Low Dose Tamoxifen for Mammographic Density Reduction (KARISMA2)

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

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.

Study Overview

• Status: Completed
• Conditions: Risk Reduction; Mammographic Density Reduction
• Intervention / Treatment: Drug: Tamoxifen Oral Tablet; Drug: Placebo Oral Tablet

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.

• Study Type: Interventional
• Enrollment (Actual): 1440
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

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

What is the study measuring?

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. 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.	From baseline (7-1days before first tablet) up to 6 months or day of discontionuation (prior to 6 months)
Drop Out Level	Assess the level of drop out in the intervention arms compared to the 20 mg arm	From initiation of treatment (first tablet) up to 6 months of planned treatment (last tablet)

Collaborators and Investigators

• Sponsor: Per Hall
• Investigators: Principal Investigator: Per Hall, Professor, Karolinska Institutet

Publications and helpful links

General Publications

• 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.

Helpful Links

• KARMA -Karolinska Mammography Project for Risk Prediction of Breast Cancer

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2016
• Primary Completion (Actual): October 1, 2019
• Study Completion (Actual): December 1, 2019

Study Registration Dates

• First Submitted: November 1, 2017
• First Submitted That Met QC Criteria: November 14, 2017
• First Posted (Actual): November 17, 2017

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 4, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Tamoxifen; Breast cancer; Prevention
• Additional Relevant MeSH Terms: Antineoplastic Agents; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Bone Density Conservation Agents; Hormone Antagonists; Estrogen Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Tamoxifen
• Other Study ID Numbers: 2016-000882-22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No