Clinical trial NCT03346200: Low Dose Tamoxifen for Mammographic Density Reduction
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Risk Reduction
Mammographic Density Reduction
Keywords: Breast cancer
Prevention
Tamoxifen
Lead sponsor: Karolinska Institutet
Sponsor class: OTHER
First posted: 2017-11-17
Enrollment: 1440
Sex: FEMALE
Minimum age (years): 40
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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

Primary outcomes:
measure: Mammograpic Density Change
timeFrame: 6 months treatment
Secondary outcomes:
measure: Level of Side Effects
timeFrame: From baseline (7-1days before first tablet) up to 6 months or day of discontionuation (prior to 6 months)
measure: Drop Out Level
timeFrame: From initiation of treatment (first tablet) up to 6 months of planned treatment (last tablet)
Other outcomes:
Locations:
Study officials:
affiliation: Karolinska Institutet
name: Per Hall, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Eriksson M, Eklund M, Borgquist S, Hellgren R, Margolin S, Thoren L, Rosendahl A, Lang K, Tapia J, Backlund M, Discacciati A, Crippa A, Gabrielson M, Hammarstrom M, Wengstrom Y, Czene K, Hall P. Low-Dose Tamoxifen for Mammographic Density Reduction: A Randomized Controlled Trial. J Clin Oncol. 2021 Jun 10;39(17):1899-1908. doi: 10.1200/JCO.20.02598. Epub 2021 Mar 18.