Trial Outcomes & Findings for Low-Dose Tamoxifen Citrate in Reducing Breast Cancer Risk in Radiation-Induced Cancer Survivors (NCT NCT01196936)

NCT ID: NCT01196936

Last Updated: 2026-01-05

Results Overview

Mammographic density was quantified as percentage of fibroglandular tissue. Using an intention-to-treat analysis, mammographic breast density (MBD) was compared between patients in the low dose tamoxifen intervention and placebo group by applying the linear mixed effects model for normally distributed data.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE2

Target enrollment

84 participants

Primary outcome timeframe

At year two post treatment

Results posted on

2026-01-05

Participant Flow

Participants were screened for eligibility at each participating institution.However, after central review of mammograms, 11 participants were ineligible for the study (mammographic density \<25%) and 1 participant was randomized but withdrew before taking the study drug. These 12 participants were excluded from the analysis.

Participant milestones

Participant milestones
Measure	Arm II (Placebo) Patients receive placebo PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Placebo: 1 tablet daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies	Arm I (Tamoxifen Citrate) Patients receive tamoxifen citrate PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Tamoxifen Citrate: 5 mg PO Daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies
Overall Study STARTED	38	34
Overall Study Year one post treatment	28	27
Overall Study COMPLETED	21	23
Overall Study NOT COMPLETED	17	11

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Low-Dose Tamoxifen Citrate in Reducing Breast Cancer Risk in Radiation-Induced Cancer Survivors

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm I (Tamoxifen Citrate) n=34 Participants Patients receive tamoxifen citrate PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Tamoxifen Citrate: 5 mg PO Daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies	Arm II (Placebo) n=38 Participants Patients receive placebo PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Placebo: 1 tablet daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies	Total n=72 Participants Total of all reporting groups
Age, Continuous	43.7 years n=9667 Participants	44.1 years n=6597 Participants	43.8 years n=16264 Participants
Sex: Female, Male Female	34 Participants n=9667 Participants	38 Participants n=6597 Participants	72 Participants n=16264 Participants
Sex: Female, Male Male	0 Participants n=9667 Participants	0 Participants n=6597 Participants	0 Participants n=16264 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=9667 Participants	5 Participants n=6597 Participants	8 Participants n=16264 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	31 Participants n=9667 Participants	33 Participants n=6597 Participants	64 Participants n=16264 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=9667 Participants	0 Participants n=6597 Participants	0 Participants n=16264 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=9667 Participants	0 Participants n=6597 Participants	0 Participants n=16264 Participants
Race (NIH/OMB) Asian	2 Participants n=9667 Participants	1 Participants n=6597 Participants	3 Participants n=16264 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=9667 Participants	0 Participants n=6597 Participants	0 Participants n=16264 Participants
Race (NIH/OMB) Black or African American	2 Participants n=9667 Participants	1 Participants n=6597 Participants	3 Participants n=16264 Participants
Race (NIH/OMB) White	30 Participants n=9667 Participants	36 Participants n=6597 Participants	66 Participants n=16264 Participants
Race (NIH/OMB) More than one race	0 Participants n=9667 Participants	0 Participants n=6597 Participants	0 Participants n=16264 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=9667 Participants	0 Participants n=6597 Participants	0 Participants n=16264 Participants
Region of Enrollment Canada	1 participants n=9667 Participants	2 participants n=6597 Participants	3 participants n=16264 Participants
Region of Enrollment United States	33 participants n=9667 Participants	36 participants n=6597 Participants	69 participants n=16264 Participants

PRIMARY outcome

Timeframe: At year two post treatment

Outcome measures

Outcome measures
Measure	Arm I (tamoxifen citrate) n=23 Participants Patients receive tamoxifen citrate PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Tamoxifen Citrate: 5 mg PO Daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies	Arm II (placebo) n=21 Participants Patients receive placebo PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Placebo: 1 tablet daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies
Mammographic Breast Density	45.2 percentage of fibrogladular tissue Standard Error 2.4	48.6 percentage of fibrogladular tissue Standard Error 2.5

SECONDARY outcome

Timeframe: Up to 2 years

IGF1 will be treated as a continuous measure. The linear mixed effects model for between group comparisons of measures from 3 time points will be applied. The unstructured mean model and linear in time model will be employed.

Outcome measures

Outcome measures
Measure	Arm I (tamoxifen citrate) n=34 Participants Patients receive tamoxifen citrate PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Tamoxifen Citrate: 5 mg PO Daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies	Arm II (placebo) n=38 Participants Patients receive placebo PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Placebo: 1 tablet daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies
Insulin Growth Factor Levels (IGF1)	144.3 ng/mL Standard Error 7.1	162.3 ng/mL Standard Error 7.2

SECONDARY outcome

Timeframe: Up to 2 years

Will be tabulated by treatment arm. Differences by treatment arm will be evaluated using Fisher exact tests.

Outcome measures

Outcome measures
Measure	Arm I (tamoxifen citrate) n=34 Participants Patients receive tamoxifen citrate PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Tamoxifen Citrate: 5 mg PO Daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies	Arm II (placebo) n=38 Participants Patients receive placebo PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Placebo: 1 tablet daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies
Number of Grade 2-4 Toxicities	77 Adverse Events	40 Adverse Events

SECONDARY outcome

Timeframe: Up to 2 years

Total cholesterol, low and high density lipoprotein, triglycerides, and anti-thrombin III enzymatic assay measurements will be treated as continuous variables. Transformed to normality as appropriate, the linear mixed effects model will be applied, using the unstructured mean model and linear in time model to assess the effects of low-dose tamoxifen on these measurements over time.

Outcome measures

Outcome measures
Measure	Arm I (tamoxifen citrate) n=34 Participants Patients receive tamoxifen citrate PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Tamoxifen Citrate: 5 mg PO Daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies	Arm II (placebo) n=38 Participants Patients receive placebo PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Placebo: 1 tablet daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies
Biomarker Levels Total Cholesterol	189.9 mg/dL Standard Error 7.1	192.5 mg/dL Standard Error 7.2
Biomarker Levels Low-density lipoprotein	105.4 mg/dL Standard Error 5.7	108.6 mg/dL Standard Error 5.8
Biomarker Levels High-density lipoprotein	57.6 mg/dL Standard Error 3.0	56.5 mg/dL Standard Error 3.0
Biomarker Levels Triglycerides	138.1 mg/dL Standard Error 13.2	116.6 mg/dL Standard Error 13.5
Biomarker Levels Anti-thrombin III	89.3 mg/dL Standard Error 5.4	98.1 mg/dL Standard Error 5.7

SECONDARY outcome

Timeframe: Up to 2 years

The number of pills taken out of the total prescribed in a 3-month period will be modeled as a random effects binomial regression model. The binomial rates from 8 time points (month 3-24) will be modeled as unstructured mean model with 7 indicator variables as well as polynomial models over time. The random-intercept and the random intercept and slope models will be considered. The significance of the time indicators or parameters by treatment interaction will be evaluated for treatment difference in compliance.

Outcome measures

Outcome measures
Measure	Arm I (tamoxifen citrate) n=34 Participants Patients receive tamoxifen citrate PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Tamoxifen Citrate: 5 mg PO Daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies	Arm II (placebo) n=38 Participants Patients receive placebo PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Placebo: 1 tablet daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies
Percentage of Pills Taken Out of the Total Prescribed	97.5 percentage of pills taken Interval 56.1 to 100.0	96.7 percentage of pills taken Interval 20.7 to 99.9

SECONDARY outcome

Timeframe: Up to 2 years

Population: Symptoms with \>10% prevalence are reported; patients were dichotomized into 2 groups: those that rated the symptom as moderately or extremely bothersome vs. slightly or quite a bit bothersome

The outcomes will be scored as a 5-point Likert-type scale (0-4) in response to questions on how much the patients are bothered by certain symptoms. The questionnaire will be administered every 6 months. The responses will be treated as normally distributed, as ordinal or dichotomized variable, and the linear mixed effects of general linear mixed model (GLMM) methods will be applied to compare changes between treatment groups. Piecewise models will also be fitted with join point at 6 months, considering linear and curvilinear trajectories between 6 and 24 month time points.

Outcome measures

Outcome measures
Measure	Arm I (tamoxifen citrate) n=34 Participants Patients receive tamoxifen citrate PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Tamoxifen Citrate: 5 mg PO Daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies	Arm II (placebo) n=38 Participants Patients receive placebo PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Placebo: 1 tablet daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies
Number of Participants With Different Patient Reported Symptoms, Measured by Questionnaire Interrupted sleep	16 participants	16 participants
Number of Participants With Different Patient Reported Symptoms, Measured by Questionnaire General aches or pains	14 participants	8 participants
Number of Participants With Different Patient Reported Symptoms, Measured by Questionnaire Hot flashes	13 participants	12 participants
Number of Participants With Different Patient Reported Symptoms, Measured by Questionnaire Joint pain or stiffness	12 participants	9 participants
Number of Participants With Different Patient Reported Symptoms, Measured by Questionnaire Feeling unusually tired	12 participants	10 participants
Number of Participants With Different Patient Reported Symptoms, Measured by Questionnaire Heartburn and/or acid stomach	11 participants	10 participants
Number of Participants With Different Patient Reported Symptoms, Measured by Questionnaire Headaches	11 participants	14 participants
Number of Participants With Different Patient Reported Symptoms, Measured by Questionnaire Muscle cramps or soreness	11 participants	8 participants

SECONDARY outcome

Timeframe: Up to 2 years

IGF3 will be treated as a continuous measure. The linear mixed effects model for between group comparisons of measures from 3 time points will be applied. The unstructured mean model and linear in time model will be employed.

Outcome measures

Outcome measures
Measure	Arm I (tamoxifen citrate) n=34 Participants Patients receive tamoxifen citrate PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Tamoxifen Citrate: 5 mg PO Daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies	Arm II (placebo) n=38 Participants Patients receive placebo PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Placebo: 1 tablet daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies
Insulin Growth Factor Levels (IGF3 )	4716.0 ng/mL Standard Error 168.0	4315.2 ng/mL Standard Error 170.8

SECONDARY outcome

Timeframe: Up to 2 years

Serum bone-specific alkaline phosphatase measurements will be treated as continuous variables. Transformed to normality as appropriate, the linear mixed effects model will be applied, using the unstructured mean model and linear in time model to assess the effects of low-dose tamoxifen on these measurements over time.

Outcome measures

Outcome measures
Measure	Arm I (tamoxifen citrate) n=34 Participants Patients receive tamoxifen citrate PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Tamoxifen Citrate: 5 mg PO Daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies	Arm II (placebo) n=38 Participants Patients receive placebo PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Placebo: 1 tablet daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies
Biomarker Levels - Alkaline Phosphatase	12.2 ug/L Standard Error 0.7	12.4 ug/L Standard Error 0.7

SECONDARY outcome

Timeframe: Up to 2 years

Urine n-telopeptide measurements will be treated as continuous variables. Transformed to normality as appropriate, the linear mixed effects model will be applied, using the unstructured mean model and linear in time model to assess the effects of low-dose tamoxifen on these measurements over time.

Outcome measures

Outcome measures
Measure	Arm I (tamoxifen citrate) n=34 Participants Patients receive tamoxifen citrate PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Tamoxifen Citrate: 5 mg PO Daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies	Arm II (placebo) n=38 Participants Patients receive placebo PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Placebo: 1 tablet daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies
Biomarker Levels - Urine N-telopeptide	33.1 nM Bone Collagen Equiv. / nM Creatinine Standard Error 3.6	32.0 nM Bone Collagen Equiv. / nM Creatinine Standard Error 3.8

Adverse Events

Arm I (Tamoxifen Citrate)

Serious events: 2 serious events

Other events: 26 other events

Deaths: 0 deaths

Arm II (Placebo)

Serious events: 3 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Arm I (Tamoxifen Citrate) n=34 participants at risk Patients receive tamoxifen citrate PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Tamoxifen Citrate: 5 mg PO Daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies	Arm II (Placebo) n=38 participants at risk Patients receive placebo PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Placebo: 1 tablet daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies
Cardiac disorders Myocardial infarction	2.9% 1/34 • Number of events 1 • Adverse events were collected every six months while the participants were on the two year study.	2.6% 1/38 • Number of events 1 • Adverse events were collected every six months while the participants were on the two year study.
Eye disorders Cataract	0.00% 0/34 • Adverse events were collected every six months while the participants were on the two year study.	2.6% 1/38 • Number of events 1 • Adverse events were collected every six months while the participants were on the two year study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm malignant	2.9% 1/34 • Number of events 1 • Adverse events were collected every six months while the participants were on the two year study.	2.6% 1/38 • Number of events 1 • Adverse events were collected every six months while the participants were on the two year study.

Other adverse events

Additional Information

Dr. Smita Bhatia

University of Alabama at Birmingham

Phone: (205) 638-2120

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Arm I (Tamoxifen Citrate) n=34 participants at risk Patients receive tamoxifen citrate PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Tamoxifen Citrate: 5 mg PO Daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies	Arm II (Placebo) n=38 participants at risk Patients receive placebo PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Placebo: 1 tablet daily Digital mammography: Correlative studies immunohistochemistry staining method: Correlative Studies pharmacological study: Correlative Studies laboratory biomarker analysis: Correlative Studies protein expression analysis: correlative studies pharmacogenomic studies: correlative studies questionnaire administration: Ancillary studies Fine needle aspiration Quality of Life Assessment: Ancillary Studies
Vascular disorders Hot flashes	23.5% 8/34 • Adverse events were collected every six months while the participants were on the two year study.	26.3% 10/38 • Adverse events were collected every six months while the participants were on the two year study.
Investigations Weight loss	20.6% 7/34 • Adverse events were collected every six months while the participants were on the two year study.	21.1% 8/38 • Adverse events were collected every six months while the participants were on the two year study.
Investigations Weight gain	26.5% 9/34 • Adverse events were collected every six months while the participants were on the two year study.	18.4% 7/38 • Adverse events were collected every six months while the participants were on the two year study.
Cardiac disorders Palpitations	8.8% 3/34 • Adverse events were collected every six months while the participants were on the two year study.	10.5% 4/38 • Adverse events were collected every six months while the participants were on the two year study.
Psychiatric disorders Psychiatric disorders - Other	26.5% 9/34 • Adverse events were collected every six months while the participants were on the two year study.	18.4% 7/38 • Adverse events were collected every six months while the participants were on the two year study.
Psychiatric disorders Depression	20.6% 7/34 • Adverse events were collected every six months while the participants were on the two year study.	18.4% 7/38 • Adverse events were collected every six months while the participants were on the two year study.
Psychiatric disorders Insomnia	11.8% 4/34 • Adverse events were collected every six months while the participants were on the two year study.	18.4% 7/38 • Adverse events were collected every six months while the participants were on the two year study.
Reproductive system and breast disorders Irregular menstruation	23.5% 8/34 • Adverse events were collected every six months while the participants were on the two year study.	15.8% 6/38 • Adverse events were collected every six months while the participants were on the two year study.
Nervous system disorders Headache	23.5% 8/34 • Adverse events were collected every six months while the participants were on the two year study.	15.8% 6/38 • Adverse events were collected every six months while the participants were on the two year study.
Endocrine disorders Endrocrine disorders - Other	17.6% 6/34 • Adverse events were collected every six months while the participants were on the two year study.	15.8% 6/38 • Adverse events were collected every six months while the participants were on the two year study.
Skin and subcutaneous tissue disorders Dry skin	17.6% 6/34 • Adverse events were collected every six months while the participants were on the two year study.	15.8% 6/38 • Adverse events were collected every six months while the participants were on the two year study.
Gastrointestinal disorders Dry mouth	8.8% 3/34 • Adverse events were collected every six months while the participants were on the two year study.	15.8% 6/38 • Adverse events were collected every six months while the participants were on the two year study.
Gastrointestinal disorders Diarrhea	17.6% 6/34 • Adverse events were collected every six months while the participants were on the two year study.	13.2% 5/38 • Adverse events were collected every six months while the participants were on the two year study.
Reproductive system and breast disorders Breast pain	17.6% 6/34 • Adverse events were collected every six months while the participants were on the two year study.	13.2% 5/38 • Adverse events were collected every six months while the participants were on the two year study.
Gastrointestinal disorders Constipation	17.6% 6/34 • Adverse events were collected every six months while the participants were on the two year study.	13.2% 5/38 • Adverse events were collected every six months while the participants were on the two year study.
General disorders Malaise	17.6% 6/34 • Adverse events were collected every six months while the participants were on the two year study.	13.2% 5/38 • Adverse events were collected every six months while the participants were on the two year study.
Nervous system disorders Dizziness	14.7% 5/34 • Adverse events were collected every six months while the participants were on the two year study.	13.2% 5/38 • Adverse events were collected every six months while the participants were on the two year study.
Reproductive system and breast disorders Reproductive system and breast disorders-Other	14.7% 5/34 • Adverse events were collected every six months while the participants were on the two year study.	15.8% 6/38 • Adverse events were collected every six months while the participants were on the two year study.
Gastrointestinal disorders Gastrointestinal disorders - other	14.7% 5/34 • Adverse events were collected every six months while the participants were on the two year study.	13.2% 5/38 • Adverse events were collected every six months while the participants were on the two year study.
Musculoskeletal and connective tissue disorders Arthralgia	14.7% 5/34 • Adverse events were collected every six months while the participants were on the two year study.	13.2% 5/38 • Adverse events were collected every six months while the participants were on the two year study.
General disorders Irritability	14.7% 5/34 • Adverse events were collected every six months while the participants were on the two year study.	13.2% 5/38 • Adverse events were collected every six months while the participants were on the two year study.
Reproductive system and breast disorders Vaginal Hemorrhage	11.8% 4/34 • Adverse events were collected every six months while the participants were on the two year study.	13.2% 5/38 • Adverse events were collected every six months while the participants were on the two year study.
Eye disorders Blurred vision	8.8% 3/34 • Adverse events were collected every six months while the participants were on the two year study.	13.2% 5/38 • Adverse events were collected every six months while the participants were on the two year study.
Gastrointestinal disorders Nausea	8.8% 3/34 • Adverse events were collected every six months while the participants were on the two year study.	13.2% 5/38 • Adverse events were collected every six months while the participants were on the two year study.
Skin and subcutaneous tissue disorders Rash maculo-papular	5.9% 2/34 • Adverse events were collected every six months while the participants were on the two year study.	13.2% 5/38 • Adverse events were collected every six months while the participants were on the two year study.
Renal and urinary disorders Urinary frequency	2.9% 1/34 • Adverse events were collected every six months while the participants were on the two year study.	13.2% 5/38 • Adverse events were collected every six months while the participants were on the two year study.
Nervous system disorders Somnolence	23.5% 8/34 • Adverse events were collected every six months while the participants were on the two year study.	10.5% 4/38 • Adverse events were collected every six months while the participants were on the two year study.
Reproductive system and breast disorders Vaginal discharge	23.5% 8/34 • Adverse events were collected every six months while the participants were on the two year study.	10.5% 4/38 • Adverse events were collected every six months while the participants were on the two year study.
Psychiatric disorders Restlessness	17.6% 6/34 • Adverse events were collected every six months while the participants were on the two year study.	10.5% 4/38 • Adverse events were collected every six months while the participants were on the two year study.
Musculoskeletal and connective tissue disorders Back pain	17.6% 6/34 • Adverse events were collected every six months while the participants were on the two year study.	10.5% 4/38 • Adverse events were collected every six months while the participants were on the two year study.
Gastrointestinal disorders Gastroesophageal reflux disease	17.6% 6/34 • Adverse events were collected every six months while the participants were on the two year study.	10.5% 4/38 • Adverse events were collected every six months while the participants were on the two year study.
Renal and urinary disorders Urinary incontinence	14.7% 5/34 • Adverse events were collected every six months while the participants were on the two year study.	10.5% 4/38 • Adverse events were collected every six months while the participants were on the two year study.
Gastrointestinal disorders Bloating	11.8% 4/34 • Adverse events were collected every six months while the participants were on the two year study.	10.5% 4/38 • Adverse events were collected every six months while the participants were on the two year study.
General disorders General disorders - Other	32.4% 11/34 • Adverse events were collected every six months while the participants were on the two year study.	7.9% 3/38 • Adverse events were collected every six months while the participants were on the two year study.
General disorders Fatigue	29.4% 10/34 • Adverse events were collected every six months while the participants were on the two year study.	7.9% 3/38 • Adverse events were collected every six months while the participants were on the two year study.
Nervous system disorders Nervous system disorders - Other	26.5% 9/34 • Adverse events were collected every six months while the participants were on the two year study.	7.9% 3/38 • Adverse events were collected every six months while the participants were on the two year study.
Injury, poisoning and procedural complications Bruising	23.5% 8/34 • Adverse events were collected every six months while the participants were on the two year study.	7.9% 3/38 • Adverse events were collected every six months while the participants were on the two year study.
Nervous system disorders Concentration impairment	20.6% 7/34 • Adverse events were collected every six months while the participants were on the two year study.	7.9% 3/38 • Adverse events were collected every six months while the participants were on the two year study.
General disorders Non-cardiac chest pain	5.9% 2/34 • Adverse events were collected every six months while the participants were on the two year study.	7.9% 3/38 • Adverse events were collected every six months while the participants were on the two year study.
Gastrointestinal disorders Dyspepsia	2.9% 1/34 • Adverse events were collected every six months while the participants were on the two year study.	7.9% 3/38 • Adverse events were collected every six months while the participants were on the two year study.
Skin and subcutaneous tissue disorders Rash acneiform	0.00% 0/34 • Adverse events were collected every six months while the participants were on the two year study.	7.9% 3/38 • Adverse events were collected every six months while the participants were on the two year study.
Respiratory, thoracic and mediastinal disorders Dyspnea	20.6% 7/34 • Adverse events were collected every six months while the participants were on the two year study.	5.3% 2/38 • Adverse events were collected every six months while the participants were on the two year study.
Nervous system disorders Paraesthesia	17.6% 6/34 • Adverse events were collected every six months while the participants were on the two year study.	5.3% 2/38 • Adverse events were collected every six months while the participants were on the two year study.
Nervous system disorders Memory impairment	17.6% 6/34 • Adverse events were collected every six months while the participants were on the two year study.	5.3% 2/38 • Adverse events were collected every six months while the participants were on the two year study.
Gastrointestinal disorders Flatulence	8.8% 3/34 • Adverse events were collected every six months while the participants were on the two year study.	5.3% 2/38 • Adverse events were collected every six months while the participants were on the two year study.
Musculoskeletal and connective tissue disorders Generalized muscle weakness	5.9% 2/34 • Adverse events were collected every six months while the participants were on the two year study.	5.3% 2/38 • Adverse events were collected every six months while the participants were on the two year study.
Renal and urinary disorders Cystitis noninfective	2.9% 1/34 • Adverse events were collected every six months while the participants were on the two year study.	5.3% 2/38 • Adverse events were collected every six months while the participants were on the two year study.
Musculoskeletal and connective tissue disorders Myalgia	17.6% 6/34 • Adverse events were collected every six months while the participants were on the two year study.	2.6% 1/38 • Adverse events were collected every six months while the participants were on the two year study.
Nervous system disorders Tremor	11.8% 4/34 • Adverse events were collected every six months while the participants were on the two year study.	2.6% 1/38 • Adverse events were collected every six months while the participants were on the two year study.
Respiratory, thoracic and mediastinal disorders Upper respiratory infection	8.8% 3/34 • Adverse events were collected every six months while the participants were on the two year study.	2.6% 1/38 • Adverse events were collected every six months while the participants were on the two year study.
Psychiatric disorders Agitation	5.9% 2/34 • Adverse events were collected every six months while the participants were on the two year study.	2.6% 1/38 • Adverse events were collected every six months while the participants were on the two year study.
Reproductive system and breast disorders Dyspareunia	11.8% 4/34 • Adverse events were collected every six months while the participants were on the two year study.	0.00% 0/38 • Adverse events were collected every six months while the participants were on the two year study.
Renal and urinary disorders Renal and urinary disorders - Other	5.9% 2/34 • Adverse events were collected every six months while the participants were on the two year study.	0.00% 0/38 • Adverse events were collected every six months while the participants were on the two year study.
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorder - Other	5.9% 2/34 • Adverse events were collected every six months while the participants were on the two year study.	0.00% 0/38 • Adverse events were collected every six months while the participants were on the two year study.
Reproductive system and breast disorders Pelvic pain	5.9% 2/34 • Adverse events were collected every six months while the participants were on the two year study.	0.00% 0/38 • Adverse events were collected every six months while the participants were on the two year study.