Low Dose Tamoxifen for Mammographic Density Reduction

Phase 2

Completed

Conditions: Risk Reduction
Mammographic Density Reduction

Interventions: Drug: Tamoxifen Oral Tablet
Drug: Placebo Oral Tablet

Registration Number: NCT03346200

Lead Sponsor: Per Hall

Brief Summary: KARISMA2 is a randomized, double-blinded, six-armed placebo controlled study to identify a low dose of tamoxifen, with less side-effects and a density reduction non-inferior to the standard dose of 20 mg.

Detailed Description: This is a dose determination study aiming to identify the optimal tamoxifen dose for reducing the risk of breast cancer. 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.

1440 healthy women 40-74 yrs were included when adhering the national Swedish mammography screening program between 2016- 2019. Women were randomized and treated daily for 6 months. Mammograms were taken at baseline and at end of treatment and side effects were measured throughout the study trough schedueled questionnaires and spontaneous AE-reporting.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 1440

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
Breast feeding 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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
20 mg tamoxifen	Tamoxifen Oral Tablet	-
2.5 mg tamoxifen	Tamoxifen Oral Tablet	-
1 mg tamoxifen	Tamoxifen Oral Tablet	-
10 mg tamoxifen	Tamoxifen Oral Tablet	-
5 mg tamoxifen	Tamoxifen Oral Tablet	-
0 mg tamoxifen	Placebo Oral Tablet	-

Primary Outcome Measures

Name	Time	Method
Mammograpic Density Change	6 months treatment	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.

Secondary Outcome Measures

Name	Time	Method
Level of Side Effects	From baseline (7-1days before first tablet) up to 6 months or day of discontionuation (prior to 6 months)	Assess the level of side effects in the intervention arms compared to the 20 mg arm. Symptoms are reported on a 5-graded Likert score scale in a 48-item symptom questionnaire at Baseline and at End of treatment ( End of treatment= full-filled the 6 month treatment or at time of discontinuation prior to 6 months). The outcome measure is based on the sum in Likert score of five symptoms ('hot flashes', 'cold sweats', 'night sweats', 'vaginal discharge' and 'muscle cramps') which were found to have a significant change from start to the end of treatment in both pre- and postmenopausal women when contrasting the effect of 20 mg tamoxifen compared to women on placebo. The maximum/minimum range of change per symtom is 4 steps increase or decrease. Accordingly, in the Top-5 symtoms the maximum/minimum range is +/- 20. Higher scores mean a worse outcome.
Drop Out Level	From initiation of treatment (first tablet) up to 6 months of planned treatment (last tablet)	Assess the level of drop out in the intervention arms compared to the 20 mg arm