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

Mammographic Breast Density Clinical Trial

— 4WARD  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03199963
• Other study ID #: BHR-700-301
• Status: Terminated
• Phase: Phase 3
• Start date: August 21, 2017
• Est. completion date: April 23, 2019

Study information

• Verified date: June 2022
• Source: BHR Pharma, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 223
• Est. completion date: April 23, 2019
• Est. primary completion date: January 14, 2019
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 35 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Mammographic Breast Density

Intervention

Drug:
• 4-OH tamoxifen
4-Hydroxytamoxifen (afimoxifene) gel
• Placebo
An absorptive hydroalcoholic gel preparation of the same ingredients as BHR-700, but without 4-OHT.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
BHR Pharma, LLC

Countries where clinical trial is conducted

United States,  Germany,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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.
Secondary	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
Secondary	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
Secondary	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