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A Randomized, Double-blind, Placebo-controlled Study of 4-hydroxytamoxifen Topical Gel in Women with Mammographically Dense Breast
The goal of this study is to determine whether putting 4-Hydroxytamoxifen (4-OHT) gel on the breast skin lowers mammographic density (MD) compared with putting placebo gel on the breast skin.
1. OBJECTIVES: The overall objective is to evaluate whether daily application of 2mg (2mL) per breast of 4-hydroxytamoxifen (4-OHT) topical gel versus placebo lowers breast density in women with mammographically dense breast, based on the intent-to-treat principle, i.e., all participants who have MD measurements from both baseline and 52 weeks, regardless of compliance, will be included in the primary analysis. 1.1 Primary Objectives: To estimate and compare the percent change in mammographic breast density (using Cumulus software) from baseline to Month 12 in women applying 2mg 4-OHT gel per breast versus placebo. 1.2 Secondary Objectives: 1. To compare the Cumulus vs. Volpara breast density measurement methods to estimate percent change in mammographic breast density from baseline to Month 12 in women applying 2mg of 4-OHT gel per breast vs. placebo. 2. To compare the percentage of women who underwent a change in BIRADS category, comparing pre-and post- treatment measurements, for recipients of active agent versus placebo. 3. To estimate percentage of women with greater than or equal to 10% absolute decrease in quantitative mammographic density percentage between baseline and 12 months, comparing between treated group 2 mg per breast 4-OHT gel to placebo. 4. To compare the 2D vs. 3D breast density measurement methods to estimate percent change in mammographic breast density from baseline to Month 12 in women applying 2mg of 4-OHT gel per breast vs. placebo. 5. To describe symptoms assessed by BCPT Eight Symptom Scale (BESS) questionnaire and laboratory toxicity assessment (Factor VIII (F VIII), Von Willebrand (vWB) factor, Sex Hormone-Binding Globulin (SHBG), lipid profile). 6. To evaluate serum measurements of 4-OHT and related metabolite levels and factors related to tamoxifen exposures, such as Insulin-like growth factor (IGF) pathway members, C-reactive protein (CRP), estradiol. 7. To evaluate tissue biomarkers (among women undergoing optional pre- and post-treatment biopsies): Terminal duct lobular unit (TDLU) Involution. Collagen structural changes. SETER/PR index: estrogen related transcription. Ki-67, COX-2, p16, CD68. 8. To examine whether any reductions in mammographic density seen after 1 year of 4-OHT vs. placebo gel application persist at 24 months, one year after gel application has stopped.