 18, 28, and 42 ................................................................ 40 
10.2.2.3 Day 56 to 57 ......................................................................................... 40 
10.2.3 Early Termination Visit .................................................................................... 41 
10.2.4 Day 63 Follow-up Evaluation .......................................................................... 41 
10.3. Assessments ................................................................................................................. 41 
10.3.1 Safety Variables................................................................................................ 41 
10.3.1.1 Clinical Laboratory Safety Assessments.............................................. 41 
10.3.1.2 Clinical Examinations .......................................................................... 42 
10.3.1.3 Adverse Events..................................................................................... 44 
10.3.2 Clinical Pharmacology ..................................................................................... 44 
10.3.2.1 Pharmacokinetic Analysis Methods ..................................................... 44 
10.3.3 Pharmacodynamics and Efficacy Variables ..................................................... 45 
10.3.3.1 Vaginal pH ........................................................................................... 45 
10.3.3.2 Vaginal Cytology ................................................................................. 45 
10.3.3.3 Symptoms of Vulvar Vaginal Atrophy ................................................ 46 
10.3.3.4 Menopause Quality of Life .................................................................. 46 
10.3.3.5 Usability and Acceptability Questionnaire .......................................... 46 
10.3.3.6 Participant Diaries ................................................................................ 46 
10.3.3.7 Pharmacodynamics............................................................................... 47 
11. ADVERSE EVENTS............................................................................................................. 48 


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11.1. Definitions .................................................................................................................... 48 
11.1.1 Adverse Events ................................................................................................. 48 
11.1.2 Adverse Drug Reaction .................................................................................... 48 
11.1.3 Unexpected Adverse Event/Adverse Drug Reaction ....................................... 48 
11.1.4 Serious Adverse Events or Serious Drug Reactions......................................... 49 
11.1.5 Significant Adverse Events .............................................................................. 49 
11.1.6 Treatment-emergent Adverse Events ............................................................... 49 
11.2. Event Assessment and Follow-up of Adverse Events.................................................. 50 
11.2.1 Assessment ....................................................................................................... 50 
11.2.2 Evaluation ......................................................................................................... 50 
11.2.2.1 Severity of Adverse Events .................................................................. 50 
11.2.2.2 Seriousness ........................................................................................... 51 
11.2.2.3 Actions Taken ...................................................................................... 51 
11.2.2.4 Outcome at the Time of Last Observation ........................................... 51 
11.2.2.5 Adverse Event Relationship to Investigational Product....................... 52 
11.2.3 Documentation ................................................................................................. 52 
11.2.4 Treatment of Adverse Events ........................................................................... 52 
11.2.5 Follow-up ......................................................................................................... 53 
11.2.6 Reporting .......................................................................................................... 53 
11.2.6.1 Serious Adverse Events........................................................................ 53 
11.2.6.2 Adverse Drug Reactions....................................................................... 54 
11.2.6.3 Nonserious Adverse Events ................................................................. 54 
11.3. Special Considerations ................................................................................................. 54 
11.3.1 Pregnancy ......................................................................................................... 54 
12. DATA SAFETY MONITORING BOARD .......................................................................... 55 
13. STATISTICS ......................................................................................................................... 56 
13.1. Statistical Analysis ....................................................................................................... 56 
13.1.1 Analysis Populations ........................................................................................ 56 
13.1.2 Study Participants and Demographics .............................................................. 56 
13.1.2.1 Disposition and Withdrawals ............................................................... 56 
13.1.2.2 Protocol Deviations .............................................................................. 56 
13.1.2.3 Demographics and Other Baseline Characteristics .............................. 57 
13.1.3 Exposure and Compliance ................................................................................ 57 
13.1.4 Safety and Tolerability Analyses...................................................................... 57 
13.1.4.1 Adverse Events..................................................................................... 58 
13.1.4.2 Clinical Laboratory Evaluations........................................................... 58 
13.1.4.3 Vital Signs ............................................................................................ 58 
13.1.4.4 Twelve-lead Electrocardiograms.......................................................... 58 


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13.1.4.5 Local Site Irritation .............................................................................. 59 
13.1.4.6 Physical Examination Findings ............................................................ 59 
13.1.4.7 Endometrial Thickening ....................................................................... 59 
13.1.4.8 Prior and Concomitant Medications..................................................... 59 
13.1.5 Pharmacokinetics.............................................................................................. 59 
13.1.6 Pharmacodynamics and Efficacy Analysis ...................................................... 59 
13.1.6.1 Primary Analysis .................................................................................. 59 
13.1.6.2 Secondary Analyses ............................................................................. 60 
13.1.6.3 Exploratory Analyses ........................................................................... 60 
13.1.7 Interim Analysis ............................................................................................... 60 
13.2. Sample Size Determination .......................................................................................... 61 
14. STUDY CONDUCT.............................................................................................................. 62 
14.1. Sponsor and Investigator Responsibilities ................................................................... 62 
14.1.1 Sponsor Responsibilities .................................................................................. 62 
14.1.2 Investigator Responsibilities ............................................................................ 62 
14.1.3 Confidentiality and Privacy .............................................................................. 62 
14.2. Site Initiation ................................................................................................................ 63 
14.3. Screen Failures ............................................................................................................. 63 
14.4. Study Documents ......................................................................................................... 63 
14.4.1 Informed Consent ............................................................................................. 63 
14.4.2 Good Clinical Practice Documents .................................................................. 64 
14.4.3 Case Report Forms ........................................................................................... 64 
14.4.4 Access to Source Data/Documents................................................................... 64 
14.5. Study Management....................................................................................................... 65 
14.5.1 Monitoring Procedures ..................................................................................... 65 
14.5.2 Data Management............................................................................................. 65 
14.5.3 Quality Control and Quality Assurance/Audit ................................................. 65 
14.6. Study Termination ........................................................................................................ 66 
14.6.1 Regular Study Termination .............................................................................. 66 
14.6.2 Premature Study Termination........................................................................... 66 
14.7. Study Site Closure ........................................................................................................ 67 
14.7.1 Record Retention .............................................................................................. 67 
14.7.2 Sample Retention.............................................................................................. 67 
14.8. Changes to the Protocol................................................................................................ 67 
14.9. Use of Information and Publication ............................................................................. 67 
15. ETHICAL AND LEGAL CONSIDERATIONS ................................................................... 69 
15.1. Declaration of Helsinki ................................................................................................ 69 
15.2. Participant Information and Informed Consent and/or Assent..................................... 69 


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15.3. Institutional Review Board/Independent Ethics Committee Approval........................ 70 
15.3.1 Ethics Review Prior to Study ........................................................................... 70 
15.3.2 Ethics Review of Other Documents ................................................................. 70 
16. REFERENCES ...................................................................................................................... 71 
17. ATTACHMENTS.................................................................................................................. 73 
17.1. Investigator’s Agreement ............................................................................................. 73 
APPENDICES .............................................................................................................................. 75 
A. 
Study-specific Requirements........................................................................................ 76 
B. 
Regulations and Good Clinical Practice Guidelines .................................................... 84 
 
 
3.1. List of In-text Tables 
Table 2-1: 
Schedule of Events ........................................................................................... 10 
Table 9-1: 
Study Design – Treatment Groups ................................................................... 34 
Table 10-1: 
Local Irritation Scoring .................................................................................... 44 
Table 10-2: 
Pharmacokinetic Parameters ............................................................................ 45 
Table 10-3: 
Assessment of Most Bothersome Symptom ..................................................... 46 
 
3.2. List of In-text Figures 
Figure 7-1: 
Study Design .................................................................................................... 26 


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AMENDED PROTOCOL 
The following are the amended protocol and appendices. 
 


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4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ABBREVIATION 
EXPLANATION 
λz 
terminal rate constant 
ADR 
adverse drug reaction 
AE 
adverse event 
AI 
aromatase inhibitor 
APTT 
activated partial thromboplastin time 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the plasma concentration-time curve 
BMI 
body mass index 
BP 
blood pressure 
Cmax 
maximum observed plasma drug concentration 
CRA 
clinical research associate 
CRF 
case report form 
CSR 
clinical study report 
CST 
cervical screening test 
DMP 
data management plan 
DVT 
deep vein thrombosis 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eCRF 
electronic case report form 
FSH 
follicle-stimulating hormone 
FU 
follow-up 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
hr. 
hour 
HR+ 
hormone receptor-positive 
HREC 
Human Research Ethics Committee 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
INR 
International Normalized Ratio 
IP 
investigational product 
ITT 
intent-to-treat 


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ABBREVIATION 
EXPLANATION 
NYHA 
New York Heart Association 
MedDRA 
Medical Dictionary for Regulatory Activities 
MENQOL 
Menopause-specific Quality of Life (questionnaire) 
OTC 
over-the-counter 
Pap 
Papanicolaou (test) 
PD 
pharmacodynamics 
PE 
pulmonary embolism 
PK 
pharmacokinetics 
PT 
prothrombin time 
RBC 
red blood cell 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SERM 
selective estrogen receptor modulator 
THC 
tetrahydrocannabinol 
TIA 
transient ischemic attack 
t1/2 
plasma terminal half-life 
Tmax 
time of occurrence of maximum observed plasma drug concentration 
TSH 
thyroid-stimulating hormone 
UTI 
urinary tract infection 
VVA 
vulvar and vaginal atrophy 
WHO-DD 
World Health Organization Drug Dictionary 


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5. INTRODUCTION 
5.1. Background and Rationale 
Vulvar and vaginal atrophy (VVA) is a common and underreported condition that is a result of 
decreased estrogenization leading to thinning of the vaginal epithelium.1,2 Typical symptoms 
include vaginal dryness, itching, burning, and painful intercourse, adversely impacting quality of 
life. Clinical findings include the diagnostic presence of pale and dry vulvovaginal mucosa with 
petechiae, as well as a vaginal pH > 5. Vulvar and vaginal atrophy most commonly occurs in the 
postmenopausal phase, during which the prevalence is close to 50%.3  
Over-the-counter (OTC) remedies such as vaginal moisturizers and lubricants can provide 
temporary symptomatic treatment at the time of use. Localized estrogen therapy 
(i.e., estrogen-containing creams, rings, and suppositories) can treat the underlying physiologic 
issue and is the most commonly prescribed treatment by physicians for VVA. However, this 
therapeutic approach is contraindicated for women with hormone receptor-positive (HR+) breast 
cancer. In addition to surgery and/or radiation, many of these women are treated with aromatase 
inhibitors (AIs), which deplete the body of estrogen and induce a menopausal state irrespective of 
age. Consequently, the prevalence of VVA in HR+ breast cancer survivors is an estimated 70%.4,5 
Although localized estrogen therapy is highly effective in reducing the symptoms of VVA in 
otherwise healthy women, it is a suboptimal intervention for HR+ patients and survivors because 
of the prolific response of these tumors to the presence of estrogen in the surrounding tissue. As a 
result of this safety concern, the current estrogen products on the market for the treatment of VVA 
are labeled as being contraindicated when the patient has a “known, suspected, or a history of 
breast cancer”. Oncologists, obstetricians, gynecologists, and primary care providers are reluctant 
to prescribe any estrogen-based products owing to concerns of reintroducing estrogen into the 
system, despite the low dose and topical delivery. 
Daré Bioscience, Inc. (Daré) is developing a novel local application of tamoxifen to mitigate the 
symptoms of VVA for patients with or at risk for HR+ breast cancer, including women currently 
on anticancer therapy. There remains a large unmet need for a novel nonhormonal VVA treatment 
specifically developed for this subset of cancer patients and survivors, and other women who 
require or prefer a treatment option that does not contain estrogen. 
Selective estrogen receptor modulators (SERMs) represent an exciting new option for the 
treatment of VVA in an HR+ patient population. Tamoxifen is a well-known and 
well-characterized SERM that has been prescribed by oncologists for decades for the treatment of 
breast cancer. Tamoxifen acts as an estrogen antagonist in the breast; it binds estrogen receptors 
in the breast tissue, effectively blocking natural estrogen from binding to these sites, and is 
therefore an effective HR+ breast cancer treatment. In contrast, in other tissues such as uterine and 
vaginal tissues, tamoxifen acts as an estrogen agonist, producing similar physiological responses 
to those produced by estrogen, without being a true estrogen.  
Studies of tamoxifen conducted over the last 40 years have documented the estrogen-like effects 
of this SERM on vaginal epithelium.6-14 A preliminary clinical study of intravaginally administered 
tamoxifen in postmenopausal women further supports the potential for locally administered 
tamoxifen to have positive effects that counter VVA in the vaginal tissue without significant 
systemic absorption (see Section 5.3). Localized tamoxifen therapy thus has the potential to 
counter the physiologic changes that lead to VVA without introducing estrogen back into the 
system. Together, these studies establish a strong scientific rationale for the continued 


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development of DARE-VVA1, as a novel intervention expected to modulate the symptoms of 
VVA in an HR+ breast cancer population without the use of estrogen-based hormones. 
5.2. Nonclinical Experience 
Vaginal tamoxifen has been evaluated in rats and rabbits. In a 3-day repeat-dose study 
(Study 3015-001) in ovariectomized female rats, intravaginal tamoxifen was evaluated at doses of 
0.2 mg/kg/day, 2.0 mg/kg/day, and 20 mg/kg/day.15 No vaginal irritation was observed at any 
dose. A dose-dependent increase in uterine wet weight was observed at all dose levels, which 
correlated 
with 
luminal 
epithelial 
and 
myometrial 
hypertrophy 
and 
stromal 
hypertrophy/hyperplasia. Microscopic evaluation showed minimal to mild focal erosions in the 
vagina at the highest dose and mild epithelial hyperplasia at all doses. A 28-day study in rabbits 
(Study 2110-001) evaluated 2 doses (1 mg and 20 mg) of tamoxifen. Inappetence was observed, 
and body weight gain was reduced at 1.0 mg, while body weight loss was observed at 20 mg. No 
test article-related vaginal irritation was observed, with sporadic findings of erythema and edema 
comparable to those seen in vehicle-treated animals. 
From previous studies in rabbits, the absorption of tamoxifen from the vagina is expected to be 
relatively rapid. In rabbits, the Tmax was 0.5 to 1.0 hour following vaginal administration of 1.0 mg 
and 20 mg tamoxifen. As stated above, this formulation is designed to release tamoxifen rapidly 
following disintegration of the gelatin capsule. The time points in the DARE-VVA1-001 study 
were chosen to collect information over the time frame when plasma concentrations are expected 
to rise and reach a steady state. There are samples taken intensively over the first 24 hours and 
then periodically up to 8 weeks (56 days). Following oral administration of tamoxifen, Tmax is 
about 5 hours. The present study will also examine PK during the time after the last dose intensely 
over 24 hours. As noted, tamoxifen has a long half-life following oral administration (5 to 7 days 
based on Nolvadex labeling16, and its metabolites can have longer half-lives). Attempting to collect 
data through several half-lives following the last vaginal dose would unduly prolong the study and 
likely not provide any new information about tamoxifen. Nonetheless, the present amendment 
removes 3 sampling time points on Day 1 and Day 56 (i.e., samples at 3 hours, 6 hours, and 18 
hours) since these are not expected to contribute to understanding of the pharmacokinetic profiles 
and parameters. 
5.3. Clinical Experience 
Daré’s drug product DARE-VVA1 has not been tested before in humans. Previously, an 
exploratory study of vaginal tamoxifen has been conducted in 4 healthy postmenopausal women, 
in which a vaginal suppository containing 13 mg tamoxifen was formulated by a compounding 
pharmacist.17 Participants self-administered the suppository once a day for 1 week, before moving 
to a twice-per-week schedule. Blood concentrations of tamoxifen were measured at 8 weeks, with 
samples collected 5 hours after insertion. Additional assessments included measurements of 
vaginal pH and improvement of vaginal dryness, and monitoring of adverse events (AEs). 
After 3 months of treatment, the median vaginal pH was 5.0 (range: 5.0 to 5.2), compared to 
7.1 (range: 6.5 to 7.5) at baseline, with a median paired difference of 2.0 (range: 2.5 to 1.5). 
Self-assessments of dryness using a visual analog scale from 0 (participant not bothered by 
dryness) to 10 (participant extremely bothered by dryness) showed an improvement, from a 
median score of 8 (range: 7.5 to 9.0) at baseline to 3.0 (range: 2.0 to 3.0) after 3 months, with a 
median paired difference of 5.5 (range: 6.0 to 4.5). 


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All 4 participants completed the 3-month treatment period. No AEs were reported, and there were 
no changes to vital signs. Measurements of blood concentrations of tamoxifen at 8 weeks were 
conducted for all 4 participants; the median plasma concentration of tamoxifen was 5.8 ng/mL 
(range: 1.0 to 10.0 ng/L). In comparison, after once daily oral treatment with 20 mg tamoxifen for 
3 months, the average steady state plasma concentration of tamoxifen is 122 ng/mL (range 71.0 to 
183.0 ng/mL).16 
This exploratory study demonstrated that vaginal administration of tamoxifen represents a possible 
new treatment approach for postmenopausal women with VVA. With this route of administration, 
tamoxifen demonstrated clinically relevant physiological changes, while systemic absorption of 
the study drug was not clinically relevant, with systemic exposure less than 10% of that seen when 
the same dose is administered orally.16 The local action of tamoxifen on the vaginal epithelium 
suggests that the parent compound itself is estrogenic and not metabolized locally in the vaginal 
epithelium, but predominantly systemically into anti-estrogens. Together, these results suggest that 
tamoxifen could be beneficial for the treatment of VVA in patients who are at risk of breast cancer, 
due to its local activity as an estrogen, and systemic activity as an estrogen antagonist. 
5.4. Summary of Potential Risks and Benefits 
The potential benefits of study participation are that participants with VVA may experience a 
reduction in the symptoms associated with VVA as a result of treatment with DARE-VVA1. No 
other benefits of participation are anticipated. 
The potential risks of study participation include those associated with exposure to tamoxifen and 
the excipients found in DARE-VVA1 and the risks of medical evaluation, including venipuncture.  
Oral tamoxifen (tablets or solution) is approved for the treatment of estrogen receptor-positive 
metastatic breast cancer and to reduce the risk of breast cancer in women at high risk.18 The label 
includes a boxed warning concerning the risk of uterine malignancies, stroke, and pulmonary 
embolism. General warnings include risks of thromboembolic events (although this risk is greater 
when co-administered with chemotherapy), embryo-fetal toxicity (which is not a risk in the present 
study population), and liver cancer and liver abnormalities.  
The National Surgical Adjuvant Breast and Bowel Project reported relative risks of serious events 
in a double-blind, placebo-controlled study of 5 years’ treatment with tamoxifen (20 mg per day) 
designed to evaluate whether treatment would reduce the incidence of invasive breast cancer in 
high-risk women. After a median treatment duration of 3.5 years in 13,388 women, the rates (per 
1,000 women per year) for major outcomes were as follows: 
Major Outcomes 
Rates for tamoxifen 
(per 1,000 women per year) 
Rates for placebo 
(per 1,000 women per year) 
Endometrial adenocarcinoma 
2.20 
0.71 
Uterine sarcoma 
0.17 
0.0 
Stroke 
1.43 
1.00 
Pulmonary emboli 
0.75 
0.25 
Deep vein thrombosis 
1.26 
0.79 
Cataracts 
25.41 
22.51 
Source: Soltamox label18 


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In addition to these serious risks, the most common adverse reactions with oral tamoxifen include 
hot flashes, mood disturbances, vaginal discharge, vaginal bleeding, nausea, and fluid retention.18 
In the present study, steps will be taken to reduce the risks associated with the use of tamoxifen. 
In addition to limiting the treatment duration to 56 days, and to the reduction of systemic exposure 
afforded by the use of intravaginal administration, the present study has been designed with 
eligibility criteria that will exclude participants who might be at particular risk of experiencing the 
more serious side effects of tamoxifen, while regular safety monitoring will be performed. Eligible 
participants who have not undergone hysterectomy will have no history of endometrial ablation or 
endometrial hyperplasia, with ultrasound at screening showing endometrial thickness ≤ 4 mm. 
Participants with a cervix will also have an up-to-date cervical cancer screening record. All 
participants must have a normal mammogram within 2 years of screening; participants who have 
not had a mammogram in the last 2 years, or have a cervix but have not had a cervical screening 
test (CST) in the last 5 years, will be required to undergo these assessments during screening. 
Participants will be excluded if they have any of the following: a history of coagulopathies, 
thrombophilia, thromboembolic disease, or significant transient ischemic attack; significant 
cardiac history; recent history of breast cancer (or suspicion of breast cancer), abnormal cervical 
screening result within 2 years; endometrial pathology; known or suspected estrogen-dependent 
neoplasia. Safety monitoring will include 12-lead electrocardiograms (ECGs) to evaluate possible 
cardiac problems; laboratory assessments will include measurement of liver functions tests and 
clotting parameters, to monitor hepatic safety and potential embolism/thrombotic events, 
respectively; and regular vaginal inspection. Due to the reported risks of endometrial 
adenocarcinoma and uterine sarcoma, transvaginal ultrasounds will be performed at screening on 
women who have not undergone hysterectomy in order to measure endometrial thickness. 
In the present study, participants allocated to active treatment will receive tamoxifen intravaginally 
for 56 days, at doses ranging from 1 mg per day to 20 mg per day for 2 weeks, before moving to a 
twice-weekly regimen. Administration of tamoxifen by intravaginal inserts is expected to yield 
significantly lower systemic concentrations of tamoxifen than oral administration. In an 
exploratory study, 4 women were treated with vaginal suppositories containing 13 mg tamoxifen 
once daily for 1 week then twice a week thereafter. Participants’ systemic plasma concentrations 
(sample taken 5 hours post last dose following 8 weeks of treatment) ranged from 1.0 to 
10.0 ng/mL17; in comparison, an average steady-state concentration of 122 ng/mL was observed 
with 20 mg oral tamoxifen once daily for 3 months.16 
Although long-term treatment with tamoxifen is associated with risks of serious adverse effects, 
the risks associated with 56 days’ treatment with tamoxifen are considered minimal. In 
comparison, the potential reduction of VVA symptoms could be beneficial to participants, with 
these symptoms affecting numerous aspects of women’s lives, such as sex life, self-esteem, and 
relationships, in addition to the improvement in physical health.19 
A summary of the pharmaceutical properties and known potential risks of DARE-VVA1 is 
provided in the current version of the Investigator’s Brochure (IB). The investigator must become 
familiar with all sections of the DARE-VVA1 IB before the start of the study. 


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6. OBJECTIVES 
6.1. Primary Objective 
The primary objectives are: 
• To evaluate the safety and tolerability of DARE-VVA1 by intravaginal administration 
• To determine the plasma pharmacokinetics (PK) of DARE-VVA1 after intravaginal 
application 
6.2. Secondary Objectives 
The secondary objective is: 
• To evaluate preliminary efficacy and pharmacodynamics (PD) in terms of most bothersome 
symptom, dyspareunia, and changes in vaginal cytology and pH 
6.3. Exploratory Objectives 
The exploratory objective is: 
• To evaluate the impact of DARE-VVA1 on quality of life using a menopause-specific 
instrument 
• To assess the usability and acceptability of DARE-VVA1 
6.4. Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
• To evaluate the safety and tolerability of 
DARE-VVA1 by intravaginal administration 
• Adverse events 
• Clinical laboratory findings 
• Vital signs results 
• 12-lead ECG results 
• Physical examination findings  
• Change in local site irritation scores from 
baseline to Day 57 
• Endometrial thickness (measured by 
transvaginal ultrasound) in women who have 
not undergone hysterectomy prior to the study 
• To determine the plasma PK of DARE-VVA1 
after intravaginal application 
• Standard PK parameters from 
noncompartmental analysis on Day 1, with 
steady-state parameters on Day 56 
• Dose-proportionality of tamoxifen 


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Secondary 
 
• To evaluate preliminary efficacy and 
pharmacodynamics of DARE-VVA1 in terms 
of most bothersome symptom, dyspareunia, 
and changes in vaginal cytology and pH 
• Change of vaginal pH from baseline to Day 57 
• Change in vaginal cytology (maturation index; 
percentage of basal and superficial cells) from 
baseline to Day 57 
• Change in most bothersome symptom from 
baseline to Day 56 
• Change in severity of dyspareunia from 
baseline to Day 56 
• Correlation between exposure and local 
changes 
Exploratory 
• To evaluate the impact of DARE-VVA1 on 
quality of life using a menopause-specific 
instrument 
• To assess the usability and acceptability of 
DARE-VVA1 
• Change in the MENQOL questionnaire from 
baseline to Day 57 
• Responses to the Usability and Acceptability 
questionnaire over time 
 
 


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7. STUDY DESIGN 
7.1. Overall Study Design and Plan 
This is a Phase 1/2, randomized, multi-center, double-blind, parallel-arm, placebo-controlled, 
dose-ranging study to evaluate the safety, tolerability, PK, and PD of DARE-VVA1, a novel 
intravaginal tamoxifen product. The investigational product (IP) will be evaluated at 4 dose levels 
(1 mg, 5 mg, 10 mg, and 20 mg) and compared to a placebo vaginal insert. With each dose level, 
the IP will be administered intravaginally for 56 days, according to the following treatment 
schedule: once daily for 2 weeks then twice a week for 6 weeks.  
Approximately 40 postmenopausal women, 20 who have undergone hysterectomy and 20 who 
have not, with VVA will be enrolled. After signing informed consent, eligible participants will be 
randomly allocated as follows: the 20 hysterectomized women will be allocated to 1 of the 5 
treatment groups, and the 20 non-hysterectomized women will be randomly allocated to one of the 
same 5 treatment groups, such that each treatment group ends up with 4 hysterectomized women 
and 4 non-hysterectomized women, for a total of 8 women. (Figure 7-1). 
Figure 7-1: 
Study Design 
 
 
 
Abbreviations: D = day; FU = follow-up; N = number of participants 
 
Participants must be healthy postmenopausal women aged 40 to 75 years (inclusive) and have 
moderate to severe VVA, as determined by a vaginal pH greater than 5 at the Screening Visit, 
≤ 5% superficial cells on vaginal cytology, and either at least 1 moderate or severe symptom on 
self-assessment of i) vaginal dryness, ii) vaginal and/or vulvar irritation/itching, iii) dysuria, or 
iv) vaginal pain with sexual activity (dyspareunia), or the presence of vaginal bleeding associated 
with sexual activity. Participants are required to have a normal-appearing vagina upon speculum 
examination. Participants with a cervix are required to have a normal appearing cervix upon 
speculum examination, Participants who have not undergone hysterectomy are required to have an 
endometrial thickness ≤ 4 mm. All participants are required to have a recent normal mammogram 
and manual breast examination at screening. Mammograms and CSTs will be conducted for those 


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participants who have not had these tests in the timeframe indicated by the inclusion criteria. 
Participants will not be eligible if they have a medical history that suggests that they may be at risk 
of serious side effects of tamoxifen (e.g., thromboembolic disease, abnormal cervical screening 
results or history of endometrial pathology). Participants will also be excluded if they are receiving 
medications that could confound assessments (e.g., vaginal hormonal products, estrogen therapy, 
or use of SERMs or AIs within 6 months prior to screening) or have previously experienced an 
unsatisfactory outcome from a vaginal hormone therapy for VVA. 
Preliminary efficacy will be assessed by vaginal cytology (for maturation index) and by vaginal 
pH, measured at baseline, every 2 weeks during treatment, following completion of treatment 
(Day 57), and at the follow-up visit conducted on Day 63. In addition, most bothersome symptom 
and dyspareunia will be evaluated during the treatment period and at follow-up. An exploratory 
assessment of quality of life will be conducted using the Menopause-specific Quality of Life 
(MENQOL) questionnaire, and participants will report on the usability and acceptability of 
DARE-VVA1 using a questionnaire. 
In each treatment group, participants will have serial blood sampling for PK analysis, with venous 
samples drawn from an indwelling line. Dense sampling will be performed following the Day 1 
and Day 56 administrations of DARE-VVA1; trough samples will be collected prior to dosing on 
Days 4, 7, 10, 18, 28, and 42, and a final sample will be collected at follow-up on Day 63. Samples 
will be analyzed using validated methods to determine plasma concentrations of tamoxifen and 
3 metabolites: 4-hydroxytamoxifen, N-desmethyl-tamoxifen, and N-desmethyl-4-hydroxy-
tamoxifen (endoxifen). 
Safety will be assessed by evaluating AEs, vital sign measurements, clinical laboratory test results, 
12-lead ECGs, and physical examination findings. In addition, vaginal speculum examinations 
will be performed, including an assessment of local irritation (in terms of erythema and edema). 
Women without a history of hysterectomy will undergo transvaginal ultrasounds at screening and 
at the end of treatment (Day 57). 
Following the completion of treatment, participants will attend a follow-up visit on Day 63. 
All AEs observed by the study personnel or reported by the participant during the study (from the 
time of the signing of the informed consent through the follow-up visit) will be documented. 
7.2. Rationale and Discussion of Study Design 
The use of estrogen-containing products for the treatment of VVA is contraindicated in women 
with HR+ breast cancer, due to their capacity to promote tumor growth. There remains a large 
unmet need for a novel nonhormonal VVA treatment for this subset of cancer patients and 
survivors, and other women who require or prefer a treatment option that does not contain estrogen. 
An exploratory study of intravaginal tamoxifen has demonstrated the potential for this SERM, 
which acts as an estrogen receptor agonist in the vagina and as an antagonist in breast tissue, to 
improve VVA symptoms (vaginal pH and patient-reported dryness). In addition, plasma 
concentrations of tamoxifen were considerably lower than those seen with oral administration. 
The present study is the first clinical evaluation of DARE-VVA1, a GMP-manufactured tamoxifen 
vaginal insert intended for self-placement. The study will evaluate 5 parallel groups of 8 patients, 
randomizing participants to receive DARE-VVA1 at 1 of the 4 dose levels or placebo. The double-
blind, placebo-controlled, randomized study is a gold standard for clinical studies, and is 
considered suitable for the present study where the placebo vaginal inserts are identical to the 


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DARE-VVA1 inserts. Inclusion of a matched placebo will allow the distinction between adverse 
effects caused by tamoxifen and those that can be attributed to excipients or to mechanical effects 
due to the presence of an insert. 
The study will be conducted in postmenopausal women with VVA, allowing a preliminary 
investigation of the PD of the IP in the target population. Eligibility criteria have been designed to 
exclude participants who might be at risk of the serious, albeit rare, side effects associated with 
tamoxifen such as thromboembolic effects and endometrial cancer; the short duration of the study 
will also reduce these risks, which are typically associated with long-term tamoxifen use.18 
7.3. Selection of Doses in the Study 
The present study will evaluate intravaginal tamoxifen at doses of 1, 5, 10, and 20 mg for 56 days, 
with participants in a control group receiving matching placebo. An exploratory study of vaginal 
tamoxifen suppositories used a dose of 13 mg tamoxifen, which is similar to the daily dose of oral 
tamoxifen as used in estrogen receptor-positive breast cancer (20-40 mg).17,18 Given that vaginal 
administration allows distribution of tamoxifen directly to the site of action, 20 mg tamoxifen will 
be the highest dose studied here. Nonclinical studies evaluating 20 mg intravaginal tamoxifen in 
rabbits for 28 days showed no significant effects on the reproductive tract. 
Inclusion of lower doses (1, 5, and 10 mg) may allow the identification of a maximally effective 
dose below 20 mg, allowing the use of a lower dose of tamoxifen, which could be beneficial when 
used long-term, particularly as this would be expected to reduce the risk of serious side effects. 
The treatment schedule in the present study comprises treatment once daily for 2 weeks followed 
by 6 weeks on a twice-per-week schedule. This schedule is commonly used for intravaginal 
estrogen products. 
7.4. Study Sites 
The study will take place at approximately 3 sites in Australia. Each site is anticipated to screen 
sufficient participants to randomize a total of approximately 40 participants. A study site with a 
high recruitment rate may be allowed to recruit more participants if other sites have slow 
enrollment. 
7.5. End of Study Definition 
A clinical trial is considered completed when the last participant’s last study visit has occurred. 


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8. PARTICIPANT POPULATION 
8.1. Selection of Study Population and Diagnosis 
This study will enroll sufficient postmenopausal female participants with moderate to severe VVA 
to randomly allocate 40 participants, 20 who have undergone hysterectomy and 20 who have not, 
to receive treatment with DARE-VVA1 (4 dose levels) or placebo, as shown in Figure 7-1. 
Participants who do not meet all the eligibility criteria will not be enrolled. 
8.2. Study Entry Criteria 
Participants must meet all inclusion criteria to be eligible for enrollment into the study.  
Participants will not be eligible for entry into this study if they meet any of the exclusion criteria 
and 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. 
8.2.1 Inclusion Criteria 
Participants must meet all inclusion criteria to be eligible for enrollment into the study. 
1. Women aged 40-75 (inclusive). 
2. Postmenopausal women with a body mass index (BMI) between 18 and 38 kg/m2, 
inclusive. 
3. Postmenopausal, defined as: 
a. For non-hysterectomized women, 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. 
b. For hysterectomized women, serum follicle-stimulating hormone (FSH) levels > 40 
mIU/mL or 6 weeks postsurgical bilateral oophorectomy 
4. Have moderate to severe VVA as determined by self-assessment of the following 
symptoms: vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, vaginal pain 
with sexual activity (dyspareunia) (all self-assessed as none, mild, moderate, or severe), or 
vaginal bleeding associated with sexual activity (self-assessed as presence versus absence). 
To be eligible, at least 1 of the first 4 symptoms must be reported as moderate or severe, 
or vaginal bleeding associated with sexual activity must be present. 
5. Women who currently have vaginal intercourse or other sexual activity (masturbation, etc.) 
at least once a month (with or without a partner), or who had intercourse or other sexual 
activity at least once a month in the past, but later decreased sexual activity due to excessive 
pain or vaginal dryness. Participants must be willing to engage in vaginal intercourse or 
other sexual activity (masturbation, etc.) at least 1 time between Days 49-56 of the clinical 
study. 
6. Participants, upon pelvic examination with speculum examination, must have a normal-
appearing vulva other than atrophic changes, and normal-appearing vagina (without 
erosions, ulcerations, scarring, or evidence of dermatoses) other than atrophic changes (loss 
of rugae, mucosal pallor, mucosal dryness, mucosal petechiae). Women without a cervix 
must have a normal-appearing vaginal cuff. 


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7. Women who have not undergone hysterectomy must have:  
a. No prior history of endometrial ablation. 
b. Endometrial thickness ≤ 4 mm on transvaginal ultrasound. 
8. Women with a cervix must: 
a. Have a normal appearing cervix other than atrophic changes (i.e., cervical stenosis 
and/or flushness with the vaginal wall) 
b. Be current on all recommended screening and management requirements for 
cervical cancer. 
9. Vaginal cellular cytology with ≤ 5% superficial cells. 
10. Vaginal pH > 5 at Screening Visit. 
11. Normal mammogram report within 2 years of screening. 
12. Normal manual breast examination by investigator at baseline. 
13. Baseline hematology, clinical chemistry, urinalysis, coagulation, and viral serologies for 
human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B surface 
antigen (HBsAg) all within normal limits OR accepted by the investigator and medical 
monitor as not clinically significant. 
14. Normal 12-lead ECG. 
15. Able to read, understand, and provide written informed consent and applicable data 
protection authorization after the nature of the study has been fully explained, and must be 
willing to comply with all study requirements. 
16. Willing and able to correctly and independently complete all study procedures. 
8.2.2 Exclusion Criteria 
Participants will not be eligible for entry into this study if they meet any of the following 
exclusionary criteria: 
1. A history of or physical examination finding for any significant cardiovascular, renal, 
pulmonary, neurological and hepatic diseases preventing compliance with this study. 
2. A medical history of or use of anticoagulant drugs to treat or prevent coagulopathies, 
thrombophilia or thromboembolic disease (deep vein thrombosis, pulmonary or systemic 
embolism, stroke, or transient ischemic attack). 
3. Uncontrolled hypertension (either systolic > 180 mmHg or diastolic > 105 mmHg), 
treatment with Class 1 antiarrhythmics or digitalis, history of congestive heart failure (New 
York Heart Association [NYHA] > Class I), or myocardial infarction within 12 months. 
4. Women with a cervix cannot have had an abnormal CST within 2 years of screening. 
Participants can have atypical squamous cells of undetermined significance if human 
papilloma virus-negative. 
5. Women who have not undergone hysterectomy cannot have a history of or current 
endometrial pathology: hyperplasia, carcinoma and/or polyp (prior history of a benign 
endometrial polyp with no current evidence of polyp is acceptable). 


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6. A medical history of breast cancer within 5 years of screening. 
Participants with a history of breast cancer more than 5 years prior to screening are 
considered eligible if their disease was node-negative, nonmetastatic, and if all treatment 
with aromatase inhibitors (AIs) or SERMs was completed at least 6 months prior to 
screening. 
7. A medical history of malignant melanoma. 
8. Any cancer (except nonmelanomatous skin cancer) diagnosed less than 5 years prior to the 
Screening Visit. 
9. A medical history of undiagnosed vaginal bleeding. 
10. A known or suspected estrogen-dependent neoplasia. 
11. Previous radiation treatment to the pelvis. 
12. Women who have previously reported an unsatisfactory outcome from a vaginal hormone 
therapy for VVA. 
13. Known hypersensitivity to any ingredients in DARE-VVA1. 
14. Use of vaginal hormonal products (rings, creams, gels, tablets, capsules) within 4 weeks 
prior to Day 1. 
15. Use of transdermal estrogen products within 4 weeks prior to Day 1. 
16. Use of oral estrogen therapy within 8 weeks prior to Day 1. 
17. Use of estrogen-alone injectable drug therapy within 12 weeks prior to Day 1. 
18. Administration of estrogen pellet therapy within 6 months prior to Day 1. 
19. Use of thyroid hormone replacement therapy unless the participant is on a stable dose for 
> 6 months, and participant is euthyroid based on a normal, sensitive immunoassay for 
thyroid-stimulating hormone (TSH). 
20. Use of SERMs or AIs within 6 months prior to screening. 
21. Use of anabolic or other steroids (including hormonal creams such as testosterone) within 
4 weeks prior to Day 1. 
22. Use of corticosteroids, > 5 mg/day prednisone or equivalent, for more than 4 weeks within 
4 weeks prior to Day 1. 
23. Participants with any self-reported active sexually transmitted disease and/or evidence of 
infection (including bacterial vaginosis) on vaginal examination by the investigator. 
24. 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). 
25. Women who have not undergone hysterectomy cannot have clinically significant uterine 
fibroids. 
26. 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 


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in the last 2 years, as assessed by the 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. 
27. 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 the Screening Visit (Visit 1).  
28. In the opinion of the investigator, participant has any disorder or finding that might 
interfere with the conduct of the study. 
8.3. Premature Participant Withdrawal 
All participants will be advised that they are free to withdraw from participation in this study at 
any time, for any reason, and without prejudice. The investigator should make every reasonable 
attempt to keep participants in the study; however, participants must be withdrawn from the study 
if they withdraw consent to participate. Investigators must attempt to contact participants who fail 
to attend scheduled visits by telephone or other means to exclude the possibility of an AE being 
the cause of withdrawal. Should this be the cause, the AE must be documented, reported, and 
followed as described in Section 11.2. 
The sponsor reserves the right to request the withdrawal of a participant due to protocol deviations 
or other reasons. 
The investigator also has the right to withdraw participants from the study at any time for lack of 
therapeutic effect that is intolerable or otherwise unacceptable to the participant, for intolerable or 
unacceptable AEs, intercurrent illness, noncompliance with study procedures, administrative 
reasons, or in the investigator’s opinion, to protect the participant’s best interest. 
If a participant is withdrawn before completing the study, the reason for withdrawal and the date 
of discontinuation will be recorded on the appropriate page of the case report form (CRF) or 
electronic case report form (eCRF). Whenever possible and reasonable, the evaluations shown in 
the Early Termination Visit in the schedule of events (Table 2-1) should be performed at the time 
of premature discontinuation. 
8.4. Discontinuation of Investigational Product 
Discontinuation from the IP does not mean discontinuation from the study, and remaining study 
procedures should be completed as indicated by the schedule of events (Table 2-1). If a clinically 
significant finding is identified (including, but not limited to, changes from baseline) after 
enrolment, the investigator or qualified designee will determine if any change in participant 
management is needed. Any new clinically relevant finding will be reported as an AE. 
Participants who are not willing to complete the remaining study procedures indicated in the 
schedule of events (Table 2-1) after discontinuing study treatment should complete the procedures 
indicated for the Early Termination Visit at a minimum. 
8.5. Participant Discontinuation/Withdrawal from the Study 
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, 


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continued participation would pose an 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 Early Termination Visit assessments 
(Section 10.2.3). 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. 
 


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9. TREATMENTS 
9.1. Identification of Investigational Products 
DARE-VVA1 will be provided in the form of vaginal inserts. The vaginal route allows direct 
delivery of tamoxifen to the site of action and will reduce systemic exposure to tamoxifen. 
DARE-VVA1 will be supplied as 1 mg, 5 mg, 10 mg, and 20 mg vaginal inserts by Catalent 
Pharma Solutions (St. Petersburg, Florida, USA).  
Matching placebo (also supplied by Catalent Pharma Solutions) will be identical in appearance, 
smell, and feel. 
9.2. Selection of Timing of Dose for Each Participant 
The 1 mg, 5 mg, 10 mg, and 20 mg dose levels and placebo will be evaluated in parallel. 
Participants will be randomly allocated to receive treatment in 1 of the 5 treatment groups shown 
in Table 9-1. All participants will receive treatment with the IP for a total of 56 days. 
Table 9-1: 
Study Design – Treatment Groups 
Dose Level 
Treatment 
Number of  
 Participants 
 
 
Placebo 
One placebo insert 
N=8 
 
 
1 mg 
One DARE-VVA1 1 mg insert 
N=8 
 
 
5 mg 
One DARE-VVA1 5 mg insert 
N=8 
 
 
10 mg 
One DARE-VVA1 10 mg insert 
N=8 
 
 
20 mg 
One DARE-VVA1 20 mg insert 
N=8 
 
 
 
The DARE-VVA1 (or placebo) vaginal insert will be inserted by the participant in the morning. 
Participants should make every effort to ensure that inserts are inserted at approximately the same 
time for each administration except on visit days when IP should be inserted after trough PK 
sample collection.  
Participants will be instructed on how to correctly self-administer the IP on Day 1, at the time of 
the first administration, and a warning should be given that the insert should not be pushed up too 
close to the cervix.  
On Days 1 and 56, blood samples for PK analysis will be collected immediately before 
administration of the IP, and at scheduled intervals after administration in accordance with the 
sampling schedule defined in the schedule of events (Table 2-1). In addition, blood samples should 
be collected within 30 minutes before administration of DARE-VVA1 on Days 4, 7, 10, 18, 28, 
and 42. A final sample will be collected at follow-up on Day 63. 
9.3. Dose Adjustment Criteria 
Dose adjustment is not allowed in this study. 
9.4. Treatment Compliance 
Participants will be instructed on how to correctly self-administer the IP on Day 1, at the time of 
the first administration.  


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Throughout the 56-day administration period, participants will be asked to record their 
administration of DARE-VVA1 on a paper diary, including the time of placement. Deviations 
from the planned doses (missed dose or timing) will be recorded on the participant’s eCRF. Study 
personnel will review diaries at each visit, and diaries will be collected as source documents. 
Information from participant diaries will be transcribed on the appropriate eCRF pages for 
documentation of participant compliance with the IP. 
9.5. Method of Assigning Participants to Treatment Groups 
In this parallel-group randomized study, participants who meet study entry criteria will be 
randomly assigned in a 1:1:1:1:1 ratio, by history of hysterectomy, to 1 of the 5 treatment groups 
indicated in Table 9-1. The randomization schedule will be computer-generated using a permuted 
block algorithm and will randomly allocate IP to randomization numbers. Study center will not be 
a blocking factor in the randomization schedule. The randomization numbers will be assigned 
sequentially by a member of the ICON Clinical Research Team who is not otherwise involved in 
the study. Contact details for obtaining randomization numbers are provided in the Study 
Reference Manual. The randomization schedule will be prepared by ICON Clinical Research 
before the start of the study. No one involved in the study performance will have access to the 
randomization schedule before official unblinding of treatment assignment. No participant will be 
randomized into this study more than once. 
9.6. Blinding and Unblinding Treatment Assignment 
The different tamoxifen-dose DARE-VVA1 vaginal inserts and placebo are indistinguishable by 
appearance, smell, and feel. 
All participants, investigators, and study personnel involved in the conduct of the study, including 
data management, will be blinded to treatment assignment with the exception of a specified 
unblinded statistician from ICON Clinical Research who will have access to the randomization 
code. The unblinded study personnel will not participate in study procedures or data analysis prior 
to unblinding of the study data to all study-related personnel. 
Study personnel will make every effort to safeguard the integrity of the study blind to minimize 
bias in the conduct of the study. Treatment unblinding is discouraged if knowledge of the treatment 
assignment will not materially change the planned management of a medical emergency. 
Unblinding will be permitted in a medical emergency that requires immediate knowledge of the 
participant’s treatment assignment. 
Unblinding should be discussed in advance with the medical monitor, if possible. For emergency 
unblinding, study personnel will contact the ICON Clinical Research Team. Contact details are 
provided in the Study Reference Manual. If the investigator is not able to discuss treatment 
unblinding in advance, then they must notify the medical monitor as soon as possible about the 
unblinding incident without revealing the participant’s treatment assignment.  
The investigator or designee must record the date and reason for treatment unblinding on the 
appropriate CRF for that participant. In all cases that are not emergencies, the investigator must 
discuss the event with the medical monitor prior to unblinding the participant’s treatment 
assignment. 
If treatment assignment is unblinded for an individual participant, study personnel will be notified 
of that participant’s treatment assignment without unblinding the treatment assignments for the 


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remaining participants in the study. Thus, the overall study blind will not be compromised. If a 
participant’s treatment assignment is unblinded, she may or may not be asked to withdraw from 
the study. The investigator will make this decision after consultation with the medical monitor. 
Overall unblinding will take place at the end of the study only after database lock has been 
achieved. 
9.7. Permitted and Prohibited Therapies 
All concomitant medications used (including OTC medications and herbal supplements) will be 
recorded in the source document and on the appropriate eCRF. 
9.7.1 Permitted Therapies 
With the exception of all prohibited therapies (see Section 9.7.2), the use of concomitant 
medications is allowed, but should be limited to those medications considered necessary. 
The use of vaginal lubricants is permitted; however, they should not be used within 6 hours of 
administration of the IP. 
9.7.2 Prohibited Therapies 
The following therapies are prohibited both during the study and in the period before the study as 
shown: 
• use of anticoagulant drugs to treat or prevent coagulopathies, thrombophilia, thromboembolic 
disease, or transient ischemic attack 
• radiation treatment to the pelvis 
• vaginal hormonal products (rings, creams, gels, tablets, capsules) (within 4 weeks prior to 
Day 1) 
• transdermal estrogen products (within 4 weeks prior to Day 1) 
• oral estrogen therapy (within 8 weeks prior to Day 1) 
• estrogen-alone injectable drug therapy (within 12 weeks prior to Day 1) 
• estrogen pellet therapy (within 6 months prior to Day 1) 
• thyroid hormone replacement therapy is prohibited unless the participant has been on a stable 
dose for > 6 months, and is euthyroid based on a normal, sensitive immunoassay for TSH 
• SERMS or AIs (within 6 months prior to Day 1) 
• anabolic or other steroids (including hormonal creams such as testosterone) (within 4 weeks 
prior to Day 1) 
• corticosteroids, > 5 mg/day prednisone or equivalent, for more than 4 weeks within 4 weeks 
prior to Day 1 
• investigational drug (within 30 days prior to screening) or non-drug eluting medical device 
(within 15 days prior to screening) 


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The following therapies are prohibited during the study: 
• intravaginal products (e.g., Femring® [estradiol acetate vaginal ring], ESTRING® 
[estradiol vaginal ring]) or medication, OTC or prescription  
NOTE: the use of vaginal lubricants is permitted, but not within 6 hours of administration 
of the IP  
• consumption of St John’s Wort (hypericum perforatum) and grapefruit, Seville (bitter) 
orange, and pomelo fruit/juice/preserves 
• the following CYP3A4/5 inducers and CYP2D6 inhibitors are prohibited: 
CYP3A4/5 inducers  
CYP2D6 inhibitors 
Apalutamide (strong), aprepitant, armodafinil 
Abiraterone, amiodarone 
Bosentan (moderate) 
Bupropion (strong) 
Carbamazepine (strong), corticosteroids 
Celecoxib, cinacalcet (moderate), cobicistat 
Dabrafenib 
Duloxetine (moderate) 
Efavirenz (moderate), encorafenib, 
enzalutamide (strong), etravirine (moderate) 
Fluoxetine (strong) 
Loriatinib (moderate), lumacaftor (strong) 
Methadone, mirabegron (moderate) 
Modafinil (moderate) 
Paroxetine (strong) 
Nevirapine 
Terbinafine (strong) 
Phenobarbital, phenytoin (strong) 
 
Rifabutin, rifampicin (strong), ritonavir, 
rufinamide 
 
Tipranavir 
 
Vemurafenib 
 
 
Participants receiving excluded therapies will be ineligible for study enrollment or for continuation 
in the study, at the discretion of Daré Bioscience Inc. and/or designee. 
9.7.3 Restrictions 
Participants will be required to engage in vaginal intercourse or other sexual activity 
(masturbation, etc.) at least 1 time between Days 49-56 of the clinical study (see Section 10.3.3.3 
for details). 
9.8. Treatment After End of Study 
After the end of the study, each participant will be treated according to standard clinical practice. 
9.9. Dispensing and Storage 
The IP manufactured by Catalent Pharma Solutions (DARE-VVA1 and placebo) and supplied by 
PCI is to be used exclusively in the clinical study according to the instructions of this protocol. 


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The investigator is responsible for dispensing the IP according to the dosage scheme and for 
ensuring proper storage of the IP. 
The investigator must confirm the receipt of the IP with his or her signature. A copy of this receipt 
must be kept by the investigator and another copy will be stored at Daré Bioscience Inc and/or 
ICON Clinical Research. Until the IP is dispensed to the participants, it must be stored at controlled 
room temperature (20 to 25°C, with excursion allowed from 15 to 30°C) in a securely locked area 
that is not generally accessible. 
The key to the storage area is to be kept by the investigator or designee responsible for the IP. The 
store will be accessible only to those persons authorized by the investigator to dispense the IP. 
Following dispensing, participants must store the IP at room temperature in a cool, dark, dry place. 
The IP should be kept out of reach of children. 
9.10. Drug Accountability 
The investigator must maintain adequate records showing the receipt, dispensing, return, or other 
disposition of the IPs, including the date, quantity, batch or code number, and identification of 
participants (participant number) who received the IPs. The investigator will not supply the IP to 
any person except those named as subinvestigators, designated study personnel, and participants 
in this study. The investigator will not dispense the IPs from any study sites other than those listed. 
The IPs may not be relabeled or reassigned for use by other participants. If any of the IPs are not 
dispensed, are lost, stolen, spilled, unusable, or are received in a damaged container, this 
information must be documented and reported to the sponsor and appropriate regulatory agencies, 
as required. 
Upon completion of the study, the IPs (partly used, unused, and empty packaging) must be left in 
the original packaging and returned to the sponsor or designee for destruction. 
9.11. Labeling and Packaging 
Labeling and packaging of DARE-VVA1 and placebo will be performed by PCI (Port Melbourne, 
Victoria, Australia), and will comply with all applicable local regulations. 
Details regarding IP packaging, labeling, and use instructions will be provided in a separate Study 
Reference Manual. 
Investigators should save all empty packaging or packaging containing unused vaginal inserts for 
final disposition by the sponsor or contract pharmacy. 


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10. STUDY PROCEDURES 
Participants must provide written informed consent before any study-related procedures are 
initiated, including the cessation of prohibited concomitant therapy. 
For the timing of assessments and procedures throughout the study, refer to the schedule of events 
(Table 2-1). Throughout the study, every reasonable effort should be made by study personnel to 
follow the timing of assessments and procedures in the schedule of events for each participant. If 
a participant misses a study visit for any reason, the visit should be rescheduled as soon as possible. 
10.1. Study Duration 
10.1.1 Overall Study Schedule 
The planned sequence and maximum duration of the study periods will be as follows: 
1. Screening: 21 days 
2. Treatment: 56 days 
3. Posttreatment: 7 days 
The maximum treatment duration for each participant is approximately 56 days.  
The maximum study duration for each participant is approximately 12 weeks. 
10.2. Study Periods and Visits 
10.2.1 Screening  
The participant must be screened within 21 days before enrollment in the study. Assessments to 
be conducted during screening are shown in the schedule of events (Table 2-1). No study-specific 
assessments should be conducted until the participant has provided written informed consent (see 
Section 14.4.1). 
Participants who have not had mammograms and CSTs in the timeframe indicated by the inclusion 
criteria will undergo these assessments during screening. 
Procedures for rescreening participants who initially fail to meet study entry criteria are described 
in Section 14.3. 
10.2.2 Double-blind Treatment Period 
The treatment period is defined as the period from Day 1 to Day 57, covering the 24-hour period 
after the final administration of the IP on Day 56.  
Participants will self-administer DARE-VVA1 or placebo as instructed between Days 1 and 56, in 
accordance with the treatment group to which they are allocated. 
Study assessments will be conducted in accordance with the schedule of events (Table 2-1). 
10.2.2.1 Day 1 to 2 
The Day 1 to Day 2 visit will be an overnight stay at the study site. Participants will attend the 
study site on the morning of Day 1.  


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Participants will be instructed on how to correctly self-administer the IP at the time of the first 
administration, and a warning should be given that the insert should not be pushed up too close to 
the cervix.  
Samples for analysis of tamoxifen PK will be collected before administration of the IP and at the 
scheduled times indicated in the schedule of events (Table 2-1) and in Section 10.3.2.1.2. Where 
multiple assessments are scheduled for the same time point, assessments should be performed 
within 15 minutes of the scheduled time with priority given to any PK blood sample procedures, 
if applicable. 
Participants will be provided with a diary in which to record their administration of DARE-VVA1, 
including the time of placement, and will be trained on its completion. Study staff should instruct 
participants to bring their diaries to all site visits for review. Diaries will be completed at site on 
days where DARE-VVA1 is administered at site. 
On Day 2, after participants have provided the 24-hour PK sample, a vaginal speculum 
examination will be conducted before the participant self-administers the second IP insert. 
Participants will be discharged from the study site on Day 2, following collection of the 24-hour 
PK sample and completion of all 24-hour assessments and insertion of the second IP insert. At 
discharge, participants will be provided with sufficient IP to last for the 56-day treatment period. 
10.2.2.2 Days 4, 7, 10, 18, 28, and 42 
Participants will return to the study site on Days 4, 7, 10, 18, 28, and 42, to complete the procedures 
shown in the schedule of events (Table 2-1).  
On Days 4, 7, 10, 18, 28, and 42, participants should not self-administer the IP at home; blood 
samples for trough PK assessments should be collected at site within 30 minutes before the IP is 
administered.  
Participants will be required to bring their diaries to each of these visits. 
10.2.2.3 Day 56 to 57 
The Day 56 to Day 57 visit will be an overnight stay at the study site. Participants will attend the 
study site in the morning of Day 56. Participants should not self-administer the IP at home on 
Day 56; the IP will be administered at the site as instructed. Any unused IP should be returned to 
the study site. 
Samples for analysis of tamoxifen PK will be collected before administration of the IP and at the 
scheduled times indicated in the schedule of events (Table 2-1) and in Section 10.3.2.1.2. Where 
multiple assessments are scheduled for the same time point, assessments should be performed 
within 15 minutes of the scheduled time with priority given to any PK blood sample procedures, 
if applicable. 
Participants will be discharged from the study site after completion of all 24-hour assessments 
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10.2.3 Early Termination Visit 
Participants who discontinue treatment with the IP before Day 56 should remain on study (see 
Section 8.4), and the remaining study procedures should be completed as indicated by the schedule 
of events (Table 2-1). Participants who are not willing to complete the remaining study procedures 
indicated in the schedule of events after discontinuing study treatment should complete the 
procedures indicated for the Early Termination Visit at a minimum. 
Participants should return all unused IP and their participant diaries.  
10.2.4 Day 63 Follow-up Evaluation 
At 7 days after the last administration of the IP, the participants will return to the study site for a 
follow-up visit. Safety and efficacy assessments will be conducted in accordance with the schedule 
of events (Table 2-1), and a final PK sample will be collected. 
10.3. Assessments 
10.3.1 Safety Variables 
Safety assessments will include the evaluation of AEs, clinical laboratory assessments, vital signs, 
12-lead ECGs, physical examinations, vaginal speculum examinations, and transvaginal 
ultrasounds. 
10.3.1.1 Clinical Laboratory Safety Assessments 
10.3.1.1.1 Clinical Laboratory Tests to be Performed 
Samples for the following laboratory tests will be collected at the time points specified in the 
schedule of events (Table 2-1). 
Hematology: 
hemoglobin, hematocrit, red blood cell (RBC) count, RBC indices (mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, 
mean corpuscular volume, red blood cell distribution width), platelet count 
(or estimate), white blood cell count including differential 
Serum Chemistry: 
albumin, total bilirubin, total protein, calcium, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, 
creatinine, glucose, sodium, potassium, chloride, bicarbonate, lactate 
dehydrogenase, uric acid 
Coagulation Panel: 
PT, APTT, fibrinogen, INR 
Urinalysis: 
Leukocytes, nitrite, pH, specific gravity, blood, glucose, protein, ketones, 
bilirubin, urobilinogen 
Viral Serology: 
HIV, HCV, and HBsAg (screening only) 
 
 
 
 
 


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Urine Drug Screen:  Urine drugs of abuse according to the local standard (including, at a 
minimum, cocaine, tetrahydrocannabinol, amphetamines and opiates) via 
urinalysis conducted by local laboratories, and alcohol screens via a 
commercially available urine dipstick  
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 
Other: 
TSH (screening only) 
FSH (at screening only, to confirm postmenopausal status in non-
hysterectomized women with spontaneous amenorrhea for ≥ 6 months but 
< 12 months and no history of bilateral oophorectomy, and in 
hysterectomized women who have not undergone bilateral oophorectomy) 
Laboratory specimens for hematology, serum chemistry, urinalysis, urine drug screens, and 
vaginal cytology will be analyzed at certified local laboratories. Bioanalytical samples for PK 
analysis will be analyzed centrally by Agilex Biolabs. 
10.3.1.1.2 Specimen Handling Requirements 
Details of specimen handling requirements are provided in the Study Reference Manual. 
10.3.1.1.3 Evaluation of Clinical Laboratory Values 
The normal ranges of values for the clinical laboratory assessments in this study will be provided 
by the responsible laboratory and submitted to Daré prior to the beginning of the study. They will 
be regarded as the reference ranges on which decisions will be made. 
If a laboratory value is out of the reference range, it is not necessarily clinically relevant. The 
investigator must evaluate the out-of-range values and record his or her assessment of the clinical 
relevance in the appropriate eCRF. 
All clinical laboratory values that in the investigator’s opinion show clinically relevant or 
pathological changes during or after termination of treatment must be reported as AEs and 
followed, as described in Section 11.2.5. 
All measurements described in this section are recognized standard methods. 
10.3.1.2 Clinical Examinations 
10.3.1.2.1 Vital Signs 
Vital signs, including pulse rate, respiratory rate, and blood pressure in accordance with the 
schedule of events (Table 2-1). Assessments will be performed after the participant has been in a 
supine position for at least 5 minutes. Temperature will also be measured. 
Normal ranges for these parameters are as follows: 
• Pulse rate: 60 to 100 beats per minute 


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• Systolic blood pressure: 90 to 140 mmHg 
• Diastolic blood pressure: 60 to 90 mmHg 
• Respiratory rate: 8 to 22 breaths per minute 
• Temperature: 35.5 to 37.5°C 
Weight and height will be assessed only assessed at screening. 
10.3.1.2.2 Twelve-lead Electrocardiogram 
Standard 12-lead ECGs will be performed in accordance with the schedule of events (Table 2-1). 
All ECGs will be performed after the participant has been supine for at least 5 minutes. All ECG 
recordings will be identified with the participant number, date, and time of the recording and will 
be attached to the participant’s eCRF. 
The ECG should be read by someone with appropriate training to determine that the recording 
shows a normal sinus rhythm with a rate of 60-100 beats per minute, without evidence of 
arrhythmias, chamber enlargements, conduction abnormalities, or ischemic heart disease. 
10.3.1.2.3 Physical Examination 
A complete physical examination (excluding rectal examinations) will be performed at screening 
and will include a manual breast examination. Subsequent physical examinations, as indicated in 
the schedule of events (Table 2-1), will be abbreviated and will be directed based on signs and 
symptoms exhibited by the participant.  
Clinically significant abnormal physical examination findings will be reported as an AE (see 
Section 11.2). 
10.3.1.2.4 Vaginal Speculum Examination 
Pelvic speculum and visual examinations will be conducted to identify vaginal abnormalities in 
accordance with the schedule of events (Table 2-1). Clinically significant abnormal findings from 
the speculum examination will be reported as an AE (see Section 11.2). 
In addition, investigators will conduct an assessment of local irritation. Erythema and edema will 
be rated according to the scores provided in Table 10-1. 
In cases of local AEs or local irritation, investigators may take photographs at their own discretion 
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Table 10-1: 
Local Irritation Scoring 
Reaction Type 
0 = None 
1 = Mild 
2 = Moderate 
3 = Severe 
Erythema 
None 
Faint or mild redness of 
any size OR moderate 
redness involving 
≤ 25% of the area 
Moderate redness 
involving > 25% of the 
area OR intense redness 
involving ≤ 25% of the 
area 
Intense redness 
involving > 25% of the 
area 
Edema 
None 
Mild visible swelling or 
barely palpable edema 
of any size OR easily 
palpable edema 
involving ≤ 25% of the 
area 
Moderate visible swelling 
OR easily palpable 
edema involving > 25% 
of the site or gross 
swelling of firm 
induration involving 
≤ 25% of the area 
Gross swelling or firm 
induration involving 
> 25% of the area 
 
 
10.3.1.2.5 Transvaginal Ultrasound 
Transvaginal ultrasound will be conducted on women without a history of hysterectomy in 
accordance with the schedule of events (Table 2-1). The procedure will be conducted in 
accordance with standard practice at the study site to determine endometrial thickness. 
10.3.1.3 Adverse Events 
The definitions and management of AEs, and any special considerations for AEs, are provided in 
Section 11. 
10.3.2 Clinical Pharmacology 
10.3.2.1 Pharmacokinetic Analysis Methods 
The PK characterization of tamoxifen concentrations for each dose to be profiled will use 
noncompartmental analysis (NCA). Three tamoxifen metabolites (4-hydroxytamoxifen, 
N-desmethyltamoxifen, and N-desmethyl-4-hydroxytamoxifen [endoxifen]) will also undergo PK 
characterization. 
Standard PK parameters assessed will include measures of the extent of absorption using estimates 
of the area under the plasma concentration-time curve (AUC), the maximum observed drug 
concentration (Cmax), and the time to reach maximum drug concentration (Tmax). Additional details 
of the parameters and their calculation and evaluation will be included in the statistical analysis 
plan (SAP). 
10.3.2.1.1 Pharmacokinetic Parameters 
The PK parameter estimates will be completed using WinNonlin (Pharsight Corporation). Actual 
sampling time will be used for all parameter estimation. 


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Table 10-2 shows the PK parameters that will be computed for each participant for samples 
obtained over the planned sampling intervals of 24 hours after administration of the IP on Days 1 
and 56, with trough samples collected before dosing on Days 4, 7, 10, 18, 28, and 42, and a final 
sample on Day 63. 
Table 10-2: 
Pharmacokinetic Parameters 
Parameter 
Description of Parameter 
Cmax 
maximum observed drug concentration 
Tmax 
time to reach maximum (peak) drug concentration 
AUC0-t 
area under plasma concentration-time curve from zero to time t 
AUC0-inf 
area under plasma concentration-time curve from time zero to infinity 
T1/2 
elimination half-life 
λz 
elimination rate constant 
Vd 
apparent volume of distribution 
CL/F 
apparent clearance 
 
10.3.2.1.2 Sample Collection 
Dense PK sampling will be performed on Day 1 and Day 56, with samples collected immediately 
before insertion of the IP and at the following time points after insertion: 
• 0.5 hours and 1 hour (±10 minutes) 
• 2, 4, 5, 8, 12, and 24 hours (±15 minutes) 
Trough samples (Days 4, 7, 10, 18, 28, and 42) should be collected within 30 minutes before 
administration of IP inserts. 
A final sample will be collected at the Day 63 follow-up visit. 
10.3.3 Pharmacodynamics and Efficacy Variables 
10.3.3.1 Vaginal pH 
Vaginal swabs for determination of pH will be collected in accordance with the schedule of events 
(Table 2-1). The pH of vaginal secretions will be measured using pH paper. Additional details and 
instructions will be provided in the Study Reference Manual. 
10.3.3.2 Vaginal Cytology 
Samples for vaginal cytology will be collected at the time points specified in the schedule of events 
(Table 2-1) 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). 


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10.3.3.3 Symptoms of Vulvar Vaginal Atrophy 
At the Screening Visit, participants will rate the first 4 items in the list of VVA symptoms in 
Table 10-3 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 2-1), and the change in severity from baseline will be determined. 
Changes from baseline in each participant’s most bothersome symptom, as well as changes in 
dyspareunia (whether dyspareunia was the participant’s most bothersome symptom or not), will 
be evaluated as study endpoints.  
Symptoms to be evaluated are shown in Table 10-3.  
All participants will be required to engage in vaginal intercourse or other sexual activity 
(masturbation, etc.) at least 1 time between Days 49-56, and complete an assessment of VVA 
symptoms in their diary.  
Table 10-3: 
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 
 
10.3.3.4 Menopause Quality of Life 
The MENQOL™ questionnaire will be given to participants before the first dose and on Day 57, 
in accordance with the schedule of events (Table 2-1). 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).20,21 
10.3.3.5 Usability and Acceptability Questionnaire 
A Usability and Acceptability questionnaire will be administered to all participants in accordance 
with the schedule of events (Table 2-1). 
10.3.3.6 Participant Diaries 
Throughout the 56-day administration period, participants will be asked to record their 
administration of DARE-VVA1 on a paper diary, including the time of placement. Deviations 
from the planned doses (missed dose or timing) will be recorded on the participant’s eCRF.  


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In addition, participants will be required to engage in vaginal intercourse or other sexual activity 
(masturbation, etc.) at least 1 time between Days 49 to 56 (see Section 10.3.3.3). Participants will 
use their diaries to capture their assessment of VVA symptoms. 
Study personnel will review diaries at each visit, and diaries will be collected as source documents. 
Information from participant diaries will be transcribed on the appropriate eCRF pages for 
documentation of participant compliance with the IP. 
10.3.3.7 Pharmacodynamics 
Pharmacodynamics will be assessed by correlating the dose administered to dose exposure of 
tamoxifen in plasma, and then by relating the exposures to local vaginal changes in cytology and 
pH as well as to the reported symptomatology over 56 days. 


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11. ADVERSE EVENTS 
11.1. Definitions 
11.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not related to the medicinal product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. (Worsening of a 
pre-existing condition is considered an AE.) 
Events that occur in participants treated with control product, or during treatment-free periods of 
the study, are also considered AEs. 
11.1.2 Adverse Drug Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions (ADRs). 
The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility, i.e., the relationship cannot be 
ruled out. All AEs judged by either the reporting investigator or the sponsor as having a reasonable 
causal relationship to an IP qualify as ADRs. 
All AEs for which the judgment of relationship to IP is “possibly related” or higher will be 
considered ADRs. If a relationship to IP is not provided, then the AE must be treated as if it were 
“possible.”  
11.1.3 Unexpected Adverse Event/Adverse Drug Reaction 
An expected AE or ADR is one for which the nature or severity is consistent with the applicable 
scientific information (e.g., IB for an unapproved IP or Product Information document or similar 
for an approved, marketed product). 
An unexpected adverse event (UAE) or unexpected adverse drug reaction (UADR) is one for 
which the nature or severity is not consistent with the applicable product information (e.g., IB for 
an unapproved IP or package insert/summary of product characteristics for an approved product). 
For example, hepatic necrosis would be unexpected (greater severity) if the IB only listed elevated 
hepatic enzymes or hepatitis. Likewise, cerebral thromboembolism and cerebral vasculitis would 
be unexpected (greater specificity) if the IB only listed cerebral vascular accidents. 
Furthermore, reports that add significant information on specificity or severity of a known, already 
documented adverse reaction also constitute unexpected events. Examples would be (a) acute renal 
failure as an expected adverse reaction with a subsequent new occurrence of interstitial nephritis 
(interstitial nephritis would be unexpected) and (b) hepatitis with a first occurrence of fulminant 
hepatitis (fulminant hepatitis would be unexpected). 


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11.1.4 Serious Adverse Events or Serious Drug Reactions 
A serious adverse event (SAE) or serious adverse drug reaction (SADR) is any untoward medical 
occurrence that at any dose: 
• results in death 
• is life-threatening 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event; it does not refer to an 
event/reaction that hypothetically might have caused death if it were more severe. 
• requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE: Inpatient hospitalization is defined as 24 hours in a hospital or an overnight stay. 
An elective hospital admission to treat a condition present before exposure to the IP, or a 
hospital admission for a diagnostic evaluation of an AE, does not qualify the condition or 
event as an SAE. Further, an overnight stay in the hospital that is only due to transportation, 
organization, or accommodation problems and without medical background does not need 
to be considered an SAE. 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the IP 
during pregnancy is an SAE. However, a newly diagnosed pregnancy in a participant that 
has received an IP is not considered an SAE unless it is suspected that the IP(s) interacted 
with a contraceptive method and led to the pregnancy.  
• is an important medical event 
NOTE: Medical and scientific judgment should be exercised in deciding whether other 
situations should be considered serious, such as important medical events that might not 
be immediately life-threatening or result in death or hospitalization but might jeopardize 
the participant or might require intervention to prevent one of the other outcomes listed in 
the definition above. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not 
result in hospitalization, or development of drug dependency, or drug abuse. The 
occurrence of malignant tumors is also to be considered serious. 
11.1.5 Significant Adverse Events 
Other significant AEs are defined as marked hematological and other laboratory abnormalities 
(other than those meeting the definition of serious) and any events that led to an intervention, 
including withdrawal of test drug, dose reduction, or significant additional concomitant therapy. 
11.1.6 Treatment-emergent Adverse Events 
An AE is defined as treatment emergent if the first onset or worsening is after the first 
administration of IP (DARE-VVA1 or placebo) and not more than 30 days after the last 
administration of IP. 


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11.2. Event Assessment and Follow-up of Adverse Events 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits 
and interviews of a study participant presenting for medical care or upon review by a study 
monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate eCRF. Information to be collected includes event description, time of onset, 
clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All 
AEs occurring while on study must be documented appropriately regardless of relationship. All 
AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates 
at any time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. Any AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
The investigator (or designee) will record all reportable events with start dates occurring any time 
after informed consent is obtained until 7 (for nonserious AEs) or 30 days (for SAEs) after the last 
day of study participation. At each study visit, the investigator will inquire about the occurrence 
of AE/SAEs since the last visit. Events will be followed for outcome information until resolution 
or stabilization. 
11.2.1 Assessment 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously. At each visit, the participant will be allowed 
time to spontaneously report any issues since the last visit or evaluation. The investigator will then 
monitor and/or ask about or evaluate AEs using nonleading questions, such as 
• “How are you feeling?” 
• “Have you experienced any issues since your last visit?” 
• “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. 
11.2.2 Evaluation 
11.2.2.1 Severity of Adverse Events 
The clinical severity 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 


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• 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 
It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity 
whereas an SAE is an AE that meets serious criteria, as described in Section 11.1.4. 
11.2.2.2 Seriousness 
The investigator is to evaluate whether the AE meets serious criteria, as described in 
Section 11.1.4. 
11.2.2.3 Actions Taken 
Actions taken may consist of: 
Dose not changed 
An indication that a medication schedule was maintained. 
Drug interrupted 
An indication that a medication schedule was modified by temporarily 
terminating a prescribed regimen of medication. 
Drug withdrawn 
An indication that a medication schedule was modified through 
termination of a prescribed regimen of medication. 
Not applicable 
Determination of a value is not relevant in the current context. 
Unknown 
Not known, not observed, not recorded, or refused. 
11.2.2.4 Outcome at the Time of Last Observation 
The outcome at the time of last observation will be classified as: 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Not recovered/not resolved 
• Fatal* 
• Unknown 
*Investigators should only select fatal as an outcome when the AE results in death. If more than 
one AE is judged to be possibly related to the participant’s death, the outcome of death should be 
indicated for each such AE. Although “fatal” is usually an event outcome, events such as sudden 
death or unexplained death should be reported as SAEs. 


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11.2.2.5 Adverse Event Relationship to Investigational Product 
The investigator must make an assessment of each AE’s relationship to the IP. The categories for 
classifying the investigator’s opinion of the relationship are as follows: 
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 drug, or the temporal 
relationship of the event to study drug administration makes a causal 
relationship unlikely 
Unlikely 
related 
The event is most likely produced by other factors such as the 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 drug 
Possibly related The event follows a reasonable temporal sequence from the time of drug 
administration, and/or follows a known response pattern to the study drug, but 
could have been produced by other factors such as the participant's clinical 
condition, intercurrent illness, or concomitant drugs 
Related 
The event follows a reasonable temporal sequence from the time of drug 
administration, and/or follows a known response pattern to the study drug, and 
cannot be reasonably explained by other factors such as the participant's 
clinical condition, intercurrent illness, or concomitant drugs 
For SAEs, the event relationship to the IP must be assessed separately by the investigator and Daré. 
11.2.3 Documentation 
All AEs that occur within the period of observation for the study must be documented in the eCRF 
with the following information, where appropriate. (The period of observation for the study is 
described in Section 11.2.) 
• AE name or term 
• When the AE first occurred (start date and time) 
• When the AE stopped (stop date and time or an indication of “ongoing”) 
• Severity of the AE 
• Seriousness (hospitalization, death, etc.) 
• Actions taken 
• Outcome 
• Investigator opinion regarding the AE relationship to the IP 
11.2.4 Treatment of Adverse Events 
Adverse events that occur during the study will be treated, if necessary, by established standards 
of care. If such treatment constitutes a deviation from the protocol, the participant may continue 


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in the study. The decision about whether the participant may continue in the study will be made 
by the sponsor after consultation with the investigator and/or medical monitor. 
If AEs occur in a participant that are not tolerable, the investigator must decide whether to stop the 
participant’s involvement in the study and/or treat the participant. Special procedures may be 
recommended for the specific IP, such as the collection of a blood sample for determining plasma 
concentrations of IP, specific tapering procedures, or treatment regimens, as appropriate. 
For double-blinded studies, it is not necessary to unblind a participant’s treatment assignment in 
most circumstances, even if an SAE has occurred. If unblinding is necessary, see Section 9.6 for a 
description of the unblinding procedures. 
11.2.5 Follow-up 
Any AE will be followed (up to a maximum of 30 days after the last dose of IP) to a satisfactory 
resolution, until it becomes stable, or until it can be explained by another known cause(s) 
(i.e., concurrent condition or medication) and clinical judgment indicates that further evaluation is 
not warranted. All findings relevant to the final outcome of an AE must be reported in the 
participant’s medical record and recorded on the eCRF page.  
11.2.6 Reporting 
11.2.6.1 Serious Adverse Events 
In the event of any SAE reported or observed during the study, whether or not attributable to the 
study drug, site personnel will report the event to ICON (ICON plc Pharmacovigilance) by email 
within 24 hours of notification of event in accordance with procedures described in the Study 
Reference Manual 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 clinical research unit to assist in collecting, organizing, 
and reporting SAEs and follow-up information.  
All SAEs should be followed to their resolution, with documentation provided to the sponsor, 
medical monitor, and ICON on a follow-up SAE Report Form. 
At the time of first notification, the investigator or designee should provide the following 
information, if available: 
• Protocol number 
• Reporter (study site and investigator) 
• Suspect IP 
• Participant’s study number 
• Participant’s year of birth 
• Participant’s gender 
• Date of first dose of IP 
• Date of last dose of IP, if applicable 


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• Adverse event term 
• Date of occurrence of the event 
• A brief description of the event, outcome to date, and any actions taken 
• The seriousness criteria(on) that were met 
• Concomitant medication at onset of the event 
• Relevant medical history information 
• Relevant laboratory test findings 
• Investigator’s opinion of the relationship to IP (“Is there a reasonable possibility that the IP 
caused the SAE? Yes or No?”) 
• Whether and when the investigator was unblinded as to the participant’s treatment 
assignment  
Any missing or additional relevant follow-up information concerning the SAE should be sent to 
ICON (ICON plc Pharmacovigilance) as soon as possible with the following minimal information 
(initial report, adverse event, date of occurrence, participant identification, study number, IP, and 
site number); this will allow the follow-up information to be linked to the initial SAE report.  
Specific information may be requested by ICON plc Pharmacovigilance using a follow-up request 
form or via email communication. 
The investigator is required to comply with applicable regulations (including local laws and 
guidance) regarding the notification of his or her health authorities, Human Research Ethics 
Committee (HREC), principal and coordinating investigators, study investigators, and institutions. 
Each investigator is obligated to learn about the reporting requirements for investigators in his/her 
country. The study monitor may be able to assist with this. 
11.2.6.2 Adverse Drug Reactions 
All ADRs should be reported by the investigator in the eCRF.  
Suspected serious ADRs must be reported to the sponsor immediately, regardless of the time 
elapsed since the end of the observation period. 
11.2.6.3 Nonserious Adverse Events 
Nonserious AEs will be recorded in the eCRF and reported in accordance with the safety 
management plan. 
11.3. Special Considerations 
11.3.1 Pregnancy 
Not applicable – participants are postmenopausal women. Women of childbearing potential are 
not eligible for participation. 


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12. DATA SAFETY MONITORING BOARD 
A data safety monitoring board will not be used in this study. 


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13. STATISTICS 
13.1. Statistical Analysis 
This section presents a summary of the planned statistical analyses. An SAP that describes the 
details of the analyses to be conducted will be written prior to database lock.  
An analysis of covariance (ANCOVA) model will be used to assess treatment differences in 
change from baseline for vaginal pH, vaginal cytology, dyspareunia, and most bothersome 
symptom, using baseline score as a covariate. With no formal testing planned for this study, the 
P values will be informational. 
Summary statistics will be provided for the variables described below. For continuous variables, 
these statistics will typically include the number of participants, mean, standard deviation (SD), 
median, minimum, and maximum. For categorical variables, these statistics will typically include 
the number and percentage of participants in each category. The denominator for percentage will 
be based on the number of participants appropriate for the purpose of analysis. 
For all calculations of change from baseline, the last observation recorded before the first 
administration of the insert (DARE-VVA1 or placebo) will be considered as the baseline 
observation. 
13.1.1 Analysis Populations 
The following 3 analysis populations are planned for this study:  
• Safety: all participants who are enrolled and receive any amount of planned IP. This 
population is used for safety analyses. 
• Intent-to-treat (ITT): all randomized participants. This population will be used for the 
analysis of secondary efficacy endpoints. 
• PK: all participants who receive at least 1 dose of IP and provide at least 1 quantifiable PK 
plasma sample. This population will be used for analyses of PK parameters. 
All analyses will be performed on non-hysterectomized participants, hysterectomized participants, 
and all participants taken together. If a participant is randomized incorrectly or is administered the 
incorrect IP, analyses of the ITT population will be based on the assigned treatment whereas all 
other analyses will be based on the actual treatment. 
13.1.2 Study Participants and Demographics 
13.1.2.1 Disposition and Withdrawals 
The numbers of participants randomized, completing, and withdrawing, along with reasons for 
withdrawal, and the number of participants in each analysis population will be tabulated by 
treatment group and overall. 
13.1.2.2 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 


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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 
• Drug dosing not administered within the time frame specified in the protocol 
• Failure to adhere to test requirements, including vital signs, laboratory tests, physical 
examinations, PK blood draws, medical history, etc. – either tests not done, incorrect tests 
done, or not done within the time frame specified in the protocol 
• Procedural deviations such as incorrect storage of 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. 
The number of participants with key/non-key protocol deviations and/or eligibility deviations will 
be tabulated in categories by treatment group and overall. 
13.1.2.3 Demographics and Other Baseline Characteristics 
These analyses will be conducted for the Safety and ITT populations. 
Demographic variables will include age, height, weight and BMI. Information on race and 
ethnicity will be collected for any eventual analysis of differences in response to the IP, in 
accordance with local regulatory requirements. These will be summarized descriptively. 
Baseline participant characteristics will include medical history, vaginal speculum examinations, 
mammograms and CSTs. These will be summarized by treatment group and overall. 
13.1.3 Exposure and Compliance 
Investigational product administration will be summarized in terms of each participant’s total dose, 
total number of missed doses, duration of exposure, and overall percentage compliance for the IP. 
Descriptive statistics for these quantities, including the mean, median, SD, minimum, maximum, 
and quartiles, will be provided by treatment group.  
13.1.4 Safety and Tolerability Analyses 
Safety analyses will be conducted using data from the safety population (as defined in 
Section 13.1.1). Descriptive statistics will be calculated for safety data and presented by visit and 
treatment group for quantitative safety data, and frequency counts will be compiled for 
classification of qualitative safety data. Safety variables include treatment-emergent adverse 


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events (TEAEs), clinical laboratory values, vital signs, ECG readings, physical examination 
results, endometrial thickening in women who have not undergone hysterectomy, and prior and 
concomitant medications. No formal inferential analyses will be conducted for safety variables, 
unless otherwise noted. 
13.1.4.1 Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 24.0 or higher.  
An AE is defined as treatment emergent if the first onset or worsening is after the first 
administration of IP (DARE-VVA1) and not more than 30 days after the last administration of IP. 
The number and percentage of participants with TEAEs will be displayed for each treatment group 
by system organ class and preferred term. Summaries of TEAEs by severity and relationship to IP 
will also be provided. All TEAEs leading to IP discontinuation and/or study discontinuation will 
be summarized separately. 
Serious adverse events will be summarized separately in a similar manner by treatment group. 
Summaries of SAEs by severity and relationship to IP will also be provided. Participant listings of 
AEs, SAEs, and AEs causing discontinuation of IP will be produced. 
13.1.4.2 Clinical Laboratory Evaluations 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual (absolute) values 
and changes from baseline values will be presented for clinical laboratory values by treatment 
group at each time point. 
The number of participants with clinical laboratory values categorized as below, within, or above 
normal ranges will be tabulated showing change from baseline (shift tables) for each clinical 
laboratory analyte by treatment group and by study visit. 
Laboratory values that are outside the normal range will also be flagged in the data listings and 
presented with the corresponding normal ranges. Any out-of-range values that are identified by 
the investigator as being clinically significant will also be shown in a data listing. 
13.1.4.3 Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline will be calculated for systolic blood pressure, diastolic blood pressure, heart 
rate, and respiratory rate, by treatment group. 
13.1.4.4 Twelve-lead Electrocardiograms 
The number and percentage of participants with normal and abnormal ECG findings will be 
summarized by treatment group at each time point. Abnormal results will be grouped as clinically 
significant and not clinically significant. 
Descriptive summaries (mean, SD, median, minimum, and maximum) will be presented for ECG 
measures of PR interval, QRS interval, QT interval, QTc interval (Bazett’s and Fridericia’s 
correction methods), and heart rate by treatment group at each time point. 


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13.1.4.5 Local Site Irritation 
Change in local irritation scores (for erythema and edema, see Table 10-1) from baseline to Day 57 
will be calculated. Descriptive summaries (mean, SD, median, minimum, and maximum) will be 
provided for absolute values and for change from baseline by treatment group. In addition, number 
and percentages of participants with each score will be summarized categorically for erythema and 
edema separately. 
13.1.4.6 Physical Examination Findings 
The number and percentage of participants with normal and abnormal findings in the complete 
physical examination will be displayed by treatment group. 
13.1.4.7 Endometrial Thickening 
Change in endometrial thickness from baseline in women who have not undergone hysterectomy 
will be summarized descriptively by treatment group. 
13.1.4.8 Prior and Concomitant Medications 
Prior medications will be presented separately from concomitant medications. Medications that 
started before the first dose of IP will be considered prior medications whether or not they were 
stopped before the first dose of IP. Any medications continuing or starting after the first dose of 
IP will be considered to be concomitant. If a medication starts before the first dose of IP and 
continues after the first dose of IP it will be considered both prior and concomitant. 
Summary tables by treatment group will be presented by World Health Organization-Anatomical 
Therapeutic Chemical Classification System (WHO-ATC) therapeutic category and preferred term 
for participants in the Safety population. 
13.1.5 Pharmacokinetics  
For noncompartmental analysis, plasma concentrations will be listed and summarized at each time 
point using descriptive statistics; geometric means and % coefficient of variation (%CV) will also 
be presented for the PK parameters by treatment group. 
Table 10-2 lists the PK parameters that are collected for each participant. The PK parameters will 
be summarized by dose using descriptive statistics. Calculation of PK parameters will be outlined 
in the SAP. 
For the assessment of dose proportionality, the power model will be implemented for Cmax and 
AUC0-t.  
13.1.6 Pharmacodynamics and Efficacy Analysis 
Efficacy variables will be summarized and analyzed using the ITT population, unless otherwise 
specified. 
13.1.6.1 Primary Analysis 
There is no primary efficacy analysis planned for this study. 


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13.1.6.2 Secondary Analyses 
The secondary efficacy endpoints are the following: 
• Change of vaginal pH from baseline to Day 57 
• Change in vaginal cytology (maturation index; percentage of basal and superficial cells) from 
baseline to Day 57 
• Change in most bothersome symptom from baseline to Day 56 
• Change in severity of dyspareunia from baseline to Day 56 
• Correlation between exposure and local changes 
Descriptive summaries (mean, SD, median, minimum, and maximum) involving change of vaginal 
pH and vaginal cytology will be presented by treatment group at each time point. In addition, an 
ANCOVA model will be used to assess treatment differences in change from baseline for vaginal 
pH, vaginal cytology, dyspareunia, and most bothersome symptom, using baseline score as a 
covariate. The P values will be informational, and no formal testing is planned for this study. 
The change in severity from baseline for the most bothersome symptom identified by participants 
at screening will be summarized categorically by treatment group (see Section 10.3.3.3 for 
assessment details). In addition, the change in severity from baseline will also be summarized 
descriptively for each of the 5 symptoms evaluated at each time point. 
For assessments of dyspareunia, change in severity from baseline will be summarized descriptively 
by time point and by treatment group. A categorical summary of severity will be presented by 
treatment group at each time point. 
Pharmacodynamics will be assessed by correlating the dose administered to exposure of tamoxifen 
in plasma, and then by relating the exposure to local vaginal change in cytology and pH as well as 
to the reported symptomatology over 56 days. Additional details of this analysis will be provided 
in the SAP. 
13.1.6.3 Exploratory Analyses 
Analysis of exploratory endpoints will be conducted in the ITT population. 
The exploratory efficacy endpoints are the following: 
• Change in the MENQOL questionnaire from baseline to Day 57 
• Responses to the Usability and Acceptability questionnaire over time 
The MENQOL questionnaire consists of 4 domains and is scored as indicated in the Appendix A. 
Change from baseline for individual domains and total questionnaire score is summarized 
descriptively by treatment group and time point. 
Details of the analysis of the responses to the Usability and Acceptability questionnaire will be 
outlined in the SAP. 
13.1.7 Interim Analysis 
No interim analyses are planned.  


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13.2. Sample Size Determination 
This dose ranging study is not powered for statistical significance. A sample size of 8 participants 
in each treatment group is considered sufficient to provide information on safety, PK, and PD 
effects, to guide the design of future studies with DARE-VVA1. A total of 40 participants are 
planned for this study. 
 


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14. STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel before the study, periodic monitoring visits, and meticulous data management. 
14.1. Sponsor and Investigator Responsibilities 
14.1.1 Sponsor Responsibilities 
The sponsor is obligated to conduct the study in accordance with strict ethical principles 
(Section 15). The sponsor reserves the right to withdraw a participant from the study (Section 8.3), 
to terminate participation of a study site at any time (Section 14.7), and/or to discontinue the study 
(Section 14.6). 
Daré agrees to provide the investigator with sufficient material and support to permit the 
investigator to conduct the study according to the study protocol. 
14.1.2 Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 17.1), the investigator indicates that he or she 
has read the protocol carefully, fully understands the requirements, and agrees to conduct the study 
in accordance with the procedures and requirements described in this protocol.  
Investigators should ensure that all persons who are delegated study-related responsibilities are 
adequately qualified and informed about the protocol, the IP, and their specific duties within the 
context of the study. Investigators are responsible for providing Daré with documentation of the 
qualifications, Good Clinical Practice (GCP) training, and research experience for themselves and 
their staff as required by the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the study may be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
14.1.3 Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor and their interventions. This confidentiality is extended to cover testing 
of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study, or the data will 
be released to any unauthorized third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the HREC, 
regulatory agencies, or pharmaceutical company supplying study product may inspect all 
documents and records required to be maintained by the investigator, including, but not limited to, 
medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. 
The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 


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for as long a period as dictated by the reviewing HREC, institutional policies, or sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to ICON. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by clinical 
sites and by ICON will be secured and password protected. At the end of the study, all study 
databases will be de-identified and archived.  
14.2. Site Initiation 
Study personnel may not screen or enroll participants into the study until after receiving 
notification from the sponsor or its designee that the study can be initiated at the study site. The 
study site will not be authorized for study initiation until: 
1. The study site has received the appropriate HREC approval for the protocol and the 
appropriate ICF. 
2. All GCP documents have been submitted to and approved by the sponsor or its designee. 
3. The study site has a Clinical Trial Agreement in place. 
4. Study site personnel, including the investigator, have participated in a study initiation 
meeting. 
14.3. Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the IP or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any SAE. 
Participants who fail inclusion and/or exclusion criteria may be rescreened for the study. 
Participants may only be rescreened once after the original Screening Visit. If a participant is 
eligible to enter the study after having previously failed screening, the participant will be assigned 
a new participant identification number. 
14.4. Study Documents 
14.4.1 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. A copy of the ICF will be given to the 
participants for their records. 


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14.4.2 Good Clinical Practice Documents 
The GCP documents are listed below. 
• Signed original protocol (i.e., Investigator’s Agreement) 
• Curricula vitae of all investigators and subinvestigators 
• Name and address of the laboratories 
• List of laboratory reference ranges, and if available, a quality certificate 
• Any other relevant GCP documents 
The GCP documents must be received from the investigator and reviewed and approved by Daré 
or its designee before Daré will authorize shipment of IP to the study site. Copies of the 
investigator’s GCP documents must be retained at the study site in a secure location. Additional 
documents, including a copy of the protocol and applicable amendment(s), the DARE-VVA1 IB, 
eCRF completion guidelines, copies of regulatory references, copies of HREC correspondence, 
and IP accountability records should also be retained as part of the investigator’s GCP documents. 
It is the investigator’s responsibility to ensure that copies of all required GCP documents are 
organized, current, and available for inspection. 
A Delegation Log for study-related duties will also be retained at the study site, following 
signature. 
14.4.3 Case Report Forms 
By signing the Investigator’s Agreement (Section 17.1), the investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all participants who sign 
an ICF. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor or its designee will provide the necessary training on the use of the 
specific eCRF system used during the study to ensure that the study information is captured 
accurately and appropriately. 
To ensure data accuracy, eCRF data for individual participant visits should be completed as soon 
as possible after the visit. All requested information must be entered in the electronic data capture 
(EDC) system according to the completion guidelines provided by the sponsor or its designee. 
The eCRFs must be signed by the investigator or a subinvestigator. These signatures serve to attest 
that the information contained in the eCRF is accurate and true. 
14.4.4 Access to Source Data/Documents 
The investigator will provide direct access to source data and documents for individuals 
conducting study-related monitoring, audits, IRB/IEC/HREC review, and regulatory review. The 
investigator must inform the study participant that his/her study-related records may be reviewed 
by the above individuals without violating the participant’s privacy of personal health information 
in compliance with Health Insurance Portability and Accountability Act (HIPAA) regulations. 
By signing this protocol, the investigator affirms to the sponsor that the investigator will maintain, 
in confidence, information furnished to him or her by the sponsor and will divulge such 


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information to the IRB/IEC/HREC under an appropriate understanding of confidentiality with such 
board. 
A paper copy of the laboratory results should be retained with each participant’s source data. 
14.5. Study Management 
14.5.1 Monitoring Procedures 
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. 
14.5.2 Data Management 
Daré or designee will be responsible for activities associated with the data management of this 
study. The standard procedures for handling and processing records will be followed per GCP and 
ICON Clinical Research’s standard operating procedures. A comprehensive data management plan 
(DMP) will be developed, including a data management overview, description of database 
contents, annotated CRF, pre-entry review list, self-evident correction conventions, query 
contacts, and consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data. Procedures for soliciting and documenting resolution to data 
queries are described in the DMP. 
14.5.3 Quality Control and Quality Assurance/Audit 
Daré Bioscience Australia Pty LTD/ICON will implement and maintain quality control and quality 
assurance procedures with written standard operating procedures to ensure the study is conducted 
and data are generated, documented, and reported in compliance with the protocol, GCP, and 
applicable regulatory requirements. 
This study will be subject to audit by Daré or its designee. Audits may be performed to check 
compliance with GCP guidelines and can include: 
• site audits 
• Trial Master File audits 
• database audits 
• document audits (e.g., protocol and/or clinical study report [CSR]) 


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Daré or its designee may conduct additional audits on a selection of study sites, requiring access 
to participant notes, study documentation, and facilities or laboratories used for the study. 
The study site, facilities, all data (including source data), and documentation will be made available 
for audit by quality assurance auditors and for HREC or regulatory authorities according to GCP 
guidelines. The investigator agrees to cooperate with the auditor during the visit and will be 
available to supply the auditor with eCRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify Daré immediately. 
Audits may be conducted under either Daré’s standard operating procedures or those of an external 
auditor. 
14.6. Study Termination 
The study may be terminated at Daré’s discretion at any time and for any reason. 
14.6.1 Regular Study Termination 
The end of this study is defined as the date of the last visit of the last participant (last participant 
out or last participant last visit) participating in the study. Within 90 days of the end of the clinical 
study, Daré or designee will notify the HRECs and regulatory authorities about the regular 
termination of the study as required according to national laws and regulations. 
14.6.2 Premature Study Termination 
The study may be temporarily suspended or terminated prematurely is there is sufficient reasonable 
cause at any time by Daré, HRECs, regulatory authorities, respective steering committees, or the 
coordinating investigator. A decision to prematurely terminate the study is binding to all 
investigators of all study sites. 
Within 15 days of premature termination of a clinical study, Daré or its designee will notify the 
HRECs and regulatory authorities about the premature termination as required according to 
national laws and regulations. Daré or its designee must clearly explain the reasons for premature 
termination. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
If the study is terminated prematurely, all investigators have to inform their participants and take 
care of appropriate follow-up and further treatment of the participants to ensure protection of the 
participants’ interests. Study sites may be asked to have all participants currently participating in 
the study complete all of the assessments for the Early Termination Visit. 


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14.7. Study Site Closure 
At the end of the study, all study sites will be closed. Daré may terminate participation of a study 
site at any time. Examples of conditions that may require premature termination of a study site 
include, but are not limited to, the following: 
• Noncompliance with the protocol and/or applicable regulations and guidelines 
• Inadequate participant enrollment 
14.7.1 Record Retention 
After completing the study, Daré will receive the original CRFs or at least a legible copy and retain 
the documents for at least 2 years after the completion of the study. 
One copy will remain with the investigator. The investigator shall arrange for the retention of the 
participant identification codes, participant files and other source data 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 the clinical development of the product. These documents need to be 
retained for a longer period of time if required by applicable regulatory authorities or by agreement 
with the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor shall have 30 days to respond to the investigator’s notice, 
and the sponsor shall have a further opportunity to retain such materials at the sponsor’s expense. 
Copies of these study records (and all study-related documents, including source data) shall be 
kept by the investigator for the maximum period of time permitted by the hospital, institution, or 
private practice. 
14.7.2 Sample Retention 
Samples may be used for purposes related to this research. The samples will be stored until the 
sponsor has determined that specimens are no longer needed, and the decision has been made that 
none of the samples needs to be reanalyzed. In addition, identifiable samples can be destroyed at 
any time at the request of the participant. 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed.  
14.8. Changes to the Protocol 
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 
IRB/IEC/HREC prior to their implementation. 
14.9. Use of Information and Publication 
All information concerning DARE-VVA1, Daré’s operations, patent applications, formula, 
manufacturing processes, basic scientific data, and formulation information supplied by Daré or 


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its designee to the investigator, and not previously published, is considered confidential and 
remains the sole property of Daré. Case report forms also remain the property of Daré. The 
investigator agrees to use this information for purposes of study execution through finalization and 
will not use it for other purposes without the written consent of the sponsor. 
The information developed in this study will be used by Daré in connection with the continued 
development of DARE-VVA1 and thus may be disclosed as required to other clinical investigators 
or government regulatory agencies. 
Daré Bioscience Australia Pty LTD will retain ownership of all data. All proposed publications 
based on this study will be subject to Daré Bioscience Australia Pty LTD’s approval requirements. 


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15. ETHICAL AND LEGAL CONSIDERATIONS 
15.1. Declaration of Helsinki 
This study will be conducted in compliance with the April 1996 ICH Guidance for Industry GCP 
E6 (including archiving of essential study documents), the Integrated Addendum to ICH E6 (R2) 
of November 2016, the Declaration of Helsinki, the applicable regulations of the country(ies) in 
which the study is conducted, and with European Regulation No. 536/2014. 
See Appendix B for regulation and guidelines. 
15.2. Participant Information and Informed Consent and/or Assent 
A properly constituted, valid HREC must review and approve the protocol, the investigator’s ICF, 
and related participant information and recruitment materials before the start of the study. 
It is the responsibility of the investigator to ensure that written informed consent is obtained from 
the participant before any activity or procedure is undertaken that is not part of routine care. 
According to the Declaration of Helsinki and ICH GCP, participants must provide their written 
informed consent prior to enrollment in a clinical study and before any protocol-specified 
procedures are performed. Participants must declare their consent by personally signing and dating 
the ICF. The written ICF will embody the elements of informed consent and/or assent as described 
in the Declaration of Helsinki and will also comply with local regulations.  
Each participant should be made aware by the investigator of the nature of the study (objectives, 
methods, and potential hazards and benefits) and the procedures involved, using the information 
on the ICF. Information should be given in both oral and written form whenever possible and 
deemed appropriate by the HREC. Participants, their relatives, or, if necessary, legal 
representatives must be given ample opportunity to inquire about details of the study.  
Participant information and the ICF must be in a language fully comprehensible to the prospective 
participant. The written information must be provided to the participant to give her sufficient time 
to understand the information and to prepare questions before being asked for her consent. The 
investigator must confirm that the text was understood by the participant. The participant will then 
sign and date the HREC-approved consent form indicating that she has given her consent to 
participate in the study. The signature confirms that the consent is based on information that has 
been understood. The form will also be signed by the investigator obtaining the consent and 
annotated with the study participant number. Each participant’s signed ICF must be kept on file 
by the investigator for possible inspection by regulatory authorities, Daré, and/or the sponsor’s 
designee. Collection of informed consent and/or assent has to be documented on the eCRF. 
Furthermore, the participant will be informed that if she wishes to drop out or withdraw (see 
Section 8.3) at any time during the study, this will not have any negative consequences. 
Participants may be withdrawn by the investigator if any change related to safety or ethics 
precludes further participation in the study. Participants will be asked to agree to a final assessment 
in the event of an early termination of the study. 
Participants will be informed that data from their case may be stored in a computer without 
inclusion of their name and that such data will not be revealed to any unauthorized third party. 
Data will be reviewed by the monitor, an independent auditor, and possibly by representatives of 


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regulatory authorities and/or HRECs. The terms of the local data protection legislation will be 
applied as appropriate. 
15.3. Institutional Review Board/Independent Ethics Committee Approval 
15.3.1 Ethics Review Prior to Study 
The investigator will ensure that the protocol and consent form are reviewed and approved by the 
appropriate IRB/IEC prior to the start of any study procedures. The IRB/IEC will be appropriately 
constituted and will perform its functions in accordance with ICH GCP guidelines and local 
requirements as applicable. 
15.3.2 Ethics Review of Other Documents 
In addition, the IRB/IEC 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 IRB/IEC and regulatory authority as 
applicable. 


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16. REFERENCES 
 
1. 
Levine KB, Williams RE, Hartmann KE. Vulvovaginal atrophy is strongly associated with 
female sexual dysfunction among sexually active postmenopausal women. Menopause. 
2008;15(4 Pt 1):661-666. 
2. 
Nappi RE, Kokot-Kierepa M. Women's voices in the menopause: results from an 
international survey on vaginal atrophy. Maturitas. 2010;67(3):233-238. 
3. 
Santoro N, Komi J. Prevalence and impact of vaginal symptoms among postmenopausal 
women. J Sex Med. 2009;6(8):2133-2142. 
4. 
Faubion SS, Larkin LC, Stuenkel CA, et al. Management of genitourinary syndrome of 
menopause in women with or at high risk for breast cancer: consensus recommendations 
from The North American Menopause Society and The International Society for the Study 
of Women's Sexual Health. Menopause. 2018;25(6):596-608. 
5. 
Nappi RE, Kokot-Kierepa M. Vaginal Health: Insights, Views & Attitudes (VIVA) - results 
from an international survey. Climacteric. 2012;15(1):36-44. 
6. 
Boccardo F, Bruzzi P, Rubagotti A, Nicolo GU, Rosso R. Estrogen-like action of tamoxifen 
on vaginal epithelium in breast cancer patients. Oncology. 1981;38(5):281-285. 
7. 
Ferrazzi E, Cartei G, Mattarazzo R, Fiorentino M. Oestrogen-like effect of tamoxifen on 
vaginal epithelium. Br Med J. 1977;1(6072):1351-1352. 
8. 
Friedrich M, Mink D, Villena-Heinsen C, et al. The influence of tamoxifen on the 
maturation index of vaginal epithelium. Clin Exp Obstet Gynecol. 1998;25(4):121-124. 
9. 
Lahti E, Vuopala S, Kauppila A, et al. Maturation of vaginal and endometrial epithelium 
in postmenopausal breast cancer patients receiving long-term tamoxifen. Gynecol Oncol. 
1994;55(3 Pt 1):410-414. 
10. 
Love RR, Kurtycz DF, Dumesic DA, Laube DW, Yang Y. The effects of tamoxifen on the 
vaginal epithelium in postmenopausal women. J Womens Health Gend Based Med. 
2000;9(5):559-563. 
11. 
Miodrag A, Ekelund P, Burton R, Castleden CM. Tamoxifen and partial oestrogen agonism 
in postmenopausal women. Age Ageing. 1991;20(1):52-54. 
12. 
Shiota A, Igarashi T, Kurose T, Ohno M, Hando T. Reciprocal effects of tamoxifen on 
hormonal cytology in postmenopausal women. Acta Cytol. 2002;46(3):499-506. 
13. 
Vardy MD, Lindsay R, Scotti RJ, et al. Short-term urogenital effects of raloxifene, 
tamoxifen, and estrogen. Am J Obstet Gynecol. 2003;189(1):81-88. 
14. 
Wardell SE, Nelson ER, Mcdonnell DP. From empirical to mechanism-based discovery of 
clinically useful Selective Estrogen Receptor Modulators (SERMs). Steroids. 2014;90:30-
38. 
15. 
Chollet J, Mermelstein F, Rocamboli SC, Friend DR. Vaginal tamoxifen for treatment of 
vulvar and vaginal atrophy: Pharmacokinetics and local tolerance in a rabbit model over 
28 days. Int J Pharm. 2019;570:118691. 
16. 
Prescribing Information: NOLVADEX (tamoxifen citrate) oral tablets. 2003. 
17. 
Chollet J, Meyn LA, Mermelstein F. Weekly vaginal administration of tamoxifen for three 
months in postmenopausal women with vulvar and vaginal atrophy: a possible new 
treatment approach? Clin Exp Obstet Gynecol. 2019;46(2):285-288. 
18. 
Prescribing Information: SOLTAMOX (tamoxifen citrate) oral solution. 2018. 


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19. 
Parish SJ, Nappi RE, Krychman ML, et al. Impact of vulvovaginal health on 
postmenopausal women: a review of surveys on symptoms of vulvovaginal atrophy. Int J 
Womens Health. 2013;5:437-447. 
20. 
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. 
21. 
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. 
 
 
 
 


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17. ATTACHMENTS 
17.1. Investigator’s Agreement 
 
PROTOCOL NUMBER: 
DARE-VVA-001 
PROTOCOL TITLE: 
Phase 1/2 Study of Intravaginal Tamoxifen (DARE-VVA1): 
Randomized, Double-blind, Placebo-controlled Study of Safety, 
Pharmacokinetics and Pharmacodynamics in Postmenopausal 
Participants with Moderate to Severe Vulvar and Vaginal Atrophy 
AMENDMENT 1 DATE: 
AMENDMENT 2 DATE: 
Version 2.0, 15-Mar-2022 
Version 3.0, 04-Apr-2022 
 
The undersigned acknowledges possession of and has read the DARE-VVA1 IB and has discussed 
these data with the study monitor. Having considered fully all the available information, the 
undersigned considers that it is ethically justifiable to give the IP to selected participants in his/her 
care, according to the study protocol. 
He or she agrees to use the study material, including IP, only as specified in the protocol. He or 
she understands that changes cannot be made to the protocol without prior written approval of 
Daré Bioscience Inc. 
He or she understands that any deviation from the protocol may lead to early termination of the 
study. 
He or she agrees to report to Daré Bioscience Inc within the specified timeframe any clinical AE 
or abnormal laboratory value that is serious, whether or not considered related to the administration 
of IP. 
He or she agrees to comply with Daré Bioscience Inc and regulatory requirements for the 
monitoring and auditing of this study. 
In addition, he or she agrees that the study will be carried out in accordance ICH, the Declaration 
of Helsinki, and the local laws and regulations relevant to the use of new therapeutic agents. 


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I, the undersigned, have carefully read this protocol and agree that it contains all the necessary 
information required to conduct the study. 
Principal Investigator: 
Printed Name: 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 
 
Investigator’s name and address (stamp) 


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APPENDICES 
A. Study-specific Requirements 
B. Regulations and Good Clinical Practice Guidelines 
 


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A. Study-specific Requirements 
 
Symptoms of Vulvar Vaginal Atrophy 
Study participants will be enrolled who have no greater than 5 percent superficial cells on a vaginal 
smear, have a vaginal pH > 5.0, and have either self-identified at least 1 of the first 4 symptoms in 
the list below as being moderate to severe, or that vaginal bleeding associated with sexual activity 
is present. 
Patient self-assessed symptoms of vulvar and vaginal atrophy include: 
• 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 vs. absence) 
 
Local Site Irritation 
Pelvic speculum and visual examinations will be conducted to identify vaginal abnormalities. As 
part of this assessment, investigators will conduct an assessment of local irritation in terms of 
erythema and edema, as shown below. 
 
Reaction Type 
0 = None 
1 = Mild 
2 = Moderate 
3 = Severe 
Erythema 
None 
Faint or mild redness of 
any size OR moderate 
redness involving 
≤ 25% of the area 
Moderate redness 
involving > 25% of the 
area OR intense redness 
involving ≤ 25% of the 
area 
Intense redness 
involving > 25% of the 
area 
Edema 
None 
Mild visible swelling or 
barely palpable edema 
of any size OR easily 
palpable edema 
involving ≤ 25% of the 
area 
Moderate visible swelling 
OR easily palpable 
edema involving > 25% 
of the site or gross 
swelling of firm 
induration involving 
≤ 25% of the area 
Gross swelling or firm 
induration involving 
> 25% of the area 
 
 
Menopause Quality of Life: MENQOL 
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). 
The MENQOL instrument is provided here. 


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B. Regulations and Good Clinical Practice Guidelines 
1. Regulations 
Refer to the following Australian regulations: 
• Therapeutic Goods Act 1989 
• Therapeutic Goods Regulations 1990 
 
2. Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URLs: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_G
uideline.pdf 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__
Step_4.pdf