Mammographic Breast DensityPhase 34WARDNCT03199963
Trial of 4-Hydroxytamoxifen (4-OHT) Gel in Women Aimed at Reducing Dense Breast Tissue
A Phase 3 study testing 4-OH tamoxifen in people with Mammographic Breast Density, run by BHR Pharma, LLC at 19 sites in 3 countries.
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. Read more about this study
- Who is it for?
- Ages 35 to 75 years, women only
- Conditions the study is for
- Mammographic Breast Density
- What is being tested?
- 4-OH tamoxifen
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 223 participants
- Where
- 19 sitesin 3 countries
- Study dates
- 21 Aug 2017to 23 Apr 2019
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 35 to 75 years
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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).
- 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.
- Ability to understand and the willingness to sign a written informed consent document.
Who cannot join
- Participants may not be receiving treatment with any investigational drug or biologic within 30 days of randomization or at any time during the study.
- Women with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to Tamoxifen.
- 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.
- Pregnancy (independent of outcome) and/or lactation within 1 year prior to the screening mammogram.
- Women with previous history of cancer (including invasive or intra-ductal breast cancer) except for non-melanoma skin cancer.
- Women who have had a prior mastectomy (unilateral or bilateral), segmental mastectomy, reduction mammoplasty or breast augmentation including implants.
Show all 15Show fewer
- Women with surgical breast biopsy(s) performed within 3 years or core biopsy(s) performed within 1 year prior to the screening mammogram.
- 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.
- 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.
- Women with active liver disease or thromboembolic disorder.
- 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.
- 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.
- Women who have received treatment with Selective Estrogen Receptor Modulators (SERMs) (e.g. tamoxifen, raloxifene) or aromatase inhibitors
- 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.
- 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.
Trial locations and contacts
19 sites in 3 countries.
19 sites in 3 countries
United States17 sites
Bosque Women Care/Cactus Clinical Research
Albuquerque, New Mexico, 87109
South Florida Medical Research
Aventura, Florida, 33180
Overlake Internal Medicine Associates, PS
Bellevue, Washington, 98004
United Clinical Research
Beverly Hills, California, 90211
University of Virginia Medical Park Northridge
Charlottesville, Virginia, 22903
Aventiv Research, Inc.
Columbus, Ohio, 43213
City of Hope
Duarte, California, 91010
Carolina Women's Research and Wellness Center
Durham, North Carolina, 27713
Affiliated Clinical Research, Inc.
Las Vegas, Nevada, 89113
Lake OB-GYN Associates of Mid-Florida
Leesburg, Florida, 34748
USC-Keck Medical Center
Los Angeles, California, 90033
Mesa Obstetricians and Gynecologists/Cactus Clinical Research
Mesa, Arizona, 85209
Coastal Carolina Research Center, Inc.
Mt. Pleasant, South Carolina, 29464
Center for Women's Health and Wellness
Plainsboro, New Jersey, 08536
Dedicated Women's Health Specialists
Puyallup, Washington, 98372
Physician Care Clinical Research, LLC
Sarasota, Florida, 34239
Visions Clinical Research
Tucson, Arizona, 85712
About this study
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
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.
Read the 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.
- Conditions
- Mammographic Breast Density
- Being tested
- 4-OH tamoxifen, Placebo
- Keywords
- Mammographic, Breast, Density, BIRADS C or D
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
4-OH tamoxifenDrug
Also called 4-OHT
4-Hydroxytamoxifen (afimoxifene) gel
PlaceboDrug
An absorptive hydroalcoholic gel preparation of the same ingredients as BHR-700, but without 4-OHT.
| Study group | Role | What they receive |
|---|---|---|
| BHR-700 (0.2% 4-OHT gel) | Experimental | 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. Receives: Drug: 4-OH tamoxifen |
| Matching Placebo Gel | Placebo comparator | An absorptive hydroalcoholic gel preparation of the same ingredients as BHR-700, but without 4-OHT. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Blinded Phase: Baseline; Week 52
Secondary outcomes (6)
Number and Severity of Adverse Events (AEs)
AEs monitored and reported throughout study
Measured: 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
Measured: 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
Measured: 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.
Measured: 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
Measured: 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.
Measured: Blinded Phase: Baseline; Week 52/EOS
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jun 2017
- Study start21 Aug 2017
- Primary completion14 Jan 2019
- Study completion23 Apr 2019
Why it stopped: Administrative - change in development strategy
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Mammographic Breast DensityStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Randomized, double blind, placebo controlled
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 223 participants (actual)
Sponsor and investigators
- Lead sponsor
- BHR Pharma, LLC
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Chief Medical Officer, Study director, BHR Pharma, LLC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03199963
- Sponsor's protocol ID
- BHR-700-301
- Acronym
- 4WARD
- Status last verified
- Jun 2022
- First submitted
- 21 Jun 2017
- Last updated
- 26 Jul 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 26 Jul 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03199963
- Acronym / sponsor ID
- 4WARD / BHR-700-301
- Conditions
- Mammographic Breast Density
- Keywords
- Mammographic, Breast, Density, BIRADS C or D
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Administrative - change in development strategy
- Enrolment
- 223 participants (actual)
- Lead sponsor
- BHR Pharma, LLCIndustry (pharma, biotech, devices)
- Study start
- 21 Aug 2017 (actual)
- Primary completion
- 14 Jan 2019 (actual)
- Study completion
- 23 Apr 2019 (actual)
- First posted
- 27 Jun 2017 (actual)
- Results
- Posted 17 Nov 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Randomized, double blind, placebo controlled
| Arm | Type | Receives |
|---|---|---|
| BHR-700 (0.2% 4-OHT gel) | Experimental | Drug: 4-OH tamoxifenThe 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. |
| Matching Placebo Gel | Placebo comparator | Drug: PlaceboAn absorptive hydroalcoholic gel preparation of the same ingredients as BHR-700, but without 4-OHT. |
Who may qualify
- Ages
- 35 to 75 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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).
- 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.
- Ability to understand and the willingness to sign a written informed consent document.
Key exclusion criteria (15 listed)
- Participants may not be receiving treatment with any investigational drug or biologic within 30 days of randomization or at any time during the study.
- Women with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to Tamoxifen.
- 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.
- Pregnancy (independent of outcome) and/or lactation within 1 year prior to the screening mammogram.
- Women with previous history of cancer (including invasive or intra-ductal breast cancer) except for non-melanoma skin cancer.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 4-OH tamoxifenAlso: 4-OHT4-Hydroxytamoxifen (afimoxifene) gel | Drug | BHR-700 (0.2% 4-OHT gel) |
| PlaceboAn absorptive hydroalcoholic gel preparation of the same ingredients as BHR-700, but without 4-OHT. | Drug | Matching Placebo Gel |
Primary outcome
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.
6 secondary outcomes
Number and Severity of Adverse Events (AEs)
Time frame: 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)
Time frame: Blinded Phase: Baseline; Week 52/EOS
Change in Serum Concentration of: Cholesterol, Triglycerides, High-density Lipoprotein (HDL), and Low-density Lipoprotein (LDL).
Time frame: Blinded Phase: Baseline; Weeks 26, 52/EOS.
Change in Serum Concentration of Select Bone Biomarkers: Bone Specific Alkaline Phosphatase (BSAP) (U/L)
Time frame: Blinded Phase: Baseline; Week 52/EOS
Number of Participants With Measurable Plasma Concentrations of the E and Z Isomers of 4-OHT by Visit
Time frame: Blinded Phase: Weeks 13, 26, 52/EOS
Change in Serum Concentration of Select Bone Biomarkers:Type I Collagen C-Telopeptides (CTx) (pg/mL)
Time frame: Blinded Phase: Baseline; Week 52/EOS
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Jul 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Chief Medical Officer study director
BHR Pharma, LLC
19 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing 4-OH tamoxifen in people with Mammographic Breast Density, run by BHR Pharma, LLC at 19 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 26 Jul 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 19 sites in United States, Germany, Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Nov 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Jul 2022.