Karma Intervention Study

Study Overview
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Brief Summary
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This is a dose determination study aiming to identify the optimal tamoxifen dose for reducing the risk of breast cancer. Instead of following a very large number of women, for many years, treated with different doses of tamoxifen and see if they develop breast cancer, the investigators will include 1,440 healthy women participating in the mammographic screening program at two Mammography units (Unilabs mammography, Lund and Södersjukhuset Breast Centre, Stockholm) and measure their change in mammographic density. The change in mammographic density is a very good marker of therapy response. Investigators will test if 1 mg, 2.5 mg, 5 mg and 10 mg reduce the mammographic density to the same extent as 20 mg. In summary Karisma 2 will be a randomized, double-blinded, six-armed placebo controlled study to identify the dose of tamoxifen with the most favourable side effect spectra and with a density reduction non-inferior to 20 mg tamoxifen.

Official Title
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A Randomised, Double Blinded, Six-armed Placebo Controlled Study to Investigate Optimal Dose of Tamoxifen With the Most Favourable Side Effect Spectre and With Mammography Density Reduction Non-inferior to That of 20 mg Tamoxifen (Karisma 2)

Conditions
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Risk Reduction, Mammographic Density Reduction

Intervention / Treatment
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* Drug: Tamoxifen Oral Tablet
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Attending the national mammography screening program, i.e. aged 40-74 and has performed a screening mammogram maximum 3 months prior to study inclusion Having a measurable mammographic density, i.e. ≥4.5 % density (volumetric) measured by Volpara Informed consent must be signed before any study specific assessments have been performed Exclusion Criteria: Pregnancy at start, during time of study medication and up to 3 months after quitting study medication Any previous or current diagnosis of breast cancer (including carcinoma in situ) Mammographic BI-RADS code 3 or above at baseline mammography, or at a diagnostic mammography during time of treatment (the first 6 months of the study) Any previous diagnosis of cancer with the exception of non-melanoma skin cancer and in situ cancer of the cervix Currently using oral oestrogen and progesterone based hormone replacement therapy Current use of hormone contraceptive with hormones, e.g. hormonal contraceptive pills, or progesterone implants. Hormonal intrauterine devices are accepted. A history of thrombo-embolic disease such as embolies, deep vein thrombosis, stroke, TIA or cardiac arrest. Known APC (Activated protein C )- resistance, an inherited hemostatic disorder A history of major surgery of the breast, e.g. reduction or enlargement, which might affect density measurements Women who have an increased risk of venous thrombosis due to immobilization, e.g. using wheelchair Known uncontrolled diabetes Hypertension at baseline, defined as systolic pressure higher than 140 mm Hg and diastolic higher than 90 mm Hg Use of drugs that interfere with CYP2D6 expression such as Seroxat (paroxetine), Fontex (fluoxetin) and Zyban / Voxra (bupropion) Use of Waran (warfarin) Non-medical approved drugs against hot-flashes including phytooestrogen Not able to understand study information and/or informed consent

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 74 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 20 mg tamoxifen<br> | Drug: Tamoxifen Oral Tablet<br>* Randomised dose of tamoxifen 1 pill/day for 180 days<br>|
| Experimental: 10 mg tamoxifen<br> | Drug: Tamoxifen Oral Tablet<br>* Randomised dose of tamoxifen 1 pill/day for 180 days<br>|
| Experimental: 5 mg tamoxifen<br> | Drug: Tamoxifen Oral Tablet<br>* Randomised dose of tamoxifen 1 pill/day for 180 days<br>|
| Experimental: 2.5 mg tamoxifen<br> | Drug: Tamoxifen Oral Tablet<br>* Randomised dose of tamoxifen 1 pill/day for 180 days<br>|
| Experimental: 1 mg tamoxifen<br> | Drug: Tamoxifen Oral Tablet<br>* Randomised dose of tamoxifen 1 pill/day for 180 days<br>|
| Placebo Comparator: 0 mg tamoxifen<br> | Drug: Placebo Oral Tablet<br>* Randomised dose of tamoxifen 1 pill/day for 180 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mammograpic density change | Change in mammography density. In particular, we will test for noninferiority in the proportion of women in the intervention arms (placebo, 1 mg, 2.5 mg, 5 mg, 10 mg) who have a density reduction as great as or greater (after 6 months) than the median density reduction in the 20 mg arm. | 6 months treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level of side effects | Assess the level of side effects in the intervention arms compared to the 20 mg arm | During time of treatment (6 months) | 
| Drop out level | Assess the level of drop out in the intervention arms compared to the 20 mg arm | During time of treatment (6 months) |