Effect of Oral (Z)-Endoxifen in Premenopausal Women With Measurable Breast Density

Study Overview
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Brief Summary
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This is a randomized, double-blinded, placebo-controlled dose-response efficacy study of oral (Z)-endoxifen in premenopausal women with measurable breast density. There will be 5 in-clinic visits (Screening, Day 1, Months 1, 3 and 6) and 3 self-report visits (Months 2, 4 and 5). Standard of care mammograms will be used for the screening mammogram as well as the 24-month follow up visit.

Official Title
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A Phase 2, Randomized, Double-blinded, Placebo-controlled, Dose-Response Study of Oral (Z)-Endoxifen in Premenopausal Women With Measurable Breast Density

Conditions
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Breast Density

Intervention / Treatment
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* Drug: Z-Endoxifen
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Premenopausal women (defined as having at least one menstruation during the prior 12 months; women with an intrauterine device are considered premenopausal if <52 years) Women of childbearing potential using a highly effective method of birth control* throughout the study period and willing to comply with monthly pregnancy testing Screening mammogram performed within 3 month of study inclusion Mammographic density assessed as BI-RADS® score B, C, or D Must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects Exclusion Criteria: Mammographic BI-RADS® malignancy code ≥3 at baseline mammography Any previous diagnosis of breast cancer, including carcinoma in situ, or any other cancer (non-melanoma skin cancer and in situ cancer of the cervix are not exclusion criteria) A history of breast surgery, e.g., reduction or enlargement, which might affect mammographic density measurements Current medical conditions: APC (activated protein C) resistance, an inherited coagulation disorder Systolic pressure higher than 160 mm Hg or diastolic higher than 100 mm Hg Cataract(s) Uncontrolled diabetes (defined as HbA1c >50 mmol/mol) Abnormal lab values deemed clinically significant by Investigator BMI > 30 Women who have an increased risk of venous thrombosis due to immobilization, e.g., using wheelchair Agents that have the potential to decrease endoxifen levels through increased metabolic clearance: Certain anti-epileptic therapies (carbamazepine, fenytoin, fenobarbital, lamotrigine) Certain antibiotics (rifamycins) St John's wort (in Swedish: johannesört) Certain HIV medications (efavirenz, ritonavir) Lactating, pregnant, or plan to become pregnant in the next year History of thromboembolic disease such as embolus, deep vein thrombosis, stroke, TIA (transient ischemic attack) or myocardial infarction Allergy to endoxifen or any of its components Previous treatment with an anti-oestrogen, including experimental drug studies (e.g., Karma CREME, Karisma-1 or Karisma-2) Prescribed and regular use of anticoagulants (defined as substances included in group B01A in the ATC-system) Participation in another investigational clinical trial in the last 6 months Not willing or able to understand the study information and/or informed consent

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>oral capsule | Drug: Placebo<br>* Placebo<br>|
| Experimental: 1 mg (Z)-endoxifen<br>oral capsule | Drug: Z-Endoxifen<br>* Z-Endoxifen<br>|
| Experimental: 2 mg (Z)-endoxifen<br>oral capsule | Drug: Z-Endoxifen<br>* Z-Endoxifen<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of mammographic density area (cm2) assessed by iCAD® software | Change from baseline | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of mammographic density area (cm2) assessed by iCAD® software | Change from baseline | 3 months | 
| Change of mammographic density area (cm2) assessed by Stratus software | Change from baseline | 6 months | 
| Change of mammographic density area (cm2) assessed by Stratus software | Change from baseline | 3 months | 
| Change from baseline responses to the Breast Cancer Prevention Trial Eight Symptom Scale (BESS) | 5-point Likert-type scale | 6 months | 
| Comparison of adverse events | assessment of adverse events | 6 months |