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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03199963
Recruitment Status : Terminated (Administrative - change in development strategy)
First Posted : June 27, 2017
Last Update Posted : July 1, 2019
Information provided by (Responsible Party):
BHR Pharma, LLC

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.

Condition or disease Intervention/treatment Phase
Mammographic Breast Density Drug: 4-OH tamoxifen Drug: Placebo Phase 3

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 EU. 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 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 223 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized, double blind, placebo controlled
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official 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
Actual Study Start Date : August 21, 2017
Actual Primary Completion Date : March 31, 2019
Actual Study Completion Date : March 31, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Tamoxifen

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 Name: 4-OHT

Placebo Comparator: Placebo
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.

Primary Outcome Measures :
  1. The percent reduction of mammographic dense breast (MBD) tissue on a follow-up mammogram compared to the baseline mammogram after 52 weeks of treatment. [ Time Frame: Blinded Phase: Baseline; Week 52 ]
    Percent MBD at screening compared to percent MBD after 52 weeks of treatment with either BHR-700 or Placebo.

Secondary Outcome Measures :
  1. 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"). [ Time Frame: Blinded Phase: Baseline; Weeks 13, 26, 39, 52. (Optional Open Label Phase) Weeks 65, 78, 91,104 ]
    AEs monitored and reported throughout study

  2. Change in serum concentration of sex hormone binding globulin (SHBG). [ Time Frame: Blinded Phase: Baseline; Week 52.(Optional Open Label Phase) Week 104 ]
    SHBG levels at baseline will be compared to levels at Week 52 and Week 104

  3. Change in serum concentration of: cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL). [ Time Frame: Blinded Phase: Baseline; Weeks 26, 52.(Optional Open Label Phase) Weeks 78, 104 ]
    Lipid levels at baseline will be compared to levels measured at time-points in the study

  4. Change in serum concentration of select bone biomarkers CTx and BSAP. [ Time Frame: Blinded Phase: Baseline; Week 52.(Optional Open Label Phase) Week 104 ]
    Bone biomarker levels at baseline will be compared to levels measured at Week 52 and 104.

  5. Plasma concentrations of the E and Z isomers of 4-OHT. [ Time Frame: Blinded Phase: Weeks 13, 26, 52. (Optional Open Label Phase) Weeks 78, 104 ]
    Blood samples will be taken to measure plasma concentrations of 4-OHT at time-points in the study

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   35 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03199963

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

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Responsible Party: BHR Pharma, LLC Identifier: NCT03199963     History of Changes
Other Study ID Numbers: BHR-700-301
First Posted: June 27, 2017    Key Record Dates
Last Update Posted: July 1, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by BHR Pharma, LLC:

Additional relevant MeSH terms:
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Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Bone Density Conservation Agents