Risk ReductionPhase 2KARISMA2NCT03346200

Low Dose Tamoxifen for Mammographic Density Reduction

A Phase 2 study testing Tamoxifen Oral Tablet in people with Risk Reduction and Mammographic Density Reduction, run by Per Hall.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 40 to 74 years, women onlyHealthy volunteers can take part
Conditions the study is for: Risk Reduction, Mammographic Density Reduction
What is being tested?: Tamoxifen Oral Tablet
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 1,440 participants
Where: No sites listed yet
Study dates: Nov 2016to Dec 2019
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 40 to 74 years
Women only
Healthy volunteers accepted
Adult, Older adult

Who may be able to join

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

Who cannot join

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

Show all 17Show fewer

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

About this study

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

Read the 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.

Conditions: Risk Reduction, Mammographic Density Reduction
Being tested: Tamoxifen Oral Tablet, Placebo Oral Tablet
Keywords: Breast cancer, Prevention, Tamoxifen
Medical subject headings: Risk Reduction Behavior, Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Tamoxifen Oral TabletDrug
Randomised dose of tamoxifen 1 pill/day for 180 days
Placebo Oral TabletDrug
Randomised dose of tamoxifen 1 pill/day for 180 days

Study groups in NCT03346200
Study group	Role	What they receive
20 mg tamoxifen	Active comparator	Not described Receives: Drug: Tamoxifen Oral Tablet
10 mg tamoxifen	Experimental	Not described Receives: Drug: Tamoxifen Oral Tablet
5 mg tamoxifen	Experimental	Not described Receives: Drug: Tamoxifen Oral Tablet
2.5 mg tamoxifen	Experimental	Not described Receives: Drug: Tamoxifen Oral Tablet
1 mg tamoxifen	Experimental	Not described Receives: Drug: Tamoxifen Oral Tablet
0 mg tamoxifen	Placebo comparator	Not described Receives: Drug: Placebo Oral Tablet

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 6 months treatment

Secondary outcomes (2)

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.
Measured: 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
Measured: From initiation of treatment (first tablet) up to 6 months of planned treatment (last tablet)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Nov 2016Dec 2019

First posted17 Nov 2017
Study startNov 2016
Primary completionOct 2019
Study completionDec 2019

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (6)Papers the sponsor has linked to this study.
Other trials for Risk ReductionStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Prevention
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind
Who is masked: Participant, Care provider, Investigator
Enrolment: 1,440 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03346200
Sponsor's protocol ID: 2016-000882-22
Other IDs: 2016
Acronym: KARISMA2
Status last verified: Mar 2025
First submitted: 1 Nov 2017
Last updated: 7 Mar 2025
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: No

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.
PubMed 33734864
Nash S, Hammarstrom M, Thorngen JO, Winqvist O, Eliasson E, Backlund M, Eriksson M, Margolin S, Thoren L, Borgquist S, Czene K, Hall P, Gabrielson M. Endocrine Biomarker Changes in a Randomised Low-Dose Tamoxifen Trial for Breast Cancer Prevention. J Natl Cancer Inst. 2026 Sep 10:djag321. doi: 10.1093/jnci/djag321. Online ahead of print.
PubMed 42720596
Goransson S, Hernandez-Varas P, Hammarstrom M, Hellgren R, Backlund M, Lang K, Rosendahl AH, Eriksson M, Borgquist S, Stromblad S, Czene K, Hall P, Gabrielson M. Low-dose tamoxifen treatment reduces collagen organisation indicative of tissue stiffness in the normal breast: results from the KARISMA randomised controlled trial. Breast Cancer Res. 2024 Nov 26;26(1):163. doi: 10.1186/s13058-024-01919-1.
PubMed 39593191
Gabrielson M, Hammarstrom M, Bergqvist J, Lang K, Rosendahl AH, Borgquist S, Hellgren R, Czene K, Hall P. Baseline breast tissue characteristics determine the effect of tamoxifen on mammographic density change. Int J Cancer. 2024 Jul 15;155(2):339-351. doi: 10.1002/ijc.34939. Epub 2024 Mar 30.
PubMed 38554131
Hammarstrom M, Gabrielson M, Crippa A, Discacciati A, Eklund M, Lundholm C, Backlund M, Wengstrom Y, Borgquist S, Bergqvist J, Eriksson M, Tapia J, Czene K, Hall P. Side effects of low-dose tamoxifen: results from a six-armed randomised controlled trial in healthy women. Br J Cancer. 2023 Jul;129(1):61-71. doi: 10.1038/s41416-023-02293-z. Epub 2023 May 6.
PubMed 37149701
Gabrielson M, Hammarstrom M, Backlund M, Bergqvist J, Lang K, Rosendahl AH, Borgquist S, Hellgren R, Czene K, Hall P. Effects of tamoxifen on normal breast tissue histological composition: Results from a randomised six-arm placebo-controlled trial in healthy women. Int J Cancer. 2023 Jun 1;152(11):2362-2372. doi: 10.1002/ijc.34430. Epub 2023 Jan 22.
PubMed 36637153

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

Official record

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Study at a glance

From the registry record, last updated by the sponsor on 7 Mar 2025. Recruitment status is as the sponsor reported it: confirm with the study team.

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
ClinicalTrials.gov ID: NCT03346200
Acronym / sponsor ID: KARISMA2 / 2016-000882-22
Conditions: Risk Reduction, Mammographic Density Reduction
Keywords: Breast cancer, Prevention, Tamoxifen
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 1,440 participants (actual)
Lead sponsor: Per HallUniversity, hospital or other
Study start: Nov 2016 (actual)
Primary completion: Oct 2019 (actual)
Study completion: Dec 2019 (actual)
First posted: 17 Nov 2017 (actual)
Results: Posted 7 Mar 2025

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Prevention
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind (participant, care provider, investigator)
Number of arms: 6

Arm	Type	Receives
20 mg tamoxifen	Active comparator	Drug: Tamoxifen Oral Tablet
10 mg tamoxifen	Experimental	Drug: Tamoxifen Oral Tablet
5 mg tamoxifen	Experimental	Drug: Tamoxifen Oral Tablet
2.5 mg tamoxifen	Experimental	Drug: Tamoxifen Oral Tablet
1 mg tamoxifen	Experimental	Drug: Tamoxifen Oral Tablet
0 mg tamoxifen	Placebo comparator	Drug: Placebo Oral Tablet

Who may qualify

Ages: 40 to 74 years
Sex: Female only
Healthy volunteers: Accepted
Age groups: Adult, Older adult

Key inclusion criteria (3 listed)

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

Key exclusion criteria (17 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Tamoxifen Oral TabletRandomised dose of tamoxifen 1 pill/day for 180 days	Drug	1 mg tamoxifen, 10 mg tamoxifen, 2.5 mg tamoxifen, 20 mg tamoxifen, 5 mg tamoxifen
Placebo Oral TabletRandomised dose of tamoxifen 1 pill/day for 180 days	Drug	0 mg tamoxifen

Primary outcome

Mammograpic Density Change
Time frame: 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.

2 secondary outcomes

Level of Side Effects
Time frame: From baseline (7-1days before first tablet) up to 6 months or day of discontionuation (prior to 6 months)
Drop Out Level
Time frame: From initiation of treatment (first tablet) up to 6 months of planned treatment (last tablet)

Results and safety

Results posted to the registry on 7 Mar 2025, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
20 mg Tamoxifen	241	171
10 mg Tamoxifen	243	167
5 mg Tamoxifen	240	157
2.5 mg Tamoxifen	235	159
1 mg Tamoxifen	239	174
0 mg Tamoxifen	242	183

Primary outcome: Mammograpic Density Change

Time frame: 6 months treatment. Mean (95% Confidence Interval). Unit: Percentage of change

Measure	20 mg Tamoxifen n = 203	10 mg Tamoxifen n = 210	5 mg Tamoxifen n = 201	2.5 mg Tamoxifen n = 200	1 mg Tamoxifen n = 205	0 mg Tamoxifen n = 211
Value	-9.6 (-14.8 to -4.5)	-6.8 (-11.8 to -1.7)	-1.0 (-6.2 to 4.1)	-6.9 (-12.1 to -1.8)	-1.0 (-6.1 to 4.1)	0.1 (-4.9 to 5.1)

20 mg Tamoxifen: Median Difference (Final Values): 52.5 (97.5% CI 41.9 to 100), p <0.01, one-sided Wald tests

2 secondary outcomes are reported in the full results.

Adverse events

Time frame: From baseline (start of treatment) to end of study (6 months or early termination). Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
20 mg Tamoxifen	2 of 241 (0.8%)	74 of 241 (30.7%)	0 of 241
10 mg Tamoxifen	1 of 243 (0.4%)	70 of 243 (28.8%)	0 of 243
5 mg Tamoxifen	2 of 240 (0.8%)	63 of 240 (26.3%)	0 of 240
2.5 mg Tamoxifen	1 of 235 (0.4%)	65 of 235 (27.7%)	0 of 235
1 mg Tamoxifen	1 of 239 (0.4%)	39 of 239 (16.3%)	0 of 239
0 mg Tamoxifen	4 of 242 (1.7%)	40 of 242 (16.5%)	0 of 242

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 7 Mar 2025.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Results publication: PubMed 33734864Eriksson 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.
Derived from this study: PubMed 42720596Nash S, Hammarstrom M, Thorngen JO, Winqvist O, Eliasson E, Backlund M, Eriksson M, Margolin S, Thoren L, Borgquist S, Czene K, Hall P, Gabrielson M. Endocrine Biomarker Changes in a Randomised Low-Dose Tamoxifen Trial for Breast Cancer Prevention. J Natl Cancer Inst. 2026 Sep 10:djag321. doi: 10.1093/jnci/djag321. Online ahead of print.
Derived from this study: PubMed 39593191Goransson S, Hernandez-Varas P, Hammarstrom M, Hellgren R, Backlund M, Lang K, Rosendahl AH, Eriksson M, Borgquist S, Stromblad S, Czene K, Hall P, Gabrielson M. Low-dose tamoxifen treatment reduces collagen organisation indicative of tissue stiffness in the normal breast: results from the KARISMA randomised controlled trial. Breast Cancer Res. 2024 Nov 26;26(1):163. doi: 10.1186/s13058-024-01919-1.
Derived from this study: PubMed 38554131Gabrielson M, Hammarstrom M, Bergqvist J, Lang K, Rosendahl AH, Borgquist S, Hellgren R, Czene K, Hall P. Baseline breast tissue characteristics determine the effect of tamoxifen on mammographic density change. Int J Cancer. 2024 Jul 15;155(2):339-351. doi: 10.1002/ijc.34939. Epub 2024 Mar 30.
Derived from this study: PubMed 37149701Hammarstrom M, Gabrielson M, Crippa A, Discacciati A, Eklund M, Lundholm C, Backlund M, Wengstrom Y, Borgquist S, Bergqvist J, Eriksson M, Tapia J, Czene K, Hall P. Side effects of low-dose tamoxifen: results from a six-armed randomised controlled trial in healthy women. Br J Cancer. 2023 Jul;129(1):61-71. doi: 10.1038/s41416-023-02293-z. Epub 2023 May 6.
Derived from this study: PubMed 36637153Gabrielson M, Hammarstrom M, Backlund M, Bergqvist J, Lang K, Rosendahl AH, Borgquist S, Hellgren R, Czene K, Hall P. Effects of tamoxifen on normal breast tissue histological composition: Results from a randomised six-arm placebo-controlled trial in healthy women. Int J Cancer. 2023 Jun 1;152(11):2362-2372. doi: 10.1002/ijc.34430. Epub 2023 Jan 22.
KARMA -Karolinska Mammography Project for Risk Prediction of Breast CancerLink provided by the sponsor.
Individual participant dataSharing planned: No

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Per Hall, Professor principal investigator

Karolinska Institutet

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Tamoxifen Oral Tablet in people with Risk Reduction and Mammographic Density Reduction, run by Per Hall.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 7 Mar 2025. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 7 Mar 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Mammograpic Density Change (time frame: 6 months treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03346200, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Mar 2025.