Mammographic Density Reduction, Risk Reduction
Conditions
Keywords
Breast cancer, Prevention, Tamoxifen
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.
Interventions
Randomised dose of tamoxifen 1 pill/day for 180 days
DRUGPlacebo Oral Tablet
Randomised dose of tamoxifen 1 pill/day for 180 days
Sponsors
Per Hall
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
40 Years to 74 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 20 mg Tamoxifen Tamoxifen Oral Tablet: Randomised dose of tamoxifen 1 pill/day for 180 days | 241 |
| 10 mg Tamoxifen Tamoxifen Oral Tablet: Randomised dose of tamoxifen 1 pill/day for 180 days | 243 |
| 5 mg Tamoxifen Tamoxifen Oral Tablet: Randomised dose of tamoxifen 1 pill/day for 180 days | 240 |
| 2.5 mg Tamoxifen Tamoxifen Oral Tablet: Randomised dose of tamoxifen 1 pill/day for 180 days | 235 |
| 1 mg Tamoxifen Tamoxifen Oral Tablet: Randomised dose of tamoxifen 1 pill/day for 180 days | 239 |
| 0 mg Tamoxifen Placebo Oral Tablet: Randomised dose of tamoxifen 1 pill/day for 180 days | 242 |
| Total | 1,440 |
Baseline characteristics
| Characteristic | 10 mg Tamoxifen | 5 mg Tamoxifen | 2.5 mg Tamoxifen | 1 mg Tamoxifen | 0 mg Tamoxifen | 20 mg Tamoxifen | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 64 Participants | 55 Participants | 54 Participants | 46 Participants | 65 Participants | 60 Participants | 344 Participants |
| Age, Categorical Between 18 and 65 years | 179 Participants | 185 Participants | 181 Participants | 193 Participants | 177 Participants | 181 Participants | 1096 Participants |
| Age, Continuous | 55.8 years STANDARD_DEVIATION 10 | 55.1 years STANDARD_DEVIATION 9.7 | 54.9 years STANDARD_DEVIATION 9.7 | 54.3 years STANDARD_DEVIATION 9.4 | 60.0 years STANDARD_DEVIATION 9.9 | 55.6 years STANDARD_DEVIATION 9.5 | 55.3 years STANDARD_DEVIATION 9.7 |
| Race and Ethnicity Not Collected | — | — | — | — | — | — | 0 Participants |
| Sex: Female, Male Female | 243 Participants | 240 Participants | 235 Participants | 239 Participants | 242 Participants | 241 Participants | 1440 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 241 | 0 / 243 | 0 / 240 | 0 / 235 | 0 / 239 | 0 / 242 |
| other Total, other adverse events | 74 / 241 | 70 / 243 | 63 / 240 | 65 / 235 | 39 / 239 | 40 / 242 |
| serious Total, serious adverse events | 2 / 241 | 1 / 243 | 2 / 240 | 1 / 235 | 1 / 239 | 4 / 242 |
Outcome results
Primary
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.
Time frame: 6 months treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 20 mg Tamoxifen | Mammograpic Density Change | -9.6 Percentage of change |
| 10 mg Tamoxifen | Mammograpic Density Change | -6.8 Percentage of change |
| 5 mg Tamoxifen | Mammograpic Density Change | -1.0 Percentage of change |
| 2.5 mg Tamoxifen | Mammograpic Density Change | -6.9 Percentage of change |
| 1 mg Tamoxifen | Mammograpic Density Change | -1.0 Percentage of change |
| 0 mg Tamoxifen | Mammograpic Density Change | 0.1 Percentage of change |
p-value: <0.0197.5% CI: [41.9, 100]one-sided Wald tests
Secondary
Drop Out Level
Assess the level of drop out in the intervention arms compared to the 20 mg arm
Time frame: From initiation of treatment (first tablet) up to 6 months of planned treatment (last tablet)
Population: ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 20 mg Tamoxifen | Drop Out Level | 65 Participants |
| 10 mg Tamoxifen | Drop Out Level | 69 Participants |
| 5 mg Tamoxifen | Drop Out Level | 79 Participants |
| 2.5 mg Tamoxifen | Drop Out Level | 71 Participants |
| 1 mg Tamoxifen | Drop Out Level | 58 Participants |
| 0 mg Tamoxifen | Drop Out Level | 53 Participants |
Secondary
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.
Time frame: From baseline (7-1days before first tablet) up to 6 months or day of discontionuation (prior to 6 months)
Population: In all 1175 women, whereof 454 (39%) premenopausal and 721 (61%) postmenopausal, constitute the per protocol population which fulfilled teh 48-item Symptom questionnaire at Baseline and at End of treatment (6month or at time of Early termination)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 20 mg Tamoxifen | Level of Side Effects | 2.71 Likert score change in Top5 Symptoms |
| 10 mg Tamoxifen | Level of Side Effects | 2.97 Likert score change in Top5 Symptoms |
| 5 mg Tamoxifen | Level of Side Effects | 2.52 Likert score change in Top5 Symptoms |
| 2.5 mg Tamoxifen | Level of Side Effects | 2.39 Likert score change in Top5 Symptoms |
| 1 mg Tamoxifen | Level of Side Effects | 1.65 Likert score change in Top5 Symptoms |
| 0 mg Tamoxifen | Level of Side Effects | 0.36 Likert score change in Top5 Symptoms |