Trial of 4-Hydroxytamoxifen (4-OHT) Gel in Women Aimed at Reducing Dense Breast Tissue (4WARD)

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

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.

Study Overview

• Status: Terminated
• Conditions: Mammographic Breast Density
• Intervention / Treatment: Drug: 4-OH tamoxifen; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 223
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Hessen
    • Frankfurt, Hessen, Germany, 60322
      • Private Practice - Gynecology
• Spain
  • Madrid, Spain, 28009
    • Instituto Palacios Salud de La Mujer
• United States
  • Arizona
    • Mesa, Arizona, United States, 85209
      • Mesa Obstetricians and Gynecologists/Cactus Clinical Research
    • Tucson, Arizona, United States, 85712
      • Visions Clinical Research
  • California
    • Beverly Hills, California, United States, 90211
      • United Clinical Research
    • Duarte, California, United States, 91010
      • City of Hope
    • Los Angeles, California, United States, 90033
      • USC-Keck Medical Center
  • Florida
    • Aventura, Florida, United States, 33180
      • South Florida Medical Research
    • Leesburg, Florida, United States, 34748
      • Lake OB-GYN Associates of Mid-Florida
    • Sarasota, Florida, United States, 34239
      • Physician Care Clinical Research, LLC
  • Nevada
    • Las Vegas, Nevada, United States, 89113
      • Affiliated Clinical Research, Inc.
  • New Jersey
    • Plainsboro, New Jersey, United States, 08536
      • Center for Women's Health and Wellness
  • New Mexico
    • Albuquerque, New Mexico, United States, 87109
      • Bosque Women Care/Cactus Clinical Research
  • North Carolina
    • Durham, North Carolina, United States, 27713
      • Carolina Women's Research and Wellness Center
  • Ohio
    • Columbus, Ohio, United States, 43213
      • Aventiv Research, Inc.
  • South Carolina
    • Mount Pleasant, South Carolina, United States, 29464
      • Coastal Carolina Research Center, Inc.
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia Medical Park Northridge
  • Washington
    • Bellevue, Washington, United States, 98004
      • Overlake Internal Medicine Associates, PS
    • Puyallup, Washington, United States, 98372
      • Dedicated Women's Health Specialists

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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 participant 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.

Exclusion Criteria:

1. Participants may not be receiving treatment with any investigational drug or 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 the screening mammogram.
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 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, raloxifene) 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BHR-700 (0.2% 4-OHT gel); 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.	Drug: 4-OH tamoxifen; 4-Hydroxytamoxifen (afimoxifene) gel; Other Names: 4-OHT
Placebo Comparator: Matching Placebo Gel; An absorptive hydroalcoholic gel preparation of the same ingredients as BHR-700, but without 4-OHT.	Drug: Placebo; An absorptive hydroalcoholic gel preparation of the same ingredients as BHR-700, but without 4-OHT.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Percent Reduction of Mammographic Dense Breast (MBD) Tissue on a Follow-up Mammogram Compared to the Baseline Mammogram After 52 Weeks of Treatment.	Percent MBD at screening compared to percent MBD after 52 weeks of treatment with either BHR-700 or Placebo.	Blinded Phase: Baseline; Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number and Severity of Adverse Events (AEs)	AEs monitored and reported throughout study	Blinded Phase: Baseline; Weeks 13, 26, 39, 52/EOS and Open Label Phase
Change in Serum Concentration of Sex Hormone Binding Globulin (SHBG) From Baseline to Week 52/End of Study (EOS)	SHBG levels at baseline will be compared to levels at Week 52/EOS	Blinded Phase: Baseline; Week 52/EOS
Change in Serum Concentration of: Cholesterol, Triglycerides, High-density Lipoprotein (HDL), and Low-density Lipoprotein (LDL).	Lipid levels at baseline will be compared to levels measured at time-points in the study	Blinded Phase: Baseline; Weeks 26, 52/EOS.
Change in Serum Concentration of Select Bone Biomarkers: Bone Specific Alkaline Phosphatase (BSAP) (U/L)	Bone biomarker levels (BSAP) at baseline will be compared to levels measured at Week 52.	Blinded Phase: Baseline; Week 52/EOS
Number of Participants With Measurable Plasma Concentrations of the E and Z Isomers of 4-OHT by Visit	Blood samples will be taken to measure plasma concentrations of 4-OHT at time-points in the study	Blinded Phase: Weeks 13, 26, 52/EOS
Change in Serum Concentration of Select Bone Biomarkers:Type I Collagen C-Telopeptides (CTx) (pg/mL)	Bone biomarker levels (CTx) at baseline will be compared to levels measured at Week 52.	Blinded Phase: Baseline; Week 52/EOS

Collaborators and Investigators

• Sponsor: BHR Pharma, LLC
• Investigators: Study Director: Chief Medical Officer, BHR Pharma, LLC

Study record dates

Study Major Dates

• Study Start (Actual): August 21, 2017
• Primary Completion (Actual): January 14, 2019
• Study Completion (Actual): April 23, 2019

Study Registration Dates

• First Submitted: June 21, 2017
• First Submitted That Met QC Criteria: June 23, 2017
• First Posted (Actual): June 27, 2017

Study Record Updates

• Last Update Posted (Actual): July 26, 2022
• Last Update Submitted That Met QC Criteria: June 30, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: Breast; Mammographic; Density; BIRADS C or D
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Bone Density Conservation Agents; Estrogen Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Tamoxifen; Afimoxifene
• Other Study ID Numbers: BHR-700-301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No