Conditions: Mammographic Breast Density
Keywords: Mammographic Breast Density BIRADS C or D
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 223
Healthy volunteers: no

Brief summary:
A study to determine the efficacy of 8 mg/day (4 mg/breast) of BHR-700 gel compared to placebo for reducing breast tissue density in women identified as having dense breast tissue upon analysis of screening mammography. The Primary Study Endpoint being the percent reduction of mammographic breast tissue density on a follow-up mammogram compared to the baseline mammogram after 52 weeks of treatment.

Detailed description:
This is a randomized, double blind, placebo-controlled study. Subjects will have been assessed as having mammographically dense breast (heterogeneously dense (C) or extremely dense (D), based on the American College of Radiology (ACR) Breast Imaging-Reporting and Data System (BIRADS©) fifth edition classification) for eligibility.

Approximately 330 subjects will be enrolled at approximately 25 sites in the US and the European Union. Subjects who give informed consent will be stratified, based on whether they are pre/peri or post-menopausal and randomized 2:1 within those groups to receive either 8 mg/day (4 mg/breast) 4-OHT or matching placebo for up to 52 weeks.

Subjects will apply the investigational gel to both breasts once per day until they have completed 52 weeks of study drug administration. There will be, in addition, an optional 52 weeks of open-label treatment for those subjects who choose to continue treatment. Subjects will capture daily gel administration in a diary to monitor compliance.

While on treatment, subjects will return to the clinic for study assessments, a review of adverse events (AEs) and to re-supply study gel at 13, 26, 39, weeks and at 52 weeks for those subjects who have agreed to take part in the open-label phase of the study. During the study, in a case of significant changes in bleeding pattern or other signs/symptoms which could be related to endometrial pathology, the Investigator will perform a uterine ultrasound followed by an endometrial biopsy if indicated.

Open-Label Treatment Phase

Secondary Outcome Measures: • Comparison of breast density measurements (Cumulus and Volpara) • Laboratory parameters will be summarized in a descriptive fashion. • Incidence and severity of AEs will be compared between BHR-700 gel and placebo.

Arms:
arm 1: The gel formulation contains 2 mg/mL 4-OH tamoxifen (0.2%) in a clear, colorless, absorptive hydro-alcoholic gel base formulated to provide continuous release of 4-OH tamoxifen. A total of 8 mg/day (4 mg/breast) of 4-OH tamoxifen will be administered daily for 52 weeks. arm 2: An absorptive hydroalcoholic gel preparation of the same ingredients as BHR-700, but without 4-OHT.

Interventions: intervention 1: 4-OH tamoxifen intervention 2: Placebo
Intervention descriptions: intervention 1: 4-Hydroxytamoxifen (afimoxifene) gel intervention 2: An absorptive hydroalcoholic gel preparation of the same ingredients as BHR-700, but without 4-OHT.

Protocol document:
Prot_000.pdf: 
NCT Number: NCT03199963




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1.2 
Principal Investigator Agreement 
A Randomized, Double-Blind, Placebo-Controlled Trial of 4-Hydroxytamoxifen Gel for 
Reducing Breast Tissue Density in Women with BI-RADS Breast Density Categories C or D 
Version: 4.0 Amendment 3 
Date:  18 April 2018 
As an Investigator conducting this study, I agree: 
•
To assume responsibility for the proper conduct of the study at this site;
•
To conduct the study in compliance with this protocol, with any future amendments, and
with any other written study conduct procedures provided and reviewed and approved by
BHR PHARMA, LLC;
•
Not to implement any deviations from or changes to this protocol without agreement
from the Sponsor and prior review and the written approval from the Institutional Review
Board, except where necessary to eliminate an immediate hazard to the subject/subjects
or for administrative aspects of the study (where permitted by all applicable regulatory
requirements);
•
That I am thoroughly familiar with the appropriate use of the investigational product, as
described in this protocol, and any other information provided by the sponsor including,
but not limited to the current study procedures or any equivalent documents provided by
BHR PHARMA, LLC;
•
That I am aware of, and will comply with Good Clinical Practice and all applicable
regulatory requirements;
•
To ensure that all persons assisting me with the study are adequately informed about the
study procedures and study devices, and that they are qualified to perform their study-
related duties and functions, as described in this protocol.
PRINCIPAL INVESTIGATOR 
Name: 
Signature 
Date 


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1.3 
Study Synopsis 
Study Title: 
A Randomized, Double-Blind, Placebo-Controlled Trial of 
4-Hydroxytamoxifen Gel for Reducing Breast Tissue Density in
Women with BI-RADS Breast Density Categories C or D
Development Phase: 
Phase 3 
Investigational Product 
(IP): 
BHR-700, 4-Hydroxytamoxifen (afimoxifene) gel 
Active Pharmaceutical 
Ingredient (API): 
4-Hydroxytamoxifen (4-OHT)
Study Centers: 
Multicenter study conducted in approximately 25 centers 
Study Duration: 
Up to 110 weeks per subject:  2 weeks screening, 52 weeks blinded 
treatment period with an optional 52 weeks open-label extension. 
Study Objective
Primary: 
To determine the efficacy of 8 mg/day (4 mg/breast) of BHR-700 gel 
compared to placebo for reducing breast tissue density in women 
identified as having dense breast tissue upon analysis of screening 
mammography using the Food and Drug Administration 
(FDA)-cleared Cumulus 2D software. 
Study Endpoints
Primary: 
The percentage reduction of mammographic breast tissue density on 
a follow-up mammogram compared to the baseline mammogram 
after 52 weeks of treatment. 
Secondary: 
Incidence and severity of adverse events (AEs) with special attention 
given to uterine abnormalities, cardiovascular events, 
thromboembolic events, and incidence of vasomotor symptoms (“hot 
flush”). 
Change in serum concentration of sex hormone binding globulin 
(SHBG). 
Change in serum concentration of: cholesterol, triglycerides, 
high-density lipoprotein (HDL), and low-density lipoprotein (LDL). 
Change in serum concentration of Protein C-activity, Protein S-
activity, Antithrombin 111 antigen, and Activated Protein C 
resistance (APCR). 
Change in serum concentration of select bone biomarkers CTx and 
BSAP. 
Plasma concentrations of the E and Z isomers of 4-OHT. 
Study Design
Methodology: 
This is a multi-center, randomized, double-blind, placebo-controlled 
study in women identified as having dense breast tissue upon 
screening mammography. 
Subjects who give informed consent will have screening evaluations, 
including hormone measures of FSH, Estradiol, Estrone and LH to 


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determine menopausal state. Some subjects may require a 
mammogram to be made at this stage because they do not have a 
mammogram that fulfills the necessary criteria (format or time 
period). Those subjects meeting entry criteria, will be stratified, 
based on their hormone levels, into pre/peri and post menopause 
groups and randomized within those groups 2:1 to receive either 8 
mg/day (4 mg/breast) BHR-700 gel or placebo for up to 52 weeks. 
At the Principal Investigator’s (PI) discretion, subjects may be 
allowed to reduce the dose to 4 mg/day (2 mg/breast) in cases of 
intolerance. 
Subjects will apply the gel to both breasts once per day.  The first 
dose will be applied under the supervision of the PI/designee.  
Subsequent doses will be self-administered daily by the subject until 
she has completed 52 weeks of study drug administration.  A diary 
will be kept by the subject to monitor compliance, the start and stop 
dates for the subject’s last menstrual cycle and any breakthrough 
bleeding experienced excluding days of normal menses. 
Subjects who complete the double-blind phase of the study will be 
offered entry into an open-label follow-up period for an additional 
52 weeks. 
While on treatment, subjects will be evaluated at Day 1 and every 
13 weeks thereafter.  
Number of Subjects: 
A planned sample size of 330 women, identified as having dense 
breast tissue upon mammography, will be randomized to receive 
either BHR-700 gel or placebo (2:1 distribution).  Considering an 
attrition rate of approximately 15%, the expectation is to have 272 
evaluable women (4-OHT: 181 & Placebo: 91) who will have both 
baseline and 52 week measurements of percent mammographic 
density (MD) of the breast. 
Inclusion Criteria: 
1. Healthy women age 35 – 75 years with either heterogeneously
dense (C) or extremely dense (D), breast tissue on 2D
mammography, based on American College of Radiology (ACR)
Breast Imaging-Reporting and Data System (BI-RADS©) fifth
edition classification) in either breast within 3 months prior to
randomization. Mammogram with BI-RADS final assessment
category 1 or 2 (negative or benign findings).
2. If the woman is of childbearing potential, she must have a
documented negative urine pregnancy test at time of screening
and randomization and no plans to become pregnant for the
duration of study participation.
3. Ability to understand and the willingness to sign a written
informed consent document.


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Exclusion Criteria: 
1. Participants may not be receiving treatment with any
investigational drug or investigational biologic within 30 days of
randomization or at any time during the study.
2. Women with a history of allergic reactions attributed to
compounds of similar chemical or biologic composition to
Tamoxifen.
3. Pregnant women are excluded from this study because the effects
of 4-OHT gel on the developing human fetus at the recommended
dose and route are unknown.
4. Pregnancy (independent of outcome) and/or lactation within 1
year prior to the screening mammogram.
5. Women with previous history of cancer (including invasive or
intra-ductal breast cancer) except for non-melanoma skin cancer.
6. Women who have had a prior mastectomy (unilateral or
bilateral), segmental mastectomy, reduction mammoplasty or
breast augmentation including implants.
7. Women with surgical breast biopsy(s) performed within 3 years
or core biopsy(s) performed within 1 year prior to randomization.
8. Women with an abnormal mammogram (BI-RADS final
assessment category 3-probably benign, 4-suspicious, or 5-
malignant findings). Women with BI-RADS 0 assessment (needs
additional imaging evaluation) that are subsequently found to
have negative (BI-RADS 1) or benign findings (BI-RADS 2), are
NOT excluded.
9. Women with only synthetic 2D mammograms generated from 3D
(tomosynthesis) are excluded as breast density measurements are
not yet validated for synthetic mammograms. Women with
combination 2D+3D mammograms are not excluded.
10. Women with active liver disease or thromboembolic disorder.
11. Women with skin conditions such as psoriasis, fungal infections,
keloids etc., or tattoos and/or piercings, which in the opinion of
the Investigator, would interfere with absorption of the IP.
12. Women who have had an abnormal gynecology exam within the
last three years with clinically significant findings, such as
secondary dysmenorrhea, polyps, or atypia, which in the opinion
of the Investigator would interfere with the study.
13. Women who have received treatment with Selective Estrogen
Receptor Modulators (SERMs) (e.g. tamoxifen, raloxifen) or
aromatase inhibitors.
14. Women taking estrogen containing contraceptives or Hormone
Replacement Therapy (HRT) must discontinue the treatment a
minimum of 6 months prior to the screening mammogram.
Progestin only contraceptives are permitted.
15. Women with a concurrent illness, disease or condition that, in the
opinion of the Investigator, would limit their compliance with
study requirements or place them at additional risk.


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Test Product, Dose, and 
Mode of Administration: 
The BHR-700 gel formulation contains 2 mg/mL 4-OH tamoxifen 
(0.2%) in a clear, colorless, absorptive hydro-alcoholic gel base 
formulated to provide continuous release of 4-OH tamoxifen.  The 
BHR-700 gel is supplied in a non-aerosol canister with a 1 mL fixed-
dose pump. 
Two (2) fixed unit doses of BHR-700 gel will be applied daily to 
each breast.  Each actuation dispenses 1 mL of gel.  A total of 
8 mg/day (4 mg/breast) of 4-OHT will be administered daily, unless 
dose reduction by the Investigator, is deemed necessary for reasons 
of tolerability. 
The placebo gel is identical in appearance and consistency to the 
BHR-700 gel. 
Treatment compliance will be monitored by the Investigator staff 
who will check subject diaries and weigh the IP canister(s) when 
dispensed and upon return. 
Duration of Treatment: 
Up to 52 weeks for primary efficacy assessment with an optional and 
additional 52 weeks of open-label treatment of BHR-700 gel. 
Criteria for Evaluation
Efficacy Measures: 
Mammograms will be centrally analyzed.  The reader will be blinded 
as to the treatment group (BHR-700 gel or placebo) and time point of 
each subject.  Cumulus 2D will be the primary endpoint method with 
Volpara 3D as a secondary endpoint method. 
Safety Measures: 
Safety assessments will include evaluation of all AEs/serious adverse 
events (SAEs), with special attention given to uterine abnormalities, 
cardiovascular events, and thromboembolic events.  Additional 
important safety parameters specific for this indication are: 
•
Endometrial changes
•
Breast evaluation
•
Coagulation factors
•
Bone biomarkers
•
Changes in menstrual cycle; unexpected vaginal bleeding
To address these safety parameters, subjects will undergo the 
following assessments: 
A bilateral mammogram with both the raw and processed 2D image 
DICOM files needs to be performed within 3 months prior to 
randomization. The same (make/model/serial number) 
mammography machine must be used for the Week 52 mammogram, 
and if the subject is participating in the Open-Label phase, the Week 
104 mammogram.  If the mammogram is older than 3 months but less 
than 18 months, or it cannot be provided in the format required for 


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the study, the mammogram can be repeated to meet the study entry 
requirement after informed consent has been obtained. 
A clinical breast examination will be performed at Screening, 
Baseline (Study Day 1-Week 1) and Study Week 52.  
Coagulation factors will be measured prior to administration of study 
drug, Study Week 26 and Study Week 52. 
Changes in bone mineral density will be assessed by measurement of 
select bone biomarkers pre-dose and at Study Week 52.  
Serum concentration of sex hormone binding globulin (SHBG) will 
be measured pre-dose and at Study Week 52.  
Routine laboratory parameters (i.e., hematology and blood chemistry) 
will be measured at Screening, on Day 1 before administration of 
study drug, Study Week 26 and Study Week 52. 
Urine pregnancy tests will be performed on women of child bearing 
potential at Screening, Randomization, at each clinic visit and at any 
point during the study when pregnancy is suspected (i.e., missed 
cycle, skipped/failed birth control).  
AEs will be collected at each Study Visit beginning with the first 
dose of study drug (Study Day 1). 
During the trial, in a case of significant changes in bleeding pattern or 
other signs/symptoms which could be related to endometrial 
pathology, the Investigator will perform a uterine ultrasound 
followed by an endometrial biopsy if indicated. 
Pharmacokinetic: 
BHR-700 (E and Z isomers) plasma concentrations will be measured 
at Study Weeks 13, 26, 52, 78, and 104. 


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Statistical Methods: 
Blinded Treatment Phase 
Primary Outcome Measure: 
•
Comparison of the reduction in breast density between
BHR-700 gel and placebo treatment groups at 52 weeks using
the Cumulus method.  Assuming a reduction from baseline of
6% on active and 2% on placebo, with a common standard
deviation of 8%, a total of 272 subjects will achieve a power
of 90% using a two sample, two-sided t-test at a significance
level of < 0.01.  Considering an attrition rate of approximately
15%, 330 subjects will be enrolled.
Secondary Outcome Measures: 
•
Comparison of breast density measurements (Cumulus and
Volpara)
•
Laboratory parameters will be summarized in a descriptive
fashion.
•
Incidence and severity of AEs will be compared between
BHR-700 gel and placebo.
Open-Label Treatment Phase 
Secondary Outcome Measures: 
•
Comparison of breast density measurements (Cumulus and
Volpara)
•
Laboratory parameters will be summarized in a descriptive
fashion.
•
Incidence and severity of AEs will be compared between
BHR-700 gel and placebo.


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Table of Contents 
1.0
CLINICAL STUDY PROTOCOL ......................................................................................1
1.1
Sponsor Approval ................................................................................................................2
1.2
Principal Investigator Agreement ........................................................................................3
1.3
Study Synopsis .....................................................................................................................4
2.0
BACKGROUND ...............................................................................................................12
2.1
Introduction ........................................................................................................................12
2.2
Rationale ..........................................................................................................................12
3.0
STUDY OBJECTIVES & PURPOSE ...............................................................................16
4.0
STUDY DESIGN...............................................................................................................16
5.0
SUBJECT SELECTION AND WITHDRAWAL .............................................................17
5.1
Inclusion Criteria ...............................................................................................................17
5.2
Exclusion Criteria ..............................................................................................................18
5.3
Dose Reduction ..................................................................................................................19
5.4
Early Withdrawal of Subjects ............................................................................................19
5.5
Subject Replacement ..........................................................................................................20
6.0
TREATMENT OF SUBJECTS .........................................................................................20
6.1
Blinding and Unblinding....................................................................................................20
6.2
Formulation, Packaging, and Labeling ..............................................................................20
6.3
Investigational Product Storage .........................................................................................21
6.4
Dispensing..........................................................................................................................21
6.5
Dosage and Administration................................................................................................21
6.6
Investigational Product Administration Precautions .........................................................22
6.7
Pregnancy and Nursing ......................................................................................................22
6.8
Assessment of Compliance ................................................................................................23
6.9
Investigational Product Accountability ..............................................................................24
6.10
Prior and Concomitant Medications ..................................................................................24
6.11
Prohibited Concomitant Medications/Therapies ................................................................24
7.0
STUDY PROCEDURES ...................................................................................................24
7.1
Screening (Within 30 days prior to randomization) ..........................................................24
7.2
Study Day 1 (Week 1):  Baseline .......................................................................................25
7.3
Blinded Phase Visits ..........................................................................................................25
7.4
Open-Label Phase Visits ....................................................................................................27
8.0
ASSESSMENTS OF SAFETY..........................................................................................29
8.1
Adverse Event Collection and Reporting ..........................................................................29
8.2
Reporting of Adverse Events .............................................................................................30
8.3
Assessment of Adverse Event Severity .............................................................................31
8.4
Serious Adverse Events .....................................................................................................31
8.5
Laboratory Tests ................................................................................................................33
8.6
Physical Examination.........................................................................................................33
8.7
Vital Signs ..........................................................................................................................33
8.8
Mammogram ......................................................................................................................34
9.0
STATISTICAL ANALYSIS .............................................................................................34
9.1
Statistical Analysis Plan .....................................................................................................34
9.2
Sample Size ........................................................................................................................35
9.3
Analysis by Study Period (Blinded Phase / Open-Label Phase)........................................35
9.4
Mammographic Density Assessments ...............................................................................35


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9.5
Data Management ..............................................................................................................35
9.6
Study Populations ..............................................................................................................36
9.7
Handling of Missing and Incomplete Data ........................................................................36
9.8
Methodology and Conventions ..........................................................................................36
10.0
REGULATORY AND PROCEDURAL REQUIREMENTS ...........................................37
10.1
Ethical Conduct of the Study .............................................................................................37
10.2
Institutional Review Board ................................................................................................37
10.3
Subject Informed Consent..................................................................................................37
10.4
Advisory Board ..................................................................................................................38
10.5
Investigator Obligations .....................................................................................................38
10.6
GCP Compliance ...............................................................................................................38
10.7
Protocol Adherence and Investigator Agreement ..............................................................38
10.8
Protocol Deviations ............................................................................................................39
10.9
Monitoring of the Study .....................................................................................................39
11.0
FINANCIAL DISCLOSURE ............................................................................................39
12.0
REFERENCES ..................................................................................................................43
APPENDIX 1.
Schedule of Study Assessments and Procedures .............................................45
APPENDIX 2.
Subject Instructions for Use .............................................................................46
APPENDIX 3.
Menstrual History Questionnaire .....................................................................49
APPENDIX 4.
Laboratory Assessments ..................................................................................51
List of Tables 
Table 1. ACR BI-RADS© Breast Tissue Composition .................................................................17


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2.0 
BACKGROUND 
2.1 
Introduction 
Breast cancer remains the most common type of cancer in women with an estimated 1.6 million 
cases per year worldwide.  Studies have shown that women with dense breast tissue have a 2-6 
fold increased risk of developing breast cancer, with only age or BRCA 1 and BRCA 2 gene 
mutation being associated with a higher increase in risk.1  Mammographic density (MD) is 
heavily influenced by and inversely proportional to age, reflecting the relative decrease in 
glandular tissue and increase in fatty breast tissue associated with aging.2 
Tamoxifen is an effective oral treatment for estrogen receptor-positive breast cancer.  
17β-estradiol, at physiologic concentrations, is known to stimulate the proliferation of normal 
breast epithelial cells.  Tamoxifen is an antiestrogen that inhibits estradiol effects through 
competitive binding to the estrogen receptor at or near the 17β-estradiol binding site resulting in 
cell-cycle arrest.3,4,5  Studies of tamoxifen in the adjuvant and preventive setting have 
demonstrated that a decline in MD of approximately 10% is consistently associated with better 
outcomes.  In a case-control analysis, Cuzick et al. observed that approximately 46% of 
tamoxifen-treated women experienced a ≥ 10% reduction in MD at 12−18 months and a 63% 
reduction in breast cancer risk when compared with all women on placebo treatment regardless 
of MD.  In contrast, tamoxifen-treated women with a < 10% reduction in MD did not experience 
risk reduction compared to all women on placebo.6 
Further retrospective analyses have reported that among women with estrogen receptor-positive 
breast cancer treated with tamoxifen, those whose mammographic density declined in the 
unaffected breast had a reduced risk of recurrence or death from breast cancer.7,8 
2.2 
Rationale 
Despite the success of tamoxifen in reducing mammographic density in breast tissue and 
reducing the recurrence risk of new estrogen receptor positive tumors, the adverse event (AE) 
profile of oral administration makes it an unacceptable treatment to many women.  Tamoxifen 
has been shown to increase the risk of endometrial cancer, thromboembolic events, vasomotor 
symptoms, arthralgia, and cataracts. 
4-Hydroxytamoxifen (4-OHT) is a potent anti-estrogenic metabolite of tamoxifen with a much
higher affinity for estrogen receptors than tamoxifen.9,10,11,12 4-OHT is produced by a step-wise
synthetic process from the commercially available raw materials: anisole, 2-phenylbutyric acid
chloride, 4-bromophenol, and 2-dimethylaminoethyl chloride: HCL.  The crude 4-OHT is
purified by recrystallization from methanol, resulting in two geometric isomers E and Z.


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A topically applied formulation of 4-OHT is being developed with the aim of achieving 
concentrations of 4-OHT in the breast that are sufficiently high to be effective in treating breast 
disease, while avoiding first pass metabolism in the liver, therefore minimizing the potential for 
systemic AEs.  The alcohol-based gel formulation solubilizes 4-OHT to allow topical 
administration and transdermal bioavailability.  Studies to date indicate that the topical 
formulation of 4-OHT is absorbed through the skin into breast tissue with an order of magnitude 
higher than in plasma of 10:1. The breast tissue/plasma ratio is approximately 5:1 following oral 
administration of tamoxifen.   
In vitro studies of 4-OHT gel formulation show linear systemic pharmacokinetics (PK) with 
much of the drug excreted in feces.  Topical 4-OHT at doses up to 200µg/kg/day in two species 
was generally well tolerated, there were no clinical signs of toxicity; however, there were cases 
of weight loss, reduced uterus and ovary size, and changes seen in the genital tract.
In vivo, topical 4-OHT has been evaluated in clinical trials for cyclical breast pain and has been 
shown to be well tolerated.  In a placebo-controlled study in cyclic mastalgia, patients were 
treated for 4 to 6 months.  Headache and nasopharyngitis were the most common AEs seen in 
15% and 2%, 20% and 11%, and 10% and 12% in patients on 2 mg/day, 4 mg day, and placebo, 
respectively.13  4-OHT and oral tamoxifen were studied in the neoadjuvant setting in 55 patients 
with invasive breast cancer; Ki-67, a prognostic parameter in breast cancer patients, was shown 
to decrease with both gel and oral treatments14.  In a recent study of 26 women with Ductal 
Carcinoma In-Situ (DCIS), treatment of topical 4-OHT gel at 4 mg/day (2 mg to each breast) or 
oral tamoxifen at 20 mg/day for 6-10 weeks resulted in similar 4-OHT breast tissue levels and 
similar reductions in breast tumor cell proliferation15.  However, systemic levels of 4-OHT were 
5-fold lower with topical 4-OHT gel when compared to oral tamoxifen resulting in reduced
effects on endocrine and coagulation parameters with transdermal delivery.  The gel was well
tolerated, with most AEs rated as mild and none as severe.  The most commonly reported AEs
were hot flushes (50% vs. 50%), breast pain (42% vs. 64%), fatigue (33% vs. 29%), and night
sweats (25% vs. 43%).
To date, topical 4-OHT has been administered to > 450 pre-and post-menopausal women and has 
been shown to be safe and well tolerated with no clinically significant AEs reported to date 
following administration of doses of 0.25 mg/day, 0.5 mg/day, 1 mg/day, 2 mg/day, and 
4 mg/day. The dose suggested for the present study is 8 mg/day, with the option of down titration 
to 4 mg/day in case of lack of tolerability. Even though breast tissue levels of 4-OHT were 
similar between 4 mg/day topical 4-OHT gel and 20 mg/day oral tamoxifen, the 8 mg/day dose 
was selected because there is another active metabolite (endoxifen) formed after oral tamoxifen 


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administration that is not seen after 4OHT gel topical administration15. The tolerability of 4 
mg/day in the placebo controlled 6 months cyclic mastalgia study was excellent and therefore 
there is no reason to believe 8 mg/day would be associated with a large increase in side effects. 
An unblinded independent DSMB will monitor plasma levels of 4OHT and adverse events 
during the study to further ensure safety of the subjects.  
BHR PHARMA, LLC has developed an investigational topical gel formulation of 4-OHT for the 
reduction of mammographic density in women at an increased risk for breast cancer.  BHR-700 
gel contains 4-Hydroxytamoxifen in an absorptive hydro-alcoholic gel base for topical 
administration to the breast(s).  The active component of the topical gel is 4-OHT, a metabolite 
of tamoxifen with approximately 100 times the potency (as measured by binding affinity to 
estrogen receptors).  The remaining components of the gel are pharmacologically inactive.  The 
chemical structure of the two isomers (E and Z) of 4-OHT is shown in Figure 1 and Figure 2.  


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Figure 1. Chemical Structure of 4-OHT (4-Hydroxytamoxifen): E isomer 
Figure 2. Chemical Structure of 4-OHT (4-Hydroxytamoxifen): Z isomer 
Common Name: 
4-Hydroxytamoxifen - (E) and (Z) isomers (50:50)
CAS Reg. No.: 
68392-35-8
Chemical Name: 
4-(1-[4-(Dimethylaminoethoxy)phenyl]-2-phenyl-1-butenyl)phenol;
4-OH Tamoxifen; cis/trans-4-Hydroxytamoxifen
Empirical Formula: 
C26H29NO2 
Molecular Weight: 
387.51 
 
 


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3.0 
STUDY OBJECTIVES & PURPOSE 
The overall purpose of this study is to evaluate whether daily application of 8 mg (4 mg/breast) 
of 4-OHT lowers breast density in women with mammographically dense breast tissue. 
Primary Objective: 
To determine the efficacy of transdermal administration of 8 mg/day (4 mg/breast) of 4-OHT 
delivered as 4 mLs BHR-700 gel compared to placebo for reducing breast tissue density in 
women identified as having dense breast tissue upon analysis of screening mammography using 
the Food and Drug Administration (FDA)-cleared Cumulus 2D software. 
Secondary Objectives: 
1. To compare the change in percent mammographic density from Baseline to the Week 52
mammogram in women applying 8 mg 4-OHT vs. placebo, using two breast density
measurement methods (Cumulus versus Volpara).
2. To compare the percentage of women who underwent a change in BI-RADS category
when comparing pre-and post-treatment measurements for recipients of 4-OHT and
placebo.
3. To compare the percentage of women with a ± 10% absolute decrease in quantitative
mammographic density (Cumulus) between baseline and 52 weeks, when comparing
between the recipients of 4-OHT and placebo.
4. To describe the symptoms assessed by laboratory toxicity assessments complete blood
count (CBC) w/diff, blood chemistry, coagulation factors, lipid panel, liver function tests,
sex hormone binding globulin (SHBG), and bone biomarkers.
5. To determine the safety and tolerability of 8 mg/day of 4-OHT after 52 weeks of
administration to the breasts such as AE collection, effects on menstrual cycle, and
laboratory values.
6. To determine whether 8 mg/day of 4-OHT will disrupt the menstrual cycle of
premenopausal women.
7. To determine the plasma concentration of the E and Z isomers of 4-OHT after 13, 26, 52,
78, and 104 weeks of application of 4 mL BHR-700 gel to the breasts.
4.0 
STUDY DESIGN 
This is a randomized, double blind, placebo-controlled study.  Subjects will have been assessed 
as having mammographically dense breast (heterogeneously dense (C) or extremely dense (D), 
based on the American College of Radiology (ACR) Breast Imaging-Reporting and Data System 
(BI-RADS©) fifth edition classification) as described in Table 1, for eligibility.  


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Table 1. ACR BI-RADS© Breast Tissue Composition 
Grade Classification 
A 
The breasts are almost entirely fatty. 
B 
There are scattered areas of fibroglandular density. 
C 
The breasts are heterogeneously dense, which may obscure small masses. 
D 
The breasts are extremely dense, which lowers the sensitivity of mammography. 
Approximately 330 subjects will be enrolled at approximately 25 sites located in the U.S. and 
Europe.  Subjects who give informed consent will have screening evaluations, including 
hormone assessments of FSH, Estradiol, Estrone and LH to determine menopausal state. Those 
subjects meeting entry criteria, will be stratified, based on their hormone levels into either 
pre/peri or post-menopausal groups and randomized 2:1 within those groups to receive either 8 
mg/day (4 mg/breast) 4-OHT or matching placebo for up to 52 weeks. 
Subjects will apply the investigational gel to both breasts once per day.  The first dose will be 
applied under the supervision of the Principal Investigator (PI) or designee.  Subsequent doses 
will be self-administered at approximately the same time daily, after showering, by the subject 
until she has completed 52 weeks of study drug administration.  There will be, in addition, an 
optional 52 weeks of open-label treatment for those subjects who choose to continue treatment. 
Subjects will capture daily gel administration in a diary to monitor compliance. 
While on treatment, subjects will return to the clinic for study assessments, a review of AEs and 
to re-supply study gel at 13, 26, 39, weeks and at 52 weeks for those subjects who have agreed to 
take part in the open-label phase of the study.  A schedule of study assessments is shown in 
Appendix 1. 
During the study, in a case of significant changes in bleeding pattern or other signs/symptoms 
which could be related to endometrial pathology, the Investigator will perform a uterine 
ultrasound followed by an endometrial biopsy if indicated.  
5.0 
SUBJECT SELECTION AND WITHDRAWAL 
5.1 
Inclusion Criteria 
1. Healthy women age 35 – 75 years with either heterogeneously dense (C) or extremely
dense (D) dense breast tissue on 2D mammography, based on ACR BI-RADS© fifth
edition classification, within 3 months prior to randomization. Mammogram with BI-
RADS final assessment category 1 or 2 (negative or benign findings).


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2. If the woman is of childbearing potential, she must have a documented negative urine
pregnancy test at the time of screening and randomization and no plans to become
pregnant for the duration of study participation.
3. Ability to understand and the willingness to sign a written informed consent document.
5.2 
Exclusion Criteria 
1. Participants may not be receiving treatment with any investigational drug or
investigational biologic within 30 days of randomization or at any time during the study.
2. Women with a history of allergic reactions attributed to compounds of similar chemical
or biologic composition to Tamoxifen.
3. Pregnant women are excluded from this study because the effects of 4-OHT gel on the
developing human fetus at the recommended dose and route are unknown.
4. Pregnancy (independent of outcome) and/or lactation within 1 year prior to the screening
mammogram.
5. Women with previous history of cancer (including invasive or intra-ductal breast cancer)
except for non-melanoma skin cancer.
6. Women who have had a prior mastectomy (unilateral/bilateral), segmental mastectomy,
reduction mammoplasty or breast augmentation including implants.
7. Women with surgical breast biopsy(s) performed within 3 years or core biopsy(s)
performed within 1 year prior to randomization.
8. Women with an abnormal mammogram (BI-RADS final assessment category 3 -
probably benign, 4-suspicious, or 5-malignant findings). Women with BI-RADS 0
assessment (needs additional imaging evaluation) that are subsequently found to have
negative (BI-RADS 1) or benign findings (BI-RADS 2), are NOT excluded.
9. Women with only synthetic 2D mammograms generated from 3D (tomosynthesis) are
excluded as breast density measurements are not yet validated for synthetic
mammograms. Women with combination 2D+3D mammograms are not excluded.
10. Women with active liver disease or thromboembolic disorder.


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11. Women with skin conditions such as psoriasis, fungal infections, keloids etc., or tattoos
and/or piercings that in the opinion of the Investigator, would interfere with absorption of
the investigational product.
12. Women who have had an abnormal gynecology exam within the last three years with
clinically significant findings, such as secondary dysmenorrhea, polyps, or atypia, which
in the opinion of the Investigator would interfere with the study.
13. Women who have received treatment with Selective Estrogen Receptor Modulators
(SERMs) (e.g. tamoxifen, raloxifen) or aromatase inhibitors.
14. Women taking estrogen containing contraceptives or Hormone Replacement Therapy
(HRT) must discontinue the treatment a minimum of 6 months prior to the screening
mammogram. Progestin only contraceptives are permitted.
15. Women with a concurrent illness, disease or condition that, in the opinion of the
Investigator, would limit their compliance with study requirements or place them at
additional risk.
5.3 
Dose Reduction 
If a subject experiences toxicity that may make her want to stop taking study drug, the dose of 
study drug will be reduced by 50%, to 2 mg (1 pump actuation) to each breast.  The reduced dose 
will be maintained for the duration of the study.   
5.4 
Early Withdrawal of Subjects 
A subject is free to withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The Investigator or Sponsor may also 
withdraw the subject at any time in the interest of subject safety.  The primary reason for 
withdrawal must be recorded in the subject’s medical record and on the withdrawal form in the 
Case Report Form (CRF).  If a subject is withdrawn for more than one reason, each reason 
should be documented in the source document and the most medically significant reason should 
be entered on the CRF.  The withdrawal of a subject from the study should be discussed where 
possible with the Medical Monitor before the subject stops administration of the study drug.  If 
the study drug is discontinued, the final evaluations will be performed as completely as possible. 
Any comments (spontaneous or elicited) or complaints made by the subject and the reason for 
termination, date of stopping study drug, and the total amount of study drug administered must 
be recorded in the CRF and source documents. 


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5.5 
Subject Replacement 
Randomized subjects who do not complete the study for any reason will not be replaced. 
6.0 
TREATMENT OF SUBJECTS 
Investigational product will only be shipped to Investigators who have provided BHR 
PHARMA, LLC (or an authorized representative) all required study documents, including 
Institutional Review Board (IRB) approval, have executed a clinical trial agreement (CTA), and 
have been approved by BHR PHARMA, LLC to begin the study.  Study drug will be provided 
by BHR PHARMA, LLC (or authorized representative) as blind-labeled ready-to-use canisters 
containing 4-OHT gel or placebo. 
6.1 
Blinding and Unblinding 
All Investigator site personnel will be blinded to treatment assignment.  The Investigator (or 
designee) will be responsible for drug accountability and dispensing of the study drug. 
In the case of an AE or serious adverse event (SAE) for which the Investigator must know a 
specific treatment allocation to ensure the subject’s safety, unblinding of treatment assignment is 
permitted.  Instructions for “breaking the blind” will be provided to the Investigator.  It should be 
stressed that unblinding the treatment allocation is only allowed for safety concerns in an 
emergency.  If time allows, the Investigator is encouraged to discuss the matter with the study 
Medical Monitor prior to “breaking the blind” whenever possible. 
If possible, the relationship of the AE to the study drug should be assessed before the treatment 
code is broken.  In all cases, the Medical Monitor must be notified within 24 hours after the code 
has been broken. 
If the treatment assignment is unblinded, study drug will be discontinued and the subject’s 
participation in the study will end. 
6.2 
Formulation, Packaging, and Labeling 
BHR-700 
BHR-700 
  The placebo gel 
is identical in appearance and consistency to the BHR-700 gel.  In this double-blind study, 
canisters will be labeled with a canister identifier and ‘For Investigational Use Only’.   


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6.3 
Investigational Product Storage 
All study drug must be stored in a secure limited-access area, at controlled room temperature 
(20 – 25º C [68° to 77°F]; excursions are permitted to 15° to 30°C [59° to 86°F]) in accordance 
with labeled storage requirements.  Subjects will be instructed to store the study drug at home at 
room temperature, and to avoid extreme heat or cold during transportation from the clinic to 
home.  Investigational labeling will include instructions to keep the product out of the reach of 
children.  
6.4 
Dispensing 
The Investigator (or designee) will only dispense the specific numbered canisters/study drug kit 
as allocated by an interactive, web-based tele-randomization system.  
6.5 
Dosage and Administration 
The first dose of treatment will be applied under the supervision of the PI or designee at the 
clinical site.  Thereafter, subjects will self-apply either BHR-700 gel or placebo as 2 fixed unit 
doses daily to each breast.  The gel should not be applied to any other parts of the body, 
including the neck, abdomen, or genitals.  It is advised to apply study drug in the morning after 
showering and to wash hands with soap and water after application.  Night-time application is 
acceptable, but caution should be taken to limit transfer to other individuals.  Application should 
occur approximately at the same time daily.  A subject study drug administration guideline is 
provided in Appendix 2. 
When a canister is used for the first time, it must be primed.  To prime the canister, remove the 
cap from the canister and push the pump all the way down until gel is dispensed.  Complete the 
priming process by pushing the pump all the way down an additional three (3) times.  Do not use 
any gel that comes out while priming.  Discard the gel by washing it down the sink to avoid 
accidental exposure to others.  It is only necessary to prime the pump before the first dose is 
dispensed.  Repeat priming each time a new canister is opened.  After priming, the canister is 
ready to use.  One complete press of the pump will deliver approximately the same amount of gel 
each time.  The Investigator (or designee) will demonstrate this to each subject and will prime 
the study drug canister(s) prior to dispensing to the subject. 
If a subject misses a dose by more than 12 hours, that dose should be noted as missed and the 
subject should wait for the next scheduled time before applying investigational product. 


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If a subject experiences toxicity that may make her want to stop taking study drug, the dose of 
study drug will be reduced by 50%, to 2 mg (1 pump actuation) to each breast.  The reduced dose 
will be maintained for the duration of the study.   
6.6 
Investigational Product Administration Precautions 
Following the initial application by the Investigator (or his/her designee) only the subject should 
apply the study drug.  Others (such as the subject’s family members) should not apply the study 
drug to the subject. 
The subject should not make contact with the area of skin where the study drug was applied for 
at least 1 hour after the application.  Subjects should not massage or rub in the gel and allow the 
gel to dry for 5 minutes before getting dressed. 
If someone else is exposed to the study drug by direct contact with the study drug, that person 
should wash the area of contact with soap and water as soon as possible.  The longer the study 
drug is in contact with the skin the greater the chance that the other person will absorb some of 
the study drug.  This is especially important for children.
No skin-to-skin transfer studies with BHR-700 (4-OHT gel) have been conducted.  However, a 
study conducted in women16 with a FDA-approved product, EstroGel® (0.06% estradiol gel), 
using a similar formulation showed that skin-to-skin contact between treated and non-treated 
women 1 hour after application of the gel, neither resulted in a statistically significant or 
clinically important transfer of estradiol gel to the non-treated women nor was there subsequent 
absorption of estradiol by the non-treated women.  Use of health and beauty products (lotions, 
creams, sunscreen, self-tanner, etc.) on the application site is allowed one (1) hour after 
application of the study gel.  
6.7 
Pregnancy and Nursing 
The effects of 4-OHT gel on the developing human fetus at the recommended dose and route are 
unknown.  For this reason, women of childbearing potential must agree to avoid pregnancy by 
using a reliable medically acceptable contraceptive method. 
A woman is not considered to be of child bearing potential if she has: 
a.
Serum follicle-stimulating hormone (FSH) levels consistent with menopause and has
had complete amenorrhea for at least 12 months prior to starting drug.
b. Documented surgical history of hysterectomy or bilateral
oophorectomy/salpingo-oophorectomy.


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A woman of child bearing potential must use one of the following contraceptive methods 
throughout the study and for at least 90 days after completing the study: 
a.
Bilateral tube ligation performed 6 months or more prior to starting study drug.
b. Consistent monogamous relationship with a male partner who has had a medically
proven vasectomy performed 6 months or more prior to starting study drug.
c.
Intrauterine device (IUD) in place for at least 3 months before starting study drug.
d. Progestin-containing hormonal birth control (oral, transdermal, injectable, or
implantable) used consistently and successfully for at least 3 months prior to starting
study drug.
e.
Double barrier contraception with spermicide, including a condom plus diaphragm or
cervical cap.  Note: Female condom should be used with male condom (as a double
barrier method of contraception) due to risk of tearing.
f.
Abstinence
True abstinence, when this is in line with the preferred and usual lifestyle of the
subject, is acceptable.  Periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of contraception.
There is an unknown but potential risk for AEs in nursing infants secondary to treatment of the 
mother with 4-OHT gel.  Therefore, it is required that breastfeeding be discontinued prior to the 
mother enrolling in this study (see also 5.2, exclusion criterion 4). 
Procedure for Reporting Pregnancy Exposure and Birth Events 
Should a female subject become pregnant or be suspected of being pregnant while participating 
in this study, the event must be reported to the Medical Monitor upon receipt of information by 
the study staff. While the pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complications should be recorded as AEs or SAEs (if applicable). Any pregnancy will be 
followed through delivery for the observation of any SAEs. Fatalities and spontaneous abortions 
must be reported as SAEs. 
6.8 
Assessment of Compliance 
Study drug compliance will be checked at each study visit.  Subjects will be asked to capture 
daily gel administration in a diary and drug canisters will be weighed on release to the subject 
and on return.  The canister weight will be recorded in grams.  If the study drug is discontinued 
or interrupted, the reason(s) will be recorded.  One or more extra canisters will be provided to 
cover loss.  Subjects who are found to be non-compliant will be re-trained on study drug 
administration by the PI or designee.  


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6.9 
Investigational Product Accountability 
The Investigator will maintain accurate records of the disposition of all clinical drug supplies 
received during the study and the dates on which drug supplies were received from BHR 
PHARMA, LLC or authorized representative.  At the conclusion of the study, any unused study 
gel will be destroyed by the site in accordance with their standard operating procedures (SOP), 
upon written authorization by BHR PHARMA, LLC and pursuant to applicable federal and state 
regulations or returned to BHR PHARMA, LLC or their designee. 
6.10 Prior and Concomitant Medications 
All medications, prescription and over-the-counter (OTC), administered or taken by the subject 
during the study are to be recorded on the concomitant medication form of the CRF.  Information 
should be recorded for: name of drug, dose, route of administration, start and end dates, and 
indication. 
Any therapeutic or surgical procedure performed for concurrent conditions through the end of 
the study, should be recorded, including the date, description of the procedure, and clinical 
findings. 
6.11 Prohibited Concomitant Medications/Therapies 
Investigational drugs or therapies should not be used at any time during the study because of 
their potential to confound the results. The following drugs or therapies are prohibited during the 
study because of their potential to confound the results:  
•
Application of prescription or OTC topical drug products (including but not limited to:
gel, patch, cream, ointment, lotion, or spray) to the study drug application site(s), i.e., on
the breast(s).
•
Prescription or OTC treatments that are known/suggested to have an estrogenic or anti-
androgenic effect including SERMs and aromatase inhibitors.
7.0 
STUDY PROCEDURES
7.1 
Screening (Within 30 days prior to randomization) 
Subjects who fulfill the Inclusion and Exclusion criteria and who have signed an Informed 
Consent Form will receive a Physical Examination including a breast exam.  Relevant medical 
history will be recorded.  Subjects will also be asked to complete a questionnaire on their 
menstrual cycle as shown in Appendix 3.  Measurements of vital signs, including height and 
weight and laboratory measurements including hematology, blood chemistry, and hormones will 
be performed.  A urine pregnancy test will be performed on women of child bearing potential.  


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A bilateral mammogram with both the raw and processed 2D image DICOM files needs to be 
performed within 3 months prior to randomization.  The same (make/model/serial number) 
mammography machine must be used for the Week 52 mammogram and if the subject is 
participating in the Open-Label phase, the Week 104 mammogram. If the mammogram is older 
than 3 months but less than 18 months, or it cannot be provided in the format required for the 
study, the mammogram can be repeated to meet the study entry requirement after informed 
consent has been obtained. 
7.2 
Study Day 1 (Week 1):  Baseline 
Prior to dosing, the Inclusion/Exclusion criteria and Informed Consent will be reaffirmed with 
each subject.   
Any changes that are found since the Screening Visit will be evaluated for an update to medical 
history and a focused Physical Examination will be performed at the Investigator’s discretion.  
Measurements of vital signs, including weight and laboratory measurements including 
hematology, blood chemistry, coagulation factors, hormones, and bone biomarkers will be 
performed.  A urine pregnancy test will be performed on women of child bearing potential. 
Subjects will be stratified into pre/peri or post-menopausal groups and will be randomized to 
receive either 8mg/day (4mg/breast) BHR-700 gel or placebo.  Each subject will be given a non-
aerosol canister with a 1mL fixed dose pump.  The subject will apply two (2) actuations 
(“squirts”) of gel containing either: 2mg 4-OHT per 1 mL or placebo for daily application to 
each breast.  The first dose will be applied under the supervision of the PI or designee.  
A study drug kit, containing 6 canisters of study treatment, which is sufficient for 13 weeks of 
dosing, will be dispensed to each subject and a diary will be provided to capture dosing 
compliance.  Subjects will be advised to call the clinic in between scheduled telephone calls and 
clinic visits if they experience AEs.  Additional canisters may be assigned to avoid missing a 
dose due to lost or damaged canisters. 
7.3 
Blinded Phase Visits 
•
Study Week 1: Telephone Call (+/- 1 day)
During this visit, the site will call the subject and review the subject’s dosing compliance, 
product application, and query for any AEs. 


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•
Study Week 4: Telephone Call (+/- 1 day)
During this visit, the site will call the subject and review the subject’s dosing compliance, 
product application, and query for any AEs. 
•
Study Week 8: Telephone call (+/- 1 day)
During this visit, the site will call the subject and review the subject’s dosing compliance, 
product application and query for any AEs. 
•
Study Week 13: (+/- 2 weeks)
Subjects will return to the clinic for study assessments.  Vital signs including weight will be 
measured and the use of any concomitant medications and AEs recorded.  A blood sample for 
PK measurements of 4-OHT isomers E and Z will be taken.  A urine pregnancy test will be 
performed on women of child bearing potential.  Treatment canisters will be weighed and the 
diary checked for study compliance.  Treatment canisters, sufficient for 13 weeks dosing, will be 
dispensed.  
•
Study Week 19: Telephone Call (+/- 2 weeks)
During this visit, the site will call the subject and review the subject’s dosing compliance, 
product application, and query for any AEs. 
•
Study Week 26: (+/- 2 weeks)
Subjects will return to the clinic for study assessments.  Vital signs including weight will be 
measured and the use of any concomitant medications and AEs recorded.  Laboratory 
measurements will be performed and will include hematology, blood chemistry, and coagulation 
factors.  A blood sample for PK measurements of 4-OHT isomers E and Z will be taken.  A urine 
pregnancy test will be performed on women of child bearing potential.  Treatment canisters will 
be weighed and the diary checked for study compliance.  Treatment canisters, sufficient for 13 
weeks dosing, will be dispensed.  
•
Study Week 32: Telephone Call (+/- 2 weeks)
During this visit, the site will call the subject and review the subject’s dosing compliance, 
product application, and query for any AEs. 


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•
Study Week 39: (+/- 2 weeks)
Subjects will return to the clinic for study assessments.  Vital signs including weight will be 
measured and the use of any concomitant medications and AEs recorded.   A urine pregnancy 
test will be performed on women of child bearing potential.  Treatment canisters will be weighed 
and the diary checked for study compliance.  Treatment canisters, sufficient for 13 weeks dosing, 
will be dispensed.  
•
Study Week 45: Telephone Call (+/- 2 weeks)
During this visit, the site will call the subject and review the subject’s dosing compliance, 
product application, and query for any AEs. 
•
Study Week 52: (+/- 2 weeks) – End of Blinded Phase and End of Study Visit
Subjects will return to the clinic for study assessments.  A Physical Examination including a 
breast exam will be performed, vital signs, height and weight will be measured and AEs and the 
use of any concomitant medications will be recorded.  Laboratory measurements will be 
performed and will include hematology, blood chemistry, coagulation factors, hormones and 
bone biomarkers.  PK measurements of 4-OHT isomers E and Z will be taken.  A urine 
pregnancy test will be performed on women of child bearing potential.  Treatment canisters will 
be weighed and the diary checked for study compliance.  A mammogram will be performed.  
Subjects will be offered the opportunity to participate in the Open-Label-Extension Phase of the 
study.  Informed consent will be obtained from those subjects choosing to continue in the Open-
Label-Extension Phase. Open-labeled study drug will be dispensed to those subjects who have 
agreed to administer the BHR-700 gel for an additional 52 weeks. 
7.4 
Open-Label Phase Visits 
•
Study Week 1 (53): Telephone call (+/- 1 day)
During this visit, the site will call the subject and review the subject’s dosing compliance, 
product application, and query for any AEs. 
•
Study Week 4 (56): Telephone Call (+/- 1 day)
During this visit, the site will call the subject and review the subject’s dosing compliance, 
product application, and query for any AEs. 


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•
Study Week 8 (60): Telephone call (+/- 1 day)
During this visit, the site will call the subject and review the subject’s dosing compliance, 
product application, and query for any AEs. 
•
Study Week 13 (65): (+/- 2 weeks)
Subjects will return to the clinic for study assessments.  Vital signs including weight will be 
measured and the use of any concomitant medications and AEs recorded.  A urine pregnancy test 
will be performed on women of child bearing potential.  Treatment canisters will be weighed and 
the diary checked for study compliance.  Treatment canisters, sufficient for 13 weeks dosing, 
will be dispensed.  
•
Study Week 19 (71): Telephone Call (+/- 2 weeks)
During this visit, the site will call the subject and review the subject’s dosing compliance, 
product application, and query for any AEs. 
•
Study Week 26 (78): (+/- 2 weeks)
Subjects will return to the clinic for study assessments.  Vital signs including weight will be 
measured and the use of any concomitant medications and AEs recorded.  Laboratory 
measurements will be performed and will include hematology, blood chemistry, and coagulation 
factors.  A blood sample for PK measurements of 4-OHT isomers E and Z will be taken.  A urine 
pregnancy test will be performed on women of child bearing potential.  Treatment canisters will 
be weighed and the diary checked for study compliance.  Treatment canisters, sufficient for 13 
weeks dosing, will be dispensed.  
•
Study Week 32 (84): Telephone Call (+/- 2 weeks)
During this visit, the site will call the subject and review the subject’s dosing compliance, 
product application, and query for any AEs. 
•
Study Week 39 (91): (+/- 2 weeks)
Subjects will return to the clinic for study assessments.  Vital signs including weight will be 
measured and the use of any concomitant medications and AEs recorded.  A urine pregnancy test 
will be performed on women of child bearing potential.  Treatment canisters will be weighed and 
the diary checked for study compliance.  Treatment canisters, sufficient for 13 weeks dosing, 
will be dispensed. 


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Study Week 45 (97): Telephone Call (+/- 2 weeks)
During this visit, the site will call the subject and review the subject’s dosing compliance, 
product application, and query for any AEs. 
•
Study Week 52 (104): (+/- 2 weeks) End of Open-Label Phase and End of Study
Visit
Subjects will return to the clinic for study assessments.  A Physical Examination including a 
breast exam will be performed, vital signs, height and weight will be measured and AEs and the 
use of any concomitant medications will be recorded.  Laboratory measurements will be 
performed and will include hematology, blood chemistry, coagulation factors, hormones, and 
bone biomarkers. PK measurements of 4-OHT isomers E and Z will be taken.  A urine 
pregnancy test will be performed on women of child bearing potential.  Treatment canisters will 
be weighed and the diary checked for study compliance.  A mammogram will be performed. 
8.0 
ASSESSMENTS OF SAFETY 
8.1 
Adverse Event Collection and Reporting 
•
Adverse Event Collection
AEs will be captured for the duration of the study.  The reporting period begins with the first 
dose of study drug (Study Day 1) and ends at Week 52 and Week 104.  The Adverse Events 
eCRF must be completed for all reported AEs and SAEs. 
For this study, 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.”  This includes any newly occurring event or previous 
condition that has increased in severity or frequency since the administration of study drug.  
AEs may also be reported spontaneously at any time.  Details of any adverse or unexpected 
events, signs, and symptoms will be collected including details of onset, resolution, frequency, 
severity (as defined below), seriousness, relationship to the drug, effect on the study drug, 
treatments administered, and outcome.  Any AE will be followed, whenever possible, until it 
returns to the baseline condition or becomes stable with no further change expected. 


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8.2 
Reporting of Adverse Events 
•
Diagnoses vs. Signs/Symptoms
Each AE should be recorded to represent a single diagnosis.  Accompanying signs (including 
abnormal laboratory values if not constituting AEs themselves) or symptoms should NOT be 
recorded as additional AEs.  If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded as an AE. 
•
Laboratory Values
Changes in laboratory values may be considered AEs if they are judged to be clinically 
significant (i.e., if some action or intervention is required or if the Investigator judges the change 
to be beyond the range of normal physiological fluctuation).  If abnormal laboratory values are 
the result of pathology for which there is an overall diagnosis (e.g., increased creatinine in renal 
failure), the diagnosis only should be reported as an AE. 
•
Pre-existing Conditions
Pre-existing conditions (present before the start of the AE collection period) are considered 
concurrent medical conditions and should NOT be recorded as AEs.  However, if the subject 
experiences a worsening or complication of such a concurrent condition, the worsening or 
complication should be recorded as an AE.  Investigators should ensure that the AE term 
recorded captures the change in the condition (e.g., “worsening of….”). 
•
Preplanned Surgeries or Procedures
Preplanned procedures (surgeries or therapies) that were scheduled prior to the start of an AE are 
not considered AEs.  However, if a preplanned procedure is performed early (e.g., as an 
emergency) due to a worsening of the preexisting condition, the worsening of the condition 
should be captured as an AE. 
•
Elective surgeries or procedures
Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs, but should be documented in the subject’s source documents. 
•
Overdose
Cases of drug overdose without manifested side effects are NOT considered AEs. 


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8.3 
Assessment of Adverse Event Severity 
The following guidelines for rating severity of adverse events should be used. 
Mild:  
Awareness of signs or symptoms, but easily tolerated; are of minor irritant type; no loss of time 
from normal activities; symptoms would not require medication or a medical evaluation; signs 
and symptoms may be transient, disappearing during continued treatment with study medication. 
Moderate: 
Discomfort enough to cause interference with usual activities; the study medication may have 
been interrupted. 
Severe: 
Incapacitating with inability to do work or do usual activities; signs and symptoms may be of 
systemic nature or require medical evaluation; the study drug may have been stopped, and 
treatment for the event may be required. 
The term “severe” is often used to describe the intensity of a specific event, as in mild, moderate 
or severe myocardial infarction; the event itself however, may be of relatively minor medical 
significance, such as severe headache. This is not the same as serious, which is based on 
subject/event outcome or action criteria usually associated with events that pose a threat to a 
subject’s life or functioning. The Investigator must decide whether each AE meets the definition 
of an SAE. 
8.4 
Serious Adverse Events 
An SAE is any untoward medical occurrence that: 
•
Results in death.
•
Is life-threatening.  Life-threatening, in the definition of serious, refers to an event in
which the subject was at risk of death at the time of the event; it does not refer to an event
which hypothetically might have caused death if it were more severe.
•
Requires hospitalization (> 24 hours) or prolongation of existing hospitalization.
•
Results in persistent or significant disability/incapacity.
•
Is a congenital anomaly/birth defect.


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Is considered medically significant by the Investigator or requires intervention to prevent
any one of the outcomes above.  Medically significant are those events considered
important in the Investigator’s opinion that may not be immediately life-threatening or
result in death or hospitalization but may jeopardize the subject or may require
intervention to prevent one of the other outcomes listed in the definition above.  These
will also usually be considered serious.
All SAEs will be captured for the duration of the study.  The reporting period begins with the 
first dose of study drug (Study Day 1) and ends at Week 52 and Week 104.  All SAEs should be 
monitored until they are resolved or are clearly determined to be due to a subject’s stable or 
chronic condition or intermittent illness.   
Cause of death is required whenever known.  If an autopsy was performed, an autopsy report 
should be provided.  Death should usually be reported as the outcome of a specific SAE. 
Reports for hospitalization of elective procedures do not need to be reported as SAEs if there are 
no precipitating signs/symptoms or worsening of a pre-existing condition that necessitated the 
procedure.  However, SAEs must be reported for any complications resulting from a procedure 
that prolonged the hospitalization. 
•
SAE Reporting
The SAE Form should be completed within 24 hours of the Investigator/Site learning of the
event and sent as a PDF by email to a secure safety email box. On receipt, the SAE form will be 
disseminated to: 
For U.S. Centers 
For European Centers 
For each SAE, the Investigator and Sponsor will independently assess whether there is a 
reasonable possibility that the event may have been caused by the study drug (“drug-related”).  
The Sponsor will evaluate each drug-related SAE to determine if the event was unexpected.  If 
the SAE is assessed to be both drug-related and unexpected, the Sponsor or designee will notify 
all Investigators, and will report it to the appropriate regulatory authorities as required by 
applicable local regulations.  The Sponsor or designee will report SAEs, including narratives, to 
the U.S. FDA and local regulatory authorities as required by 21 CFR 312.32 and the 
International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice.  The 
Investigator is responsible for notifying his/her respective IRB. 


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8.5 
Laboratory Tests 
Laboratory tests (hematology and blood chemistry) will be performed by a central laboratory.  
Laboratory tests will be performed at screening, at pre-dose, at Week 26 and Week 52.  For those 
subjects who have elected to continue open-label treatment for a further 52 weeks, laboratory 
tests will also be performed at Week 78 and Week 104.  The Investigator will assess all abnormal 
lab values for clinical significance; if categorized as AEs, they will be collected and recorded 
similarly to other AEs.  All clinically significant abnormal lab values will be followed until 
resolution.  If resolution is not seen, a justification as to the cause for such an abnormality, such 
as due to an underlying pre-existing condition, associated co-morbidity, etc., will be recorded.  
The following laboratory assessments will be performed for this study: 
Hematology, Blood Chemistry, Coagulation factors, Hormones, and Bone biomarkers. 
Any residual biological samples will be destroyed after test results are confirmed by the 
respective testing laboratory. No samples will be retained for future testing. 
8.6 
Physical Examination 
A Physical Examination (PE) including a breast exam will be performed at screening, pre-dose 
on Day 1 (only if the subject has reported any changes since the Screening Visit), and Week 52.  
For those subjects who have elected to continue open-label treatment for a further 52 weeks, a 
PE will also be performed at Week 104.  A breast exam and mammogram will be performed at 
Week 104 for those subjects who have elected to continue open-label treatment for a further 52 
weeks.  Any significant findings present prior to the first dose of study drug (Study Day 1) must 
be reported on the PE CRF.  Significant findings made after the first dose of study drug which 
meet the definition of an AE must be recorded on the AE CRF.  The PE will include an 
assessment of all body systems.  
8.7 
Vital Signs 
The measurement of Vital Signs and weight will be made at screening, pre-dose and at weeks 13, 
26, 39, and 52.  For those subjects who have elected to continue open-label treatment for a 
further 52 weeks, Vital Signs will also be performed at weeks 65, 78, 91, and 104.  Any 
significant findings present prior to the first dose of study drug (Study Day 1) must be reported 
on the Vital Signs CRF.  Sitting vital signs to be measured are: heart rate (beats/minute), 
respiration rate (breaths/minute), systolic and diastolic blood pressure (mmHg), and body 
temperature.  Height will also be measured at pre-dose, week 52 and week 104 for those who 
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8.8 
Mammogram 
A bilateral mammogram with both the raw and processed 2D image DICOM files needs to be 
performed within 3 months prior to randomization.  The same (make/model/serial number) 
mammography machine must be used for the Week 52 and if the subject is participating in the 
Open-Label phase, the Week 104 mammogram. If the mammogram is older than 3 months but 
less than 18 months, or it cannot be provided in the format required for the study, the 
mammogram can be repeated to meet the study entry requirement after informed consent has 
been obtained.  Assuming the original mammogram has been made within 3 months before the 
date of randomization, the BI‐RADS classification of this original mammogram will be used to 
assess and demonstrate the eligibility of the subject on inclusion criterion 1, a BI‐RADS 
assessment C or D. The repeat mammogram will be used for determining the baseline density 
measurements, but not for re‐assessment and/or confirmation of the BI‐RADS criterion. 
The mammography report must also be obtained.  The breast density classification of C 
(heterogeneously dense) or D (extremely dense) should be recorded in the subject’s study chart. 
9.0 
STATISTICAL ANALYSIS 
9.1 
Statistical Analysis Plan 
A statistical analysis plan (SAP) will be written and finalized prior to any lock of the study 
database.  The SAP will give a detailed description of the summaries and statistical 
methodologies for analyses that will be performed and clearly describe when these analyses will 
take place.  Should any inconsistencies exist between the analyses described in this section and 
the analyses described in the more detailed SAP, the SAP will take precedence. 
Blinded Treatment Phase 
Primary Outcome Measure: 
•
A comparison of reduction in breast density between BHR-700 gel and placebo treatment
groups at 52 weeks using the Cumulus method.
Secondary Outcome Measures: 
•
Comparison of the reduction in breast density as calculated with the Volpara method and
the Cumulus method.
•
Laboratory parameters will be summarized in a descriptive fashion.
•
Incidence and severity of AEs will be compared between BHR-700 gel and placebo.


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Open-Label Treatment Phase 
Secondary Outcome Measures: 
•
Comparison of the reduction in breast density as calculated with the Volpara method and
the Cumulus method.
•
Laboratory parameters will be summarized in a descriptive fashion.
•
Incidence and severity of AEs will be compared between BHR-700 gel and placebo.
9.2 
Sample Size 
Assuming a reduction from baseline of 6% on active and 2% on placebo, with a common 
standard deviation of 8%, a total of 272 subjects will achieve a power of 90%, using a two 
sample, two-sided t-test at a significance level of < 0.01.  Considering an attrition rate of 15%, 
330 subjects are planned for enrollment in this study. 
9.3 
Analysis by Study Period (Blinded Phase / Open-Label Phase) 
Study data will be cleaned and monitored prior to lock of the study database following the last 
subject exiting the blinded phase of the study.  An analysis will be done on this data and results 
reported and described in a study report.  An additional analysis will be done at the end of the 
study when the database has been monitored and cleaned, following the exit of the last subject 
from the open-label portion of the study.  These analyses will be described in the study SAP. 
9.4 
Mammographic Density Assessments 
Mammographic density will be measured using a 2D image (A “synthesized” 2D image created 
from a 3D image cannot be used).  Both the processed and raw 2D image files will be sent for 
analysis by a central reader.  The reader will be blinded as to the treatment group (BHR-700 or 
placebo) of each subject and the time point of each mammogram.  The primary method used for 
analysis will be Cumulus 2D with Volpara 3D used as the secondary endpoint method. 
9.5 
Data Management 
An electronic data capture (EDC) system will be used to collect the background information, 
safety and efficacy data from each subject.  This information will be used for statistical analysis. 
The study datasets will be created from data from the EDC system including laboratory data 
information.  Data queries will be generated and resolved according to the pre-specified data 
cleaning plan.  In addition, range checks, plausibility and consistency checks will be performed 
to assess consistency, accuracy, and completeness of the data collected.  Standard SAS datasets 
will be generated from the final study database for analysis.  A complete audit trail of all 
corrections will be made and kept as a part of EDC database. 


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Although there is no reason to assume concerns about safety or tolerability of the test drug, a 
DSMB will be set up to review and evaluate unblinded data (plasma levels of 4OHT and adverse 
events data) to ensure subject safety and study integrity.    
9.6 
Study Populations 
Three analysis populations will be defined and analyzed: 
1. Intent-to-treat (ITT) population will contain all subjects who are randomized into the
study.  All efficacy parameters will be analyzed using the ITT population.  In the case
of a subject who was randomized but did not take the study drug, the analysis will be
done for this subject using the randomized treatment.
2. Per-protocol population will contain all ITT subjects who do not have any major
protocol deviation.  The major protocol deviations will be described in the SAP and
identified by BHR PHARMA, LLC before the database is locked.
3. Safety population will contain all subjects who receive at least one dose of study drug.
All safety parameters will be analyzed using safety population.
9.7 
Handling of Missing and Incomplete Data 
The SAP will describe how to handle missing efficacy data.  Missing date or time for the safety 
date will be imputed.  The SAP will include all detailed imputation rules.  
9.8 
Methodology and Conventions 
Safety and efficacy data will be summarized and presented by treatment group and time point in 
summary tables.  Continuous variables will be presented by descriptive statistics: n, mean, 
standard deviation, median, minimum, and maximum.  Categorical variables will be tabulated by 
frequency count and percentage. 
When the actual treatment received by a subject is different from the randomized treatment 
assigned, the subject will be analyzed per the randomized treatment for the efficacy parameters 
(using the ITT population); while she will be analyzed per actual treatment that was taken for the 
safety parameters (using the safety population). 
Unless otherwise stated, all statistical tests will be two-sided hypothesis tests performed at the 
5% level of significance for main effects and all confidence intervals will be two-sided 95% 
confidence intervals. 


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10.0 
REGULATORY AND PROCEDURAL REQUIREMENTS 
10.1 Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve the participation of human 
subjects.  This study will be conducted in compliance with GCP and the applicable national 
regulations to assure that the rights, safety, and well-being of the participating study subjects are 
protected consistent with the ethical principles that have their origin in the Declaration of 
Helsinki.  
10.2 Institutional Review Board 
The Sponsor (or an authorized representative) or the Investigator (according to national 
provisions) is responsible for following the regional law where the study is to be conducted to 
obtain written approval for the clinical study protocol (including all substantial protocol 
amendments), the subject informed consent, informed consent updates, subject recruitment 
procedures (e.g., advertisements), and any other information to be provided to subjects from an 
IRB that complies with the local regulatory requirements. 
Written approval of the study must be obtained from the IRB prior to the study being 
implemented (i.e., shipment of clinical supplies to the Investigator or screening of subjects).  
Copies of the approval documentation will be maintained by both the Investigator and the 
Sponsor (or an authorized representative) in the designated study documentation files. 
The Sponsor (or an authorized representative) or the Investigator (according to national 
provisions) will submit written reports of the clinical study status to the IRB annually, or more 
frequently if requested by the IRB.  A final study notification should be forwarded to the IRB 
within 90 days after the study has completed, or in the event of premature termination of the 
study within 15 days, with the rationale for study termination clearly explained.  Copies of all 
clinical study status reports (including termination) will be maintained by both the Investigator 
and the Sponsor (or an authorized representative) in the study documentation files. 
In accordance with national provisions and the rules of FDA, or applicable national or state laws, 
the Sponsor (or an authorized representative) will inform all participating IRBs and applicable 
national authorities of all SAEs or other safety-related information, which occur during the 
clinical study as appropriate. 
10.3 Subject Informed Consent 
It is the responsibility of the Investigator to obtain written Informed Consent from the subject 
prior to initiating any study procedures.  All consent documentation must be in accordance with 


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applicable regulations and GCP.  Each subject is requested to sign the subject Informed Consent 
Form after the subject has received an explanation of what the study involves, including but not 
limited to, the following: the objectives, potential benefits and risk, inconveniences, and the 
subject’s rights and responsibilities.  A copy of the informed consent documentation (Consent 
Form) must be given to the subject.  
10.4 Advisory Board 
An Advisory Board, composed of experts in the field of Breast Cancer, will provide scientific 
and clinical leadership for this study in consultation with BHR PHARMA, LLC. 
10.5 Investigator Obligations 
The PI agrees to conduct the clinical study in compliance with this protocol which was approved 
by the IRB in compliance with local regulatory requirements.  The Investigator and the Sponsor 
will sign the protocol (Page 3) to confirm this agreement. 
10.6 GCP Compliance 
The Investigator must undertake to perform the study in accordance with ICH GCP Guideline 
E6(R2) (NOV 2016) and the applicable regulatory requirements.  Copies of these guidelines are 
available at www.ich.org and will be provided to the site by BHR PHARMA, LLC upon request. 
It is the Investigator’s responsibility to ensure that adequate time and appropriate resources are 
available at the study site prior to commitment to participate in this study.  The Investigator 
should also be able to estimate or demonstrate a potential for recruiting the required number of 
suitable subjects within the agreed recruitment period. 
The Investigator will maintain a list of appropriately qualified persons to whom the Investigator 
has delegated significant study-related tasks.  An up-to-date copy of the curriculum vitae for the 
Investigator, sub-investigator(s), and essential study staff, as appropriate, will be provided to 
BHR PHARMA, LLC (or designee) before starting the study. 
10.7 Protocol Adherence and Investigator Agreement 
The Investigator must adhere to the protocol as detailed in this document.  The Investigator will 
be responsible for enrolling only those subjects who have met protocol eligibility criteria.  The 
Investigators will be required to sign an Investigator Agreement to confirm acceptance and 
willingness to comply with the study protocol. 


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It is the Investigator’s responsibility to communicate with their IRB to ensure accurate and 
timely information is provided at all phases during the study.  The appropriate approvals must be 
in place prior to recruitment, notification of any SAEs during the study must take place and the 
IRB must be informed of study completion. 
10.8 Protocol Deviations 
The Investigator will not deviate from the protocol without prior written approval from the 
Sponsor or designee, except in medical emergencies.  In the event of a medical emergency, the 
Medical Monitor must be notified as soon as possible.  The governing IRB/ will be informed of 
all protocol changes issued by the Sponsor by the Investigator in accordance with the IRBs 
established procedure. 
10.9 Monitoring of the Study 
Site visits and inspections will be conducted by the Sponsor or designee at regular intervals in 
accordance with FDA and ICH guidelines.  The Investigator will permit representatives of the 
Sponsor’s monitoring team, Ethics Committee, FDA, or local health authority auditors to inspect 
facilities and records relevant to this study. 
11.0 
FINANCIAL DISCLOSURE 
Under the applicable regulations, the Sponsor is required to submit to FDA a list of clinical 
Investigators who conducted the clinical studies and certify and/or disclose certain financial 
arrangements as follows: 
1. Certification that no financial arrangements with an Investigator have been made where study
outcome could affect compensation; that the Investigator has no proprietary interest in the
tested product; that the Investigator does not have a significant equity interest in the Sponsor
of the covered study; and that the Investigator has not received significant payments of other
sorts; and/or
2. Disclosure of specified financial arrangements and any steps taken to minimize the potential
for bias.
Disclosable Financial Arrangements: 
1. Compensation made to the Investigator in which the value of compensation could be affected
by study outcome.  This requirement applies to all covered studies, whether ongoing or
completed as of February 2, 1999.


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2. A proprietary interest in the tested product, including, but not limited to, a patent, trademark,
copyright, or licensing agreement.  This requirement applies to all covered studies, whether
ongoing or completed as of February 2, 1999.
3. Any equity interest in the Sponsor of a covered study, i.e., any ownership interest, stock
options, or other financial interest whose value cannot be readily determined through
reference to public prices.  This requirement applies to all covered studies, whether ongoing
or completed;
4. Any equity interest in a publicly held company that exceeds $50,000 in value.  These must be
disclosed only for covered clinical studies that are ongoing on or after February 2, 1999.  The
requirement applies to interests held during the time the clinical Investigator is carrying out
the study and for 1 year following completion of the study; and
5. Significant payments of other sorts, which are payments that have a cumulative monetary
value of $25,000 or more made by the Sponsor of a covered study to the Investigator or the
Investigators' institution to support activities of the Investigator exclusive of the costs of
conducting the clinical study or other clinical studies, (e.g., a grant to fund ongoing research,
compensation in the form of equipment or retainers for ongoing consultation or honoraria)
during the time the clinical Investigator is carrying out the study and for 1 year following
completion of the study.  This requirement applies to payments made on or after
February 2, 1999.
In consideration of participation in the study, BHR PHARMA, LLC, will pay the Investigator or 
nominated payee the sums set out in the payment schedule attached to the Investigator 
agreement. 
11.1 
Documentation and Retention of Records 
•
Case Report Forms
Data collection for this protocol will be accomplished using EDC.  Therefore, the term CRF 
refers to an electronic data record. 
CRFs are required and must be completed for each randomized subject.  It is the Investigator’s 
responsibility to ensure the accuracy and completeness of the data reported on the subject’s CRF. 
CRFs should be completed in a timely fashion to support the study timelines.   
Source documentation supporting the CRF data should indicate the subject’s participation in the 
study and should document the dates and details of study procedures, AEs, and status.  The 
Investigator or designee should complete and the Investigator should verify the source 
documents as the information is collected.  Completed CRFs must be submitted for each subject.  
The Investigator will retain a copy of all completed source documents. 


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•
Recording, Access, and Retention of Source Data
Source data to be reviewed during this study may include, but is not limited to: subject’s medical 
file, original laboratory reports, radiology reports, and histology and pathology reports.  All key 
data must be recorded in the subject’s medical records. 
The Investigator must permit authorized representatives of BHR PHARMA, LLC, the respective 
national, local, or foreign regulatory authorities, the IRB, auditors, and interested commercial 
parties to inspect facilities and records relevant to this study. 
The monitor, auditors, IRB, or regulatory inspectors, may check the CRF entries against the 
source documents.  The consent form will include a statement by which the subjects allow the 
monitor/auditor/inspector from BHR PHARMA, LLC or its representatives, national, or local 
regulatory authorities or the IRB access to source data (e.g., subject’s medical file), which 
substantiate information recorded in the CRFs.  
As described in the ICH GCP Guidelines, ‘essential documents’, including CRFs, source 
documents, consent forms, laboratory test results, and study drug inventory records, should be 
retained by the Investigator 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 at least 2 years have elapsed since the formal discontinuation of clinical 
development of the study drug.  These documents should be retained for a longer period however 
if required by the applicable regulatory requirements or by an agreement with BHR PHARMA, 
LLC.  The Investigator must obtain written permission from BHR PHARMA, LLC prior to the 
destruction of any study document. 
These records must be made available at reasonable times for inspection and duplication, if 
required, by a properly authorized representative of the U.S. FDA in accordance with the U.S. 
Code of Federal Regulations 21 CFR 312.68 or other national or foreign regulatory authorities in 
accordance with regulatory requirements. 
11.2 
Disclosure of Data 
Individual subject’s medical information obtained because of this study is considered 
confidential and disclosure to third parties other than those noted below is prohibited.  Subject 
confidentiality will be further assured by utilizing subject identification code numbers.  If results 
of this study are reported in medical journals or at meetings, the subject’s identity will remain 
confidential.  Medical information may be provided to the subject’s personal physician, at the 
subject’s request, or to other appropriate medical personnel responsible for the subject’s welfare. 


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Data generated because of this study are to be available for inspection on request by FDA/local 
health authority auditors, the sponsor’s monitors, and by the IRBs.  If the FDA or other 
regulatory agency should schedule an inspection, the Medical Monitor should be advised 
immediately.   
11.3 
Publication 
By signing the study protocol, the Investigator agrees that the results of the study may be used 
for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals by the Sponsor.  
Publications or presentations based on the study may not be made until the study is completed, 
unless so decided by the Sponsor.  Once the Sponsor or designee publishes the final report and 
main study manuscript, or if publication has not occurred within 18 months after completion of 
the study (final database lock), an Investigator may individually publish or present information 
on this study, preferably providing the manuscript to the Sponsor for review prior to publication. 
The Clinical Trial Agreement between the Investigator and the Sponsor may provide additional 
terms regarding publication or presentation based on the study. 


BHR-700 (0.2% 4-Hydroxytamoxifen (4-OHT) Gel) 
Phase 3 Protocol 
BHR PHARMA, LLC 
BHR-700-301 
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12.0 
REFERENCES 
1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D,
Global cancer statistics, CA Cancer J Clin 2011; 61:69-90
2. Checka CM, Chun JE, Schnabel FR, et al: The relationship of mammographic density
and age; implications for breast cancer screening. Am J Roentgenol 2012 198; W292-295
3. Jordan VC. Molecular mechanisms of antiestrogen action in breast cancer. Breast Cancer
Research and Treatment 1994; 31:41-52
4. Gallo MA, Kaufman D. Antagonistic and agonistic effects of tamoxifen: significance in
human cancer. Seminars in Oncology. 1997. 24: S1-71; S1-80
5. Linares-Cruz G, Fournier S, Lalardrie JP, Lignieres B. Human breast dynamics during
menstrual cycle. Anticancer Research, 1998; 18:3813-3892
6. Cuzick J, Warwick J, Pinney E Et al. Tamoxifen-induced reduction in MD and breast
cancer risk reduction. JNCI 2011 103; 9:744-752
7. Li J, Humphreys K, Eriksson L, et al. Mammographic density reduction is a prognostic
marker of response to adjuvant tamoxifen therapy in postmenopausal patients with breast
cancer. J Clin Oncol 2013, 31: 2249-2256
8. Nyante SJ, Sherman ME, Pfieffer RM, et al. Prognostic significance of mammographic
density change after initiation of tamoxifen for ER-positive breast cancer. J Natl Cancer
Inst.2015, 107
9. Kuiper GG, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, Gustafsson A.
Comparison of the ligand binding specificity and transcript tissue distribution of estrogen
receptors alpha and beta. Encrinology 1997; 138:863-870
10. Coezy E, Borgna JL, Rochefort H, Tamoxifen and metabolites in MCF7 cells: correlation
between binding to estrogen receptor and inhibition of cell growth. Cancer Research
1982; 42:317-323
11. Malet C, Gompel A, Spritzer P, Bricout N, Yaneva H, Mowszowiez I, Kuttenn F,
Mauvais-Jarvis P. Tamoxifen and hydroxytamoxifen isomers versus estrodial effects on
normal human breast cells in culture. Cancer Research 1988. 48: 7193-7199
12. Lonning PE, Lien EA, Lundgren S, Kvinnsland S. Clinical pharmacokinetics of
endocrine agents used in advanced breast cancer 1992. Clin Pharmacokinetics 1992;
22:327-358
13. Mansel R, Goyal A, Nestour EL, et al; Phase 11 trial of 4-OHT gel for cyclical mastalgia.
Breast Cancer Res Treat 2007106:389-397
14. Rouanet P, Linares-Cruz G, Dravet F Et al. Neoadjuvant percutaneous 4-OHT decreases
breast tumoral cell proliferation. J Clin Oncol 2005 23: 2980-2987
15. Lee O, Page K, Ivancic, et al. Transdermal 4-OHT vs Tamoxifen in women with DCIS.
Clinical Cancer Research 2014; 20:3672-3682


BHR-700 (0.2% 4-Hydroxytamoxifen (4-OHT) Gel) 
Phase 3 Protocol 
BHR PHARMA, LLC 
BHR-700-301 
Confidential 
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16. Zumbrunnen TL, Meuwsen I, de Vries M, Brennan JJ. The effect of washing and the
absence of interindividual transfer of Estradiol Gel. Am J. Drug Delivery 2006 4(2): 89-
95




BHR-700 (0.2% 4-Hydroxytamoxifen (4-OHT) Gel) 
Phase 3 Protocol 
BHR PHARMA, LLC 
BHR-700-301 
Confidential  
Page 46 of 51 
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APPENDIX 2. 
SUBJECT INSTRUCTIONS FOR USE 
BHR-700 
BHR-700 
The clear, colourless gel provides delivery of 4-Hydroxytamoxifen through the skin of the breast(s). 
BHR-700 gel is for topical use only.  Do not swallow. 
For Investigational Use, Only 
PRECAUTIONS: 
1.
BHR-700 is flammable until dry. Do not apply BHR-700 gel near fire, flame or heat.
2.
Be sure to follow your doctor’s instructions carefully throughout the course of the study.
3.
Inform your doctor about any new medicine you take during the study (including dose(s), duration
and reason), or any change(s) to medicines you take regularly.
4.
Inform your doctor about any unusual symptoms or side effects occurring during the study.
INSTRUCTIONS FOR USE: 
Step 1. Applying BHR-700 gel 
Do not allow other people to apply BHR-700 to your skin for you. 
Apply BHR-700 gel once daily preferably in the morning  
Apply BHR-700 gel once daily at the same time of day. 
•
Apply BHR-700 gel to clean, dry breast(s) after your bath or shower.
•
Remove the cap from the canister.  Hold the canister in one hand and place the palm of your
other hand under the pump to catch the gel; see Figure A.  Be sure to press down completely on
the pump and release it completely to dispense one dose of gel.  Repeat to dispense prescribed
dose.
Figure A
  


BHR-700 (0.2% 4-Hydroxytamoxifen (4-OHT) Gel) 
Phase 3 Protocol 
BHR PHARMA, LLC 
BHR-700-301 
Confidential  
Page 47 of 51 
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•
Using your hand, apply the BHR-700 gel.  Spread the gel as thinly as possible – avoid contact
with the nipple.  Do not massage or rub in BHR-700 gel.  Allow the gel to dry for 5 minutes*
before you get dressed (BHR-700 gel is colorless and will not stain your clothing).  Use the same
application method every time you apply the gel.
* If it takes more than 5 minutes for the gel to air-dry or a sticky residue remains on your skin after 5
minutes, you need to spread the gel over a larger area of the breast(s).
Step 2. After applying BHR-700 gel
•
Replace the cap on top of the canister after each BHR-700 gel application to protect the pump.
•
Wash your hands right away with soap and water after applying the BHR-700 gel.
•
Avoid water activities (i.e., swimming) after you apply the BHR-700 gel.  If not possible, try to
wait at least one (1) hour after applying the BHR-700 gel before participating in the water
activity.
•
Do not apply transdermal patches (i.e., nicotine patch) to your breast(s) at any time during the
study.
•
Use of health and beauty products (lotions, creams, sunscreen, self-tanner, etc.) on the
application site is allowed one (1) hour after application of the study gel.
RECOMMENDATIONS: 
•
The following precautions are recommended to minimize potential transfer of the BHR-700 gel to
other individuals (i.e. your child, your sexual partner, or other persons):
o
Wash your hands immediately after gel application.
o
Cover the application site with clothing after the gel has dried.
o
Skin contact is permitted AFTER the application area (breasts) has been washed.
o
In the event that unwashed or unclothed skin to which study gel has been applied comes in
direct contact with the skin of another person, the general area of contact on the other person
should be washed with soap and water as soon as possible.
•
If you forget to apply a dose, do not double the next dose to “catch up.”  If you have a study visit
scheduled that day, tell the study staff about your missed dose and they will instruct you on what to
do.  If you do not have a study visit scheduled that day, contact your Study Coordinator about your
missed dose.


BHR-700 (0.2% 4-Hydroxytamoxifen (4-OHT) Gel) 
Phase 3 Protocol 
BHR PHARMA, LLC 
BHR-700-301 
Confidential  
Page 48 of 51 
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STORAGE:
•
Keep BHR-700 gel at room temperature 68°F to 77°F (20°C to 25°C).
•
Keep out of the reach of children.
•
Avoid exposure to extreme heat or cold during transportation from the clinic to home.
REMEMBER TO: Bring the study drug canister with you to each clinic visit.
This is very important for the conclusion of the study: 
After completing treatment, be sure to give all of the unused study gel back to your Doctor. Do Not 
throw out your unused study gel. 


BHR-700 (0.2% 4-Hydroxytamoxifen (4-OHT) Gel) 
Phase 3 Protocol 
BHR PHARMA, LLC 
BHR-700-301 
Confidential  
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APPENDIX 3. 
MENSTRUAL HISTORY QUESTIONNAIRE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


BHR-700 (0.2% 4-Hydroxytamoxifen (4-OHT) Gel) 
Phase 3 Protocol 
BHR PHARMA, LLC 
BHR-700-301 
Confidential  
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Version 4.0 Amendment 3: 18 April 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


BHR-700 (0.2% 4-Hydroxytamoxifen (4-OHT) Gel) 
Phase 3 Protocol 
BHR PHARMA, LLC 
BHR-700-301 
Confidential  
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APPENDIX 4. 
LABORATORY ASSESSMENTS 
BLOOD CHEMISTRY 
ALAT (SGPT)  
ALBUMIN  
ALKALINE PHOSPHATASE  
ASAT (SGOT)  
UREA NITROGEN  
CALCIUM   
CARBON DIOXIDE (CO2)   
CHLORIDE  
CHOLESTEROL, TOTAL 
HDL  
LDL-CHOL CALCULATION  
CREATININE  
BILIRUBIN, DIRECT   
GLUCOSE  
LACTIC DEHYDROGENASE 
POTASSIUM  
SODIUM  
BILIRUBIN, TOTAL  
PROTEIN, TOTAL SERUM  
TRIGLYCERIDES 
HEMATOLOGY WITH % DIFFERENTIAL 
HEMATOCRIT  
HEMOGLOBIN   
WHITE CELL COUNT 
BASOPHILS  
EOSINOPHILS  
LYMPHOCYTES  
MONOCYTES  
NEUTROPHIL, SEGS  
TOTAL NEUTROPHILS 
RED CELL COUNT  
PLATELET COUNT 
BONE BIOMARKERS 
BONE CTx  
BONE BSAP 
HORMONES 
FOLLICLE STIMULATING HORMONE (FSH) 
LUTEINIZING HORMONE (LH) 
SEX HORMONE BINDING GLOBULIN (SHBG) 
ESTRADIOL  
ESTRONE 
COAGULATION FACTORS 
PROTEIN C ACTIVITY  
PROTEIN S ACTIVITY 
ANTITHROMBIN III ANTIGEN 
ACTIVATED PROTEIN C RESISTANCE 
(APCR) 

SAP_001.pdf: 
Statistical Analysis Plan 
Study:  BHR-700-301 
Page 1 of 15 
Confidential & Proprietary Information of Peachtree BioResearch Solutions, Inc. 
STATISTICAL ANALYSIS PLAN 
Final v1.0 
Protocol BHR-700-301(Amendment 3, v4.0, 18 April 2018) 
A Randomized, Double-blind, Placebo Controlled Trial of 4-Hydroxytamoxifen Gel 
for Reducing Breast Tissue Density in Women with BI-RADS Breast Density 
Categories C or D
Date:  November 13, 2020 
NCT Number: NCT03199963


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Confidential & Proprietary Information of Peachtree BioResearch Solutions, Inc. 
TABLE OF CONTENTS 
List of Abbreviations .............................................................................................................................. 3 
1.
INTRODUCTION ............................................................................................................................ 4 
1.1 
Objectives ................................................................................................................................ 4 
1.2 
Design ..................................................................................................................................... 4 
1.3 
Change in Study Conduct ........................................................................................................ 4 
2.
ELABORATION OF STUDY PROTOCOL ...................................................................................... 5 
2.1 
Study Populations .................................................................................................................... 5 
2.2 
Study Endpoints ...................................................................................................................... 5 
2.2.1 
Primary Endpoint .............................................................................................................. 5 
2.2.2 
Secondary Endpoints ........................................................................................................ 5 
2.3 
Sample Size ............................................................................................................................ 6 
3.
STATISTICAL METHODS .............................................................................................................. 6 
3.1 
General .................................................................................................................................... 6 
3.2 
Subject Disposition, Demographics, Baseline Characters and Study Drug Compliance ........... 6 
3.3 
Analysis of Study Endpoints .................................................................................................... 7 
3.3.1 
Safety Analysis ................................................................................................................. 7 
3.3.2 
Efficacy Analysis ............................................................................................................... 7 
3.3.3 
Subgroup analyses and Multiplicity adjustment................................................................. 7 
3.4 
Handling of Missing Data ......................................................................................................... 7 
3.4.1 
Imputation of Missing Date for Safety Analyses ................................................................ 8 
3.4.2 
Imputation of Missing Data for Efficacy Analyses .............................................................. 8 
3.5 
Protocol Deviations .................................................................................................................. 8 
3.6 
Pharmacodynamic and Pharmacokinetic (PD/PK) Data ........................................................... 8 
3.7 
Key Data Items ........................................................................................................................ 8 
3.8 
Change to Planned Protocol Analysis .................................................................................... 10 
4.
OUTPUT PLANNED FOR THE STUDY REPORT (BLINDED PHASE) ........................................ 10 
4.1 
Tables to be Included in Study Report ................................................................................... 10 
4.1.1 
Summary of subject information ..................................................................................... 10 
4.1.2 
Summary of safety endpoints ......................................................................................... 11 
4.1.3 
Summary of PK/PD endpoints ........................................................................................ 11 
4.2 
Listings to be Included in the Clinical Study Report................................................................ 11 
4.2.1 
Listings of subject information ......................................................................................... 11 
4.2.2 
Listings of safety data ..................................................................................................... 12 
4.2.3 
Listings of efficacy and PK/PD data ................................................................................ 12 
5.
OUTPUT PLANNED FOR THE STUDY REPORT (OPEN-LABELPHASE) .................................. 12 
5.1 
Tables to be Included in Study Report ................................................................................... 12 
5.1.1 
Summary of subject information ..................................................................................... 12 
5.1.2 
Summary of safety endpoints ......................................................................................... 12 
5.2 
Listings to be Included in the Clinical Study Report................................................................ 13 
5.2.1 
Listings of subject information ......................................................................................... 13 
5.2.2 
Listings of safety data ..................................................................................................... 13 
6.
References ................................................................................................................................... 14 
7.
Attachment: The Shells of Tables, Figures and Listings planned for Clinical Study Report ........... 14 


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Confidential & Proprietary Information of Peachtree BioResearch Solutions, Inc. 
LIST OF ABBREVIATIONS 
AE 
Adverse Events 
CC 
Cranial-Caudal 
CI 
Confidence Interval 
FDA 
Food and Drug Administration  
ITT 
Intend-to-Treat 
ICH 
International Committee for Harmonization 
MD 
Mammographic Density 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
MLO 
Mediolateral Oblique 
PBRS 
Peachtree BioResearch Solution 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PI 
Principal Investigator 
PP 
Per-Protocol 
SAE 
Serious Adverse Events 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SOC 
System Organ Class 
US 
United States 


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1.
INTRODUCTION
1.1 
Objectives
The primary objective of this study is to determine the efficacy of 8 mg/day (4 mg/breast) of BHR-
700 gel compared to placebo for reducing breast tissue density in women identified as having
dense breast tissue upon analysis of screening mammography using the Food and Drug
Administration (FDA) cleared Cumulus 2D software..
1.2 
Design
This is a multi-center, randomized, double-blind, placebo-controlled study in women identified as
having dense breast tissue upon screening mammography.
Subjects who give informed consent will have screening evaluations, including hormone measures
of FSH, Estradiol and Estrone to determine menopausal state. Those subjects meeting entry criteria,
will be stratified, based on their hormone levels, into pre/peri and post menopause groups and
randomized within those groups 2:1 to receive either 8 mg/day (4 mg/breast) BHR-700 gel or
placebo for up to 52 weeks.  At the Principal Investigator’s (PI) discretion, subjects may be allowed
to reduce the dose to 4 mg/day (2 mg/breast) in cases of intolerance.
Subjects will apply the gel to both breasts once per day.  The first dose will be applied under the
supervision of the PI/designee.  Subsequent doses will be self-administered daily by the subject
until she has completed 52 weeks of study drug administration.  Study drug compliance will be
checked at each study visit. Subjects will be asked to capture daily gel administration in a diary and
drug canisters will be weighed on release to the subject and on return. The canister weight will be
recorded in grams. If the study drug is discontinued or interrupted, the reason(s) will be recorded.
During treatment period, subjects will be evaluated at Day 1 and every 13 weeks (±2 weeks)
thereafter.
A planned sample size of 330 women, identified as having dense breast tissue upon screening
mammography, will be randomized to receive either BHR-700 gel or placebo (at 2:1 ratio).
Considering an attrition rate of approximately 15%, it is expected to have 272 evaluable women (4-
OHT: 181 & Placebo: 91) who will have both baseline and 52 week measurements of percent
mammographic density (MD) of the breast.
Subjects who complete the double-blind phase of the study will be offered entry into an open-label
follow-up period for an additional 52 weeks.
1.3 
Change in Study Conduct
The study was early terminated. Following careful consideration and review of the development
program for BHR700 (4-Hydroxytamoxifen Gel, 4-OHT), it was determined that breast density
reduction may not be the optimal surrogate marker to support drug development for a target
indication of the reduction of the risk of breast cancer.
Planned analyses will be conducted using data available in the clinical database. The sample size
of the study may no longer be powered due to the lower number of subjects and shorter duration of
treatment for a large proportion of subjects due to the early termination of the study. Therefore, the


Page 5 of 15 
Confidential & Proprietary Information of Peachtree BioResearch Solutions, Inc. 
interpretation of the analysis results will be cautious. Moreover, the emphasis of the statistical 
analysis will be on descriptive statistics, rather than hypothesis testing. 
2.
ELABORATION OF STUDY PROTOCOL
2.1 
Study Populations
Three analysis populations will be defined and analyzed:
1.
Intent-to-treat (ITT) population will contain all subjects who are randomized into the study.
All efficacy parameters will be analyzed using the ITT population.  In the case of a subject
who was randomized but did not take the study drug, the analysis will be performed for this
subject using the randomized treatment.
2.
Per-protocol (PP) population will contain all ITT subjects who completed Week 52
assessments and do not have any major protocol deviation.  The major protocol deviations
will be identified by BH Ireland before the database is locked and unblinded.
3.
Safety population will contain all subjects who receive at least one dose of study drug.  All
safety parameters will be analyzed using safety population.
2.2 
Study Endpoints
2.2.1 Primary Endpoint 
Primary endpoint is the percentage reduction of mammographic left breast tissue density on a 
follow-up mammogram compared to the baseline mammogram after 52 weeks of treatment. 
A comparison of percentage reduction in breast density between BHR-700 gel and placebo 
treatment groups at 52 weeks using the FDA-cleared Cumulus 2d software will be performed. 
The primary endpoint will be analyzed for blind treatment phase only. 
2.2.2 Secondary Endpoints 
1 The percentage reduction in breast density at Week 52 using two breast density 
measurement methods (Cumulus versus Volpara). 
2 The percentage of women who underwent a change in BI-RADS category when comparing 
pre-and post-treatment measurements. 
3 The percentage of women with a ± 10% absolute decrease in quantitative mammographic 
density (Cumulus) between baseline and 52 weeks, 
4 Change in serum concentration of: cholesterol, triglycerides, high-density lipoprotein (HDL), 
and low-density lipoprotein (LDL). 
5 Change in serum concentration of sex hormone binding globulin (SHBG). 
6 Change in serum concentration of Protein C-activity, Protein S-activity, Antithrombin 111 
antigen, and Activated Protein C resistance (APCR). 
7 Change in serum concentration of select bone biomarkers CTx and BSAP. 
8 Incidence and severity of AEs and laboratory values. 
9 The menstrual cycle of premenopausal women. 
10 Pharmacokinetic (PK) plasma concentration of the E and Z isomers of 4-OHT after 13, 26, 
52, 78, and 104 weeks of application of 4 mL BHR-700 gel to the breasts. 


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Confidential & Proprietary Information of Peachtree BioResearch Solutions, Inc. 
The secondary endpoints are for both blind and open-label treatment phases. 
2.3 
Sample Size 
Assuming a reduction from baseline in breast density of 6% on active and 2% on placebo, with a 
common standard deviation of 8%, a sample size of 272 subjects will achieve a power of 90%, 
using a two sample, two-sided t-test at a significance level of < 0.01.  Considering an attrition rate of 
15%, 330 subjects are planned for enrollment in this study. 
3.
STATISTICAL METHODS
3.1 
General
All data will be analyzed using the Statistical Analysis System (SAS®; Version 9.2 or higher).
Safety and efficacy data will be summarized and presented by treatment group and time point in
summary tables.  Continuous variables will be presented by descriptive statistics: n, mean, standard
deviation, median, minimum, and maximum.  Categorical variables will be tabulated by frequency
count and percentage.
When the actual treatment received by a subject is different from the randomized treatment
assigned, the subject will be analyzed per the randomized treatment for the efficacy parameters
(using the ITT population); while the subject will be analyzed per actual treatment that was taken for
the safety parameters (using the safety population).
Where appropriate, all statistical tests will be two-sided hypothesis tests performed at the 5% level
of significance for main effects and all confidence intervals will be two-sided 95% confidence
intervals.
3.2 
Subject Disposition, Demographics, Baseline Characters and Study Drug 
Compliance 
Subject disposition will be summarized for all enrolled subjects.
Demographics and baseline characters will be summarized on ITT population using
descriptive statistics.
General medical history, breast cancer history, menstrual history and concomitant
medications data will be summarized on ITT population.
Study drug compliance will be summarized by visit using descriptive statistics. The
compliance (%) is defined as the percentage of drug administrated as planned dose, which
will be calculated as below
                                                           
                                       
      
The expected weight of daily dose is based on BHR “Rule of Thumb” guidance below. 

4 squirts is an 8 mg/day dose.

Each squirt is supposed to be 1 mL.

1 mL of gel = 0.88 g (based on the density of the gel: 0.88g/mL).

4 squirts (mL)×0.88 g/mL = 3.52 g expected in a normal 8mg/day  dose day.


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Confidential & Proprietary Information of Peachtree BioResearch Solutions, Inc. 
Sections 4.1.1 and 4.2.1 list the planned summary tables and data listings for blinded phase.  
Sections 5.1.1 and 5.2.2 list the planned summary tables and data listings for open-label phase. 
Drug compliance will be calculated only for the subjects who returned all canisters dispensed. Drug 
compliance will be set as missing for the subjects who didn’t return all canisters dispensed. 
3.3 
Analysis of Study Endpoints 
3.3.1 Safety Analysis 
The safety analysis will be conducted on safety population. The safety population includes all 
subjects who received at least one dose of study drug.  
Adverse Events 

All adverse events (AE) will be summarized with MedDRA primary system organ class
(SOC) and preferred term.

Summary tables of severe AEs, SAEs and study drug related AEs will also be provided.

Listings of all AE, serious adverse events (SAE), and severe AEs will be provided.
Laboratory Tests 

Laboratory data (haematology and blood chemistry) will be summarized for baseline, post
baseline, and change from baseline.
Vital sign and Physical Exam 

Vital sign and physical exam abnormalities will be summarized. The data listings of
individual abnormalities will be provided.
Urine Pregnancy Test 

Urine pregnancy test results will be listed by subjects.
Sections 4.1.2 and 4.2.2 list the summary tables and data listings planned for blinded phase.  
Sections 5.1.2 and 5.2.2 list the summary tables and data listings planned for open-label phase. 
3.3.2 Efficacy Analysis 
Since the study was terminated early, no efficacy analysis planned for the study report, while safety 
data will be summarized and reported in the study report.   
However, with careful review of the mammographic data after database lock, mammographic 
efficacy data may be analyzed as ad-hoc analyses as necessary.  
3.3.3 Subgroup analyses and Multiplicity adjustment 

Multiplicity adjustment will not be applied for multiple testing in this study.
3.4 
Handling of Missing Data


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3.4.1 
Imputation of Missing Date for Safety Analyses 
For safety analyses, the incomplete date and time for the safety events will be imputed using the 
following rules.  

Missing start time of an AE reported on the first dose day will be imputed as dose time + 1
minute, and the AE will be considered as Treatment emergent AE (TEAE).

Missing start time of an AE other than the first dose day will be imputed as 00:01 (hh:mm).

Missing end time of an AE other than the first dose day will be imputed as 23:59 (hh:mm).

Missing start date of any AE will be imputed as the 1st of the month.

Missing end date of any AE will be imputed as the last day of the month.
If the severity of an AE is missing, then the AE will be considered as “Severe”. If the relationship to 
the study agent of an AE is missing, then the AE will be considered as “Related” to study agent.  
3.4.2 
Imputation of Missing Data for Efficacy Analyses 
The study was terminated early so no statistical methods will be implemented for imputing missing 
data. The statistical analysis will focus on descriptive statistics of observed data. 
3.5 
Protocol Deviations  
Listing for all protocol deviations will be provided. 
Listing for major deviations that result in excluding from the PP population will also be provided for 
blinded phase.  
See sections 4.2.1 and 5.2.1 for the data listings planned for blinded phase and open-label phase. 
3.6 
Pharmacodynamic and Pharmacokinetic (PD/PK) Data 

Bone biomarkers (CTx and BSAP) level and change from baseline will be summarized by
visit and treatment group.  Individual data listing will also be provided.

Plasma concentration of study agent (4-OHT E&Z isomers) will be summarized by visit and
treatment group.  Individual data listing will also be provided.

Hormones (FSH, Estradiol and Estrone) will be summarized by visit and treatment group.
Individual data listing will also be provided.

Coagulation parameters (Protein C Activity, Protein C antigen, Protein S antigen total,
Protein S antigen free, Antithrombin III antigen, Activated protein C resistance) will be
summarized by visit and treatment group.  Individual data listing will be provided as well.
3.7 
Key Data Items 
Study Analysis Population Definition: 

Intended-To-Treat (ITT) population:  All subjects who are randomized into the study.

Per-Protocol (PP) population:  All ITT subjects without any major protocol violations.

Safety Population:  All ITT subjects who receive at least one dose of study drug.


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Important Derived Variables: 

Age = (Screening Date – Date of Birth +1)/365.25.

Prior Medications and Treatments: the medications and treatments started before the subject
was enrolled to the study without any change after enrollment.

Concomitant Medication and Treatments:  the medications and treatments started after the
subject was enrolled to the study.  Any medications and treatments started before enrollment
but changed after enrollment will be considered as concomitant medications and treatments.

Baseline:  All clinical measurements (safety and efficacy data) collected at Day 1 or before the
first dose will be analyzed as baseline.  One baseline is for both blinded phase and open-label
phase.

Post Baseline:  All clinical measurements (safety and efficacy data) collected after the first dose
will be analyzed as post baseline.  For blinded phase, the scheduled post-baseline visits are at
Week 13, 26, 39 and 52. For open-label phase, the scheduled post-baseline visits are at Week
65, 78, 91 and 104.

Study Drug Compliance by Visit
                                                                
                                   
        
o
The  number of days between visits = the date of current visit – the date of last visit +1
o
Drug compliance will be calculated only for the subjects who returned all canisters
dispensed.

Overall study drug compliance of the study phase will be the average of visit compliance

Treatment emergent Adverse Events (TEAE):  Any AEs started on or after the day of the first
study drug dosed.
Normal Ranges for Vital Signs 
Vital Signs (unit) 
Lower Limit 
Upper Limit 
Systolic BP (mmHg) 
<90 
>120
Diastolic BP (mmHg) 
<60 
>80
Pulse Rate (bpm) 
<60 
>100
Respiration Rate (bmp) 
<12 
>18
Body Temperature (F) 
<98 
>99.1
LABORATORY ASSESSMENTS 
BLOOD CHEMISTRY 
ALAT (SGPT) 
ALBUMIN 
ALKALINE PHOSPHATASE 
ASAT (SGOT) 
UREA NITROGEN 
CALCIUM 
CARBON DIOXIDE (CO2) 
CHLORIDE 
HEMATOLOGY WITH % 
DIFFERENTIAL 
HEMATOCRIT 
HEMOGLOBIN 
WHITE CELL COUNT 
BASOPHILS 
EOSINOPHILS 
LYMPHOCYTES 
MONOCYTES 
BONE BIOMARKERS 
BONE CTx 
BONE BSAP 
HORMONES 
FOLLICLE STIMULATING HORMONE (FSH) 
LUTEINIZING HORMONE (LH) 
SEX HORMONE BINDING GLOBULIN (SHBG) 


Page 10 of 15 
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CHOLESTEROL, TOTAL 
HDL 
LDL-CHOL CALCULATION 
CREATININE 
BILIRUBIN, DIRECT 
GLUCOSE 
LACTIC DEHYDROGENASE 
POTASSIUM 
SODIUM 
BILIRUBIN, TOTAL 
PROTEIN, TOTAL SERUM 
TRIGLYCERIDES 
NEUTROPHIL, SEGS 
TOTAL NEUTROPHILS 
RED CELL COUNT 
PLATELET COUNT 
ESTRADIOL 
ESTRONE 
COAGULATION FACTORS 
PROTEIN C ACTIVITY 
PROTEIN S ACTIVITY 
ANTITHROMBIN III ANTIGEN 
ACTIVATED PROTEIN C RESISTANCE (APCR) 
Formulas of Metric Conversion: 

1 inch = 2.54 cm

1 lb = 0.4536 kg
 
oC = (oF – 32)x5/9 
3.8 
Change to Planned Protocol Analysis 
Since the study was early terminated, many subjects did not have visit of End of Blinded Phase at 
week 52. The current nominal Visit of “Week 52” will include both “Week 52” and “End of Study” 
(EOS). No imputation will be done for the missing data.  
Since the study was terminated early, a brief clinical study report will be planned for this study and 
will focus on the safety and PK/PD results, where PK/PD results of blind phase will be reported 
only.  The baseline characters, safety data and PK/PD data will be reported in the study report.    
However, mammographic efficacy data may be analyzed appropriately as ad-hoc analyses after 
carefully reviewed data.  The results of ad-hoc analyses will be reported separately.  
4.
OUTPUT PLANNED FOR THE STUDY REPORT (BLINDED PHASE)
4.1 
Tables to be Included in Study Report
In the following sections, the different results are presented in the order in which it is planned to
make them appear in the study report.
The table templates are available in the Appendix of the SAP. The content shown in the templates
are an example only. It is not based on real study data or details concerning design.
4.1.1 Summary of subject information
1. Table [TDS01a] Subject Disposition (Blinded Phase) – All Subjects
2. Table [TDM01a] Summary of Demographics (Blinded Phase) – ITT Population
3. Table [TMH01a] Summary of General Medical History – ITT Population
4. Table [TMH02a] Summary of Breast Cancer Medical History – ITT Population
5. Table [TMH03a] Summary of Menstrual History – ITT Population


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6. Table [TCM01a] Summary of Prior Medications and Treatments (Blinded Phase) – ITT
Population
7. Table [TCM02a] Summary of Concomitant Medications and Treatments (Blinded Phase) – ITT
Population
8. Table [TSD01a] Summary of Study Drug Compliance by Visit (Blinded Phase) – ITT Population
4.1.2 Summary of safety endpoints 
9. Table [TAE01a] Summary of Adverse Events (Blinded Phase) – Safety Population
10. Table [TAE02a] Number (%) of Subjects with Adverse Events by Body System and Preferred
Term (Blinded Phase) – Safety Population
11. Table [TAE03a] Number (%) of Subjects with Serious Adverse Events by Body System and
Preferred Term (Blinded Phase) – Safety Population
12. Table [TAE04a] Number (%) of Subjects with Severe Adverse Events by Body System and
Preferred Term (Blinded Phase) – Safety Population
13. Table [TAE05a] Number (%) of Subjects with Study Agent Related Adverse Events by Body
System and Preferred Term (Blinded Phase) – Safety Population
14. Table [TAE06a] Number (%) of Subjects with Adverse Events by Preferred Term and Overall
Frequency (Blinded Phase) – Safety Population
15. Table [TVS01a] Summary of Vital Signs and Change from Baseline (Blinded Phase) – Safety
Population
16. Table [TPE01a] Summary of Physical Examination (Blinded Phase) – Safety Population
17. Table [TLB01a] Summary of Laboratory (Hematology) Test Results – Safety Population
18. Table [TLB02a] Summary of Laboratory (Blood Chemistry) Test Results – Safety Population
19. Table [TLB03a] Summary of Urine Pregnancy Test Results (Blinded Phase) – Safety Population
4.1.3 
Summary of PK/PD endpoints 
20. Table [THR01a] Summary of Hormones Results (Blinded Phase) – ITT Population
21. Table [TBB01a] Summary of Bone Biomarker Results (Blinded Phase) – ITT Population
22. Table [TCP01a] Summary of Coagulation Parameters Results (Blinded Phase) – ITT Population
23. Table [TPK01a] Summary of Plasma Concentration Results (Blinded Phase) – ITT Population
24. Table [TEM01a] Summary of Endometrial Change (Blinded Phase) – ITT Population (Only if
data available)
4.2 
Listings to be Included in the Clinical Study Report 
4.2.1 Listings of subject information 
1. Listing [LDS01a] Discontinued Subjects (Blinded Phase) – ITT Population
2. Listing [LDM01a] Demographic Characteristics (Blinded Phase) – ITT Population
3. Listing [LRN01a] Randomization (Blinded Phase) – ITT Population
4. Listing [LMH01a] General Medical History – ITT Population
5. Listing [LMH02a] Special Medical History (Breast Cancer) – ITT Population
6. Listing [LMH02a] Menstrual History – ITT Population
7. Listing [LCM01a] Prior Medications and Treatments (Blinded Phase) – ITT Population
8. Listing [LCM02a] Concomitant Medications and Treatments (Blinded Phase) – ITT Population
9. Listing [LPD01a] Protocol Deviations (Blinded Phase) – ITT Population


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10. Listing [LPD02a] Protocol Deviations Lead to Exclusion from PP Population (Blinded Phase) –
ITT Population
11. Listing [LSD01a] Study Drug Compliance (Blinded Phase) – ITT Population
4.2.2 Listings of safety data 
12. Listing [LAE01a] Adverse Events (Blinded Phase) – Safety Population
13. Listing [LAE02a] Serious Adverse Events (Blinded Phase) – Safety Population
14. Listing [LAE03a] Severe Adverse Events (Blinded Phase) – Safety Population
15. Listing [LAE04a] Study Drug Related Adverse Events (Blinded Phase) – Safety Population
16. Listing [LAB01a] Results of Laboratory Tests - Hematology (Blinded Phase) – ITT Population
17. Listing [LAB02a] Results of Laboratory Tests – Blood Chemistry (Blinded Phase) – ITT
Population
18. Listing [LAB03a] Results of Urine Pregnant Tests (Blinded Phase) – ITT Population
19. Listing [LVS01a] Vital Signs (Blinded Phase) – ITT Population
20. Listing [LPE01a] Abnormalities of Physical Exam (Blinded Phase) – ITT Population
4.2.3 Listings of efficacy and PK/PD data 
21. Listing [LEF01a] Breast Density (Blinded Phase) – ITT Population
22. Listing [LBR01a] Breast Tissue Composition BI-RADS Grade (Blinded Phase) – ITT Population
23. Listing [LHR01a] Hormones Results (Blinded Phase) – ITT Population
24. Listing [LBB01a] Bone Biomarkers (Blinded Phase) – ITT Population
25. Listing [LCR01a] Coagulation Parameters (Blinded Phase) – ITT Population
26. Listing [LPK01a] Plasma PK Concentrations (Blinded Phase) – ITT Population
27. Listing [LEM01a] Endometrial Results (Blinded Phase) – ITT Population (only if data available)
5.
OUTPUT PLANNED FOR THE STUDY REPORT (OPEN-LABELPHASE)
5.1 
 Tables to be Included in Study Report
In the following sections, the different results are presented in the order in which it is planned to
make them appear in the study report.
The table templates are available in the Appendix of the SAP. The content shown in the templates
does only mean as an example. It is not based on real study data or details concerning design.
5.1.1 Summary of subject information
25. Table [TDS01b] Subject Disposition (Open-Label Phase) – All Subjects
26. Table [TDM01b] Summary of Demographics (Open-Label Phase) – ITT Population
27. Table [TCM01b] Summary of Medications and Treatments Ongoing from the Blinded Phase
(Open-Label Phase) – ITT Population
28. Table [TCM02b] Summary of Concomitant Medications and Treatments (Open-Label Phase) –
ITT Population
5.1.2 Summary of safety endpoints 
29. Table [TAE01b] Summary of Adverse Events (Open-Label Phase) – Safety Population


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30. Table [TAE02b] Number (%) of Subjects with Adverse Events by Body System and Preferred
Term (Open-Label Phase)  – Safety Population
31. Table [TAE03b] Number (%) of Subjects with Serious Adverse Events by Body System and
Preferred Term (Open-Label Phase) – Safety Population
32. Table [TAE04b] Number (%) of Subjects with Severe Adverse Events by Body System and
Preferred Term (Open-Label Phase) – Safety Population
33. Table [TAE05b] Number (%) of Subjects with Study Agent Related Adverse Events by Body
System and Preferred Term (Open-Label Phase) – Safety Population
34. Table [TAE06b] Number (%) of Subjects with Adverse Events by Preferred Term and Overall
Frequency (Open-Label Phase) – Safety Population
35. Table [TVS01b] Summary of Vital Signs and Change from Baseline (Open-Label Phase) –
Safety Population
36. Table [TPE01b] Summary of Physical Examination (Open-Label Phase) – Safety Population
37. Table [TLB01b] Summary of Laboratory (Hematology) Test Results (Open-Label Phase) –
Safety Population
38. Table [TLB02b] Summary of Laboratory (Blood Chemistry) Test Results (Open-Label Phase) –
Safety Population
39. Table [TLB03b] Summary of Urine Pregnancy Test Results (Open-Label Phase) – Safety
Population
5.2 
Listings to be Included in the Clinical Study Report 
5.2.1 Listings of subject information 
28. Listing [LDS01b] Discontinued Subjects (Open-Label Phase) – ITT Population
29. Listing [LDM01b] Demographic Characteristics (Open-Label Phase) – ITT Population
30. Listing [LCM01b] Medication and Treatments Ongoing from the Blinded Phase (Open-Label
Phase) – ITT Population
31. Listing [LCM02b] Concomitant Medications and Treatments (Open-Label Phase) – ITT
Population
32. Listing [LPD01b] Protocol Deviations (Open-Label Phase) – ITT Population
33. Listing [LSD01b] Study Drug Compliance (Open-Label Phase) – ITT Population
5.2.2 Listings of safety data 
34. Listing [LAE01b] Adverse Events (Open-Label Phase) – Safety Population
35. Listing [LAE02b] Serious Adverse Events (Open-Label Phase) – Safety Population
36. Listing [LAE03b] Severe Adverse Events (Open-Label Phase) – Safety Population
37. Listing [LAE04b] Study Drug Related Adverse Events (Open-Label Phase) – Safety Population
38. Listing [LAB01b] Results of Laboratory Tests – Hematology (Open-Label Phase) – ITT
Population
39. Listing [LAB02b] Results of Laboratory Tests – Blood Chemistry (Open-Label Phase) – ITT
Population
40. Listing [LAB03b] Results of Urine Pregnant Tests (Open-Label Phase) – ITT Population
41. Listing [LVS01b] Vital Signs (Open-Label Phase) – ITT Population
42. Listing [LPE01b] Abnormalities of Physical Exam (Open-Label Phase) – ITT Population


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6.
REFERENCES
Protocol:  A Randomized, Double-blind, Placebo Controlled Trial of 4 Hydroxytamoxifen Gel for
Reducing Breast Tissue Density in Women with BI-RADS Breast Density Categories C or D,
Amendment 3, v4.0, April 16, 2018, BHR Pharma, LLC.
7.
ATTACHMENT: THE SHELLS OF TABLES, FIGURES AND LISTINGS PLANNED FOR
CLINICAL STUDY REPORT


Statistical Analysis Plan 
Study:  BHR-700-301 
Page 15 of 15 
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Approval for  
Statistical Analysis Plan 
Title: 
A Randomized, Double-blind, Placebo Controlled Trial of 4 
Hydroxytamoxifen Gel for Reducing Breast Tissue Density in 
Women with BI-RADS Breast Density Categories C or D 
Reference: 
BHR-700-301/SAP 
Version: 
1.0 
Date effective: 
Author: 
Author’s signature: 
Date: 
The above Statistical Analysis Plan has been reviewed and approved by the Sponsor: 
Name of Reviewer/Approver: 
Position: 
Signature for sponsor: 
Date: