E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The mammographic density reduction in healthy women |
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E.1.1.1 | Medical condition in easily understood language |
Mammographic breast tissue density reduction |
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E.1.1.2 | Therapeutic area | Body processes [G] - Physiological processes [G07] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the dose-response relationship of daily oral (Z) endoxifen by measurement of mammographic breast density area (cm2) reduction. |
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E.2.2 | Secondary objectives of the trial |
The secondary objective of this study is to assess the safety and tolerability of daily oral (Z)-endoxifen.
The exploratory objectives of this study are: -To determine if daily oral (Z)-endoxifen for a maximum of six months results in at least a one category reduction in the BI-RADS® scale -To determine the durability of (Z)-endoxifen on breast density response at 24 months post standard of care screening mammogram (difference between end of treatment and 24-month breast density) -To evaluate the levels of endoxifen over time and correlate endoxifen values to density change
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.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 2.Attending the national mammography screening program. The screening mammogram should have been performed within 3 month of study inclusion. 3.Mammographic density assessed as BI-RADS® score B, C or D. 4.40-55 years old premenopausal women (defined as having at least one menstruation during the prior 12 months; women whose status is questionable in the mind of the PI will have an FSH test to confirm (FSH<26 U/L). 5.Women of childbearing potential using a highly effective method of birth control throughout the study period and willing to comply with monthly pregnancy testing.
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E.4 | Principal exclusion criteria |
1.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. 2.A history of breast surgery, e.g., reduction or enlargement, which might affect mammographic density measurements. 3.Mammographic BI-RADS® malignancy code ≥3 at baseline. 4.Previous treatment with an anti-oestrogen, including experimental drug studies (e.g., Karma CREME, Karisma-1 or Karisma-2). 5.A history of thromboembolic disease such as embolus, deep vein thrombosis, stroke, TIA (transient ischemic attack) or myocardial infarction. 6.Moderate hypertension at baseline defined as systolic pressure higher than 160 mm Hg or diastolic higher than 100 mm Hg. 7.BMI > 30. 8.Known APC (activated protein C) resistance, an inherited coagulation disorder. 9.Prescribed and regular use of anticoagulants (defined as substances included in group B01A in the ATC-system). 10.Allergy to endoxifen or any of its components. 11.Agents that have the potential to decrease endoxifen levels through increased metabolic clearance: a.Certain anti-epileptic therapies (carbamazepine, fenytoin, fenobarbital, lamotrigine) b.Certain antibiotics (rifamycins) c.St John’s wort (in Swedish: johannesört) d.Certain HIV medications (efavirenz, ritonavir) 12. Current, or within prior 6 months, use of hormone replacement therapy to treat menopausal symptoms 13. Women who have an increased risk of venous thrombosis due to immobilization, e.g., using wheelchair. 14.Uncontrolled diabetes (defined as HbA1c >50 mmol/mol). 15.Cataract. 16.Pregnant or plan to become pregnant in the next year. 17.Lactating. 18.Not able to understand the study information and/or informed consent. 19.Participation in another investigational clinical trial in the last 6 months. 20.Any reason for which the investigator considers the patient is not suitable for the study.
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E.5 End points |
E.5.1 | Primary end point(s) |
Change of mammographic density area (cm2) assessed by iCAD® software after 6 months of daily (Z) endoxifen treatment.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Change from baseline of safety and tolerability of daily oral (Z)-endoxifen by subject responses to the BCPT Eight Symptom Scale (BESS) questionnaire and AE collection. Clinical assessment, laboratory tests, and participant responses to questionnaires. Change from baseline on the BI-RADS® scale assessed by iCAD® software after 3 and 6 months of daily (Z)-endoxifen treatment. Exploratory endpoints: Reduction of at least one category on the BI-RADS® scale assessed by both iCAD® and Stratus software after a maximum of 6 months of daily (Z)-endoxifen treatment. Durability of breast density response at 24 months post standard of care screening mammogram (difference between end of treatment and 24-month breast density). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |