Trial Outcomes & Findings for Suppression of Ovarian Function With Either Tamoxifen or Exemestane Compared With Tamoxifen Alone in Treating Premenopausal Women With Hormone-Responsive Breast Cancer (NCT NCT00066690)

Last Updated: 2026-02-06

Results Overview

Estimated percentage of patients alive and disease-free at 5 years from randomization, where disease-free survival is defined as the time from randomization to the first appearance of one of the following: invasive breast cancer recurrence at local, regional, or distant site, invasive contralateral breast cancer, second (non-breast) invasive cancer, or death without cancer event; or censored at date of last follow-up.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

3066 participants

Primary outcome timeframe

5-year estimates, reported at a median follow-up of 67 months.

Results posted on

2026-02-06

Participant Flow

3066 patients were randomized between 17Dec03 and 27Jan11 at 426 centers in 25 countries.

Participant milestones

Participant milestones
Measure	Tamoxifen Tamoxifen 20mg orally daily for 5 years	T+OFS Tamoxifen 20mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)	E+OFS Exemestane 25mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)
Overall Study STARTED	1021	1024	1021
Overall Study COMPLETED	654	751	719
Overall Study NOT COMPLETED	367	273	302

Reasons for withdrawal

Reasons for withdrawal
Measure	Tamoxifen Tamoxifen 20mg orally daily for 5 years	T+OFS Tamoxifen 20mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)	E+OFS Exemestane 25mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)
Overall Study Adverse Event	146	70	135
Overall Study Death	3	0	2
Overall Study Lack of Efficacy	114	113	77
Overall Study Lost to Follow-up	50	33	39
Overall Study Withdrawal by Subject	54	57	49

Baseline Characteristics

Suppression of Ovarian Function With Either Tamoxifen or Exemestane Compared With Tamoxifen Alone in Treating Premenopausal Women With Hormone-Responsive Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tamoxifen n=1018 Participants Tamoxifen 20mg orally daily for 5 years	T+OFS n=1015 Participants Tamoxifen 20mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)	E+OFS n=1014 Participants Exemestane 25mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)	Total n=3047 Participants Total of all reporting groups
Tumor grade 2	48.33 percent of participants n=192 Participants	50.64 percent of participants n=170 Participants	53.65 percent of participants n=185 Participants	152.62 percent of participants n=177 Participants
Age, Continuous	43 years n=192 Participants	43 years n=170 Participants	43 years n=185 Participants	43 years n=177 Participants
Sex/Gender, Customized Female	100 percent of participants n=192 Participants	100 percent of participants n=170 Participants	100 percent of participants n=185 Participants	300 percent of participants n=177 Participants
Sex/Gender, Customized Male	0 percent of participants n=192 Participants	0 percent of participants n=170 Participants	0 percent of participants n=185 Participants	0 percent of participants n=177 Participants
Race/Ethnicity, Customized American Indian/Alaskan native	1 Participants n=192 Participants	5 Participants n=170 Participants	3 Participants n=185 Participants	9 Participants n=177 Participants
Race/Ethnicity, Customized Asian	36 Participants n=192 Participants	34 Participants n=170 Participants	33 Participants n=185 Participants	103 Participants n=177 Participants
Race/Ethnicity, Customized Black/African American	32 Participants n=192 Participants	27 Participants n=170 Participants	34 Participants n=185 Participants	93 Participants n=177 Participants
Race/Ethnicity, Customized Hawaiian/Pacific Islander	5 Participants n=192 Participants	4 Participants n=170 Participants	3 Participants n=185 Participants	12 Participants n=177 Participants
Race/Ethnicity, Customized White/Caucasian	877 Participants n=192 Participants	873 Participants n=170 Participants	866 Participants n=185 Participants	2616 Participants n=177 Participants
Race/Ethnicity, Customized Other	4 Participants n=192 Participants	2 Participants n=170 Participants	3 Participants n=185 Participants	9 Participants n=177 Participants
Race/Ethnicity, Customized Unknown	19 Participants n=192 Participants	22 Participants n=170 Participants	22 Participants n=185 Participants	63 Participants n=177 Participants
Race/Ethnicity, Customized Hispanic/Latino/South American native	44 Participants n=192 Participants	48 Participants n=170 Participants	50 Participants n=185 Participants	142 Participants n=177 Participants
Lymph-node status Negative	65.03 percent of participants n=192 Participants	65.22 percent of participants n=170 Participants	66.17 percent of participants n=185 Participants	196.42 percent of participants n=177 Participants
Lymph-node status Positive	34.97 percent of participants n=192 Participants	34.78 percent of participants n=170 Participants	33.83 percent of participants n=185 Participants	103.58 percent of participants n=177 Participants
Tumor size Unknown	2.65 percent of participants n=192 Participants	2.46 percent of participants n=170 Participants	2.07 percent of participants n=185 Participants	7.18 percent of participants n=177 Participants
Tumor size <=2 cm	66.40 percent of participants n=192 Participants	64.63 percent of participants n=170 Participants	66.86 percent of participants n=185 Participants	197.89 percent of participants n=177 Participants
Tumor size >2cm	30.94 percent of participants n=192 Participants	32.91 percent of participants n=170 Participants	31.07 percent of participants n=185 Participants	94.92 percent of participants n=177 Participants
Tumor grade Unknown	2.36 percent of participants n=192 Participants	2.36 percent of participants n=170 Participants	2.17 percent of participants n=185 Participants	6.89 percent of participants n=177 Participants
Tumor grade 1	27.01 percent of participants n=192 Participants	26.11 percent of participants n=170 Participants	24.36 percent of participants n=185 Participants	77.48 percent of participants n=177 Participants
Tumor grade 3	22.30 percent of participants n=192 Participants	20.89 percent of participants n=170 Participants	19.82 percent of participants n=185 Participants	63.01 percent of participants n=177 Participants
HER2-status Unknown	4.32 percent of participants n=192 Participants	2.86 percent of participants n=170 Participants	2.66 percent of participants n=185 Participants	9.84 percent of participants n=177 Participants
HER2-status Negative	84.18 percent of participants n=192 Participants	85.42 percent of participants n=170 Participants	84.52 percent of participants n=185 Participants	254.12 percent of participants n=177 Participants
HER2-status Positive	11.49 percent of participants n=192 Participants	11.72 percent of participants n=170 Participants	12.82 percent of participants n=185 Participants	36.03 percent of participants n=177 Participants

PRIMARY outcome

Timeframe: 5-year estimates, reported at a median follow-up of 67 months.

Population: Intention-to-treat

Outcome measures

Outcome measures
Measure	T+OFS n=1015 Participants Tamoxifen 20mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)	E+OFS n=1014 Participants Exemestane 25mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)	Tamoxifen n=1018 Participants Tamoxifen 20mg orally daily for 5 years
Disease-free Survival	86.6 percentage of participants Interval 84.2 to 88.7	89 percentage of participants Interval 86.8 to 90.9	84.7 percentage of participants Interval 82.2 to 86.9

SECONDARY outcome

Timeframe: 5-year estimates, reported at a median follow-up of 67 months.

Population: Intention-to-treat

Estimated percentage of patients alive and disease-free at 5 years from randomization, where breast cancer-free interval is defined as the time from randomization to invasive breast cancer recurrence at local, regional, or distant site, or invasive contralateral breast cancer; or censored at date of last follow up.

Outcome measures

Outcome measures
Measure	T+OFS n=1015 Participants Tamoxifen 20mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)	E+OFS n=1014 Participants Exemestane 25mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)	Tamoxifen n=1018 Participants Tamoxifen 20mg orally daily for 5 years
Breast Cancer-free Interval	88.4 percentage of participants Interval 86.1 to 90.3	90.9 percentage of participants Interval 88.9 to 92.6	86.4 percentage of participants Interval 84.0 to 88.5

SECONDARY outcome

Timeframe: 5-year estimates, reported at a median follow-up of 67 months.

Population: Intention-to-treat

Estimated percentage of patients alive and disease-free at 5 years from randomization, where distant recurrence-free Interval is defined as the time from randomization to invasive breast cancer recurrence at distant site, or invasive contralateral breast cancer; or censored at date of last follow up.

Outcome measures

Outcome measures
Measure	T+OFS n=1015 Participants Tamoxifen 20mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)	E+OFS n=1014 Participants Exemestane 25mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)	Tamoxifen n=1018 Participants Tamoxifen 20mg orally daily for 5 years
Distant Recurrence-free Interval	91.3 percentage of participants Interval 89.2 to 92.9	93.0 percentage of participants Interval 91.2 to 94.5	90.7 percentage of participants Interval 88.6 to 92.4

SECONDARY outcome

Timeframe: 8-year estimates, reported at a median follow-up of 8 years

Population: Intention-to-treat

Estimated percentage of patients alive at 8 years from randomization, where overall survival is defined as the time from randomization to death from any cause; or censored at date last known alive.

Outcome measures

Outcome measures
Measure	T+OFS n=1015 Participants Tamoxifen 20mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)	E+OFS n=1014 Participants Exemestane 25mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)	Tamoxifen n=1018 Participants Tamoxifen 20mg orally daily for 5 years
Overall Survival	93.3 percentage of participants Interval 91.4 to 94.8	92.1 percentage of participants Interval 90.0 to 93.7	91.5 percentage of participants Interval 89.4 to 93.2

Adverse Events

E+OFS

Serious events: 375 serious events

Other events: 980 other events

Deaths: 80 deaths

Tamoxifen

Serious events: 315 serious events

Other events: 951 other events

Deaths: 87 deaths

T+OFS

Serious events: 375 serious events

Other events: 982 other events

Deaths: 68 deaths

Serious adverse events

Other adverse events

Additional Information

Dr. Heidi Roschitzki-Voser, Head Trial Activities/Deputy Director

ETOP IBCSG Partners Foundation

Phone: +41 31 511 94 00

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Serious adverse events
Measure	E+OFS n=1001 participants at risk Exemestane 25mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)	Tamoxifen n=1007 participants at risk Tamoxifen 20mg orally daily for 5 years	T+OFS n=1007 participants at risk Tamoxifen 20mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)
Blood and lymphatic system disorders Hemoglobin	0.20% 2/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.20% 2/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.20% 2/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Cardiac disorders Cardiac Arrhythmia-Other (Specify)	0.00% 0/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Cardiac disorders Cardiac-ischemia/infarction	0.30% 3/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.40% 4/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Cardiac disorders Conduction abnormality/Atrioventricular heart block - AV block-third degree (complete AV block)	0.10% 1/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Cardiac disorders Conduction abnormality/Atrioventricular heart block - Sick sinus syndrome	0.10% 1/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Cardiac disorders Left ventricular diastolic dysfunction	0.10% 1/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Cardiac disorders Left ventricular systolic dysfunction	0.30% 3/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.20% 2/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Cardiac disorders Pain - Cardiac/heart	0.10% 1/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Cardiac disorders Restrictive cardiomyopathy	0.10% 1/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Cardiac disorders Right ventricular dysfunction (cor pulmonale)	0.10% 1/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Cardiac disorders Supraventricular and nodal arrhythmia - Atrial fibrillation	0.10% 1/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Cardiac disorders Supraventricular and nodal arrhythmia - Sinus arrhythmia	0.00% 0/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Cardiac disorders Supraventricular and nodal arrhythmia - Supraventricular tachycardia	0.00% 0/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Cardiac disorders Valvular heart disease	0.00% 0/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.20% 2/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Ear and labyrinth disorders Auditory/Ear-Other (Specify)	0.00% 0/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Ear and labyrinth disorders Hearing: patients without baseline audiogram and not enrolled in a monitoring program	0.10% 1/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Endocrine disorders Thyroid function, high (hyperthyroidism, thyrotoxicosis)	0.10% 1/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Endocrine disorders Thyroid function, low (hypothyroidism)	0.10% 1/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Endocrine disorders Adrenal insufficiency	0.00% 0/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Endocrine disorders Endocrine-Other (Specify)	0.00% 0/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Eye disorders Cataract	0.10% 1/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Eye disorders Ocular/Visual-Other (Specify)	0.00% 0/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Eye disorders Optic disc edema	0.10% 1/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Eye disorders Retinal detachment	0.10% 1/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.30% 3/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Eye disorders Vision-flashing lights/floaters	0.10% 1/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Gastrointestinal disorders Distention/bloating, abdominal	0.00% 0/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Gastrointestinal disorders Necrosis, GI - Ileum	0.00% 0/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Gastrointestinal disorders Obstruction, GI - Small bowel NOS	0.00% 0/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Gastrointestinal disorders Stricture/stenosis (including anastomotic), GI - Small bowel NOS	0.10% 1/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Gastrointestinal disorders Ulcer, GI - Anus	0.00% 0/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Gastrointestinal disorders Colitis	0.10% 1/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.20% 2/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Gastrointestinal disorders Constipation	0.00% 0/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Gastrointestinal disorders Diarrhea	0.10% 1/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.20% 2/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Gastrointestinal disorders Dysphagia (difficulty swallowing)	0.00% 0/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Gastrointestinal disorders Gastrointestinal-Other (Specify)	0.20% 2/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.20% 2/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Gastrointestinal disorders Heartburn/dyspepsia	0.10% 1/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Gastrointestinal disorders Hemorrhoids	0.10% 1/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Gastrointestinal disorders Mucositis/stomatitis (functional/symptomatic) - Oral cavity	0.00% 0/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Gastrointestinal disorders Nausea	0.20% 2/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.00% 0/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.40% 4/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Gastrointestinal disorders Pain - Abdomen NOS	0.40% 4/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.30% 3/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.30% 3/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.

Other adverse events
Measure	E+OFS n=1001 participants at risk Exemestane 25mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)	Tamoxifen n=1007 participants at risk Tamoxifen 20mg orally daily for 5 years	T+OFS n=1007 participants at risk Tamoxifen 20mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)
Cardiac disorders Cardiac-ischemia/infarction	0.50% 5/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.20% 2/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Gastrointestinal disorders Nausea	22.8% 228/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	23.7% 239/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	21.4% 215/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
General disorders Fatigue (asthenia, lethargy, malaise)	59.0% 591/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	56.7% 571/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	59.1% 595/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
General disorders Injection site reaction/extravasation changes	8.4% 84/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.40% 4/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	8.7% 88/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Immune system disorders Allergic reaction/hypersensitivity (including drug fever)	4.6% 46/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	3.1% 31/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	4.2% 42/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Injury, poisoning and procedural complications Fracture	5.1% 51/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	4.1% 41/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	4.6% 46/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Injury, poisoning and procedural complications Thrombosis/embolism (vascular access-related)	0.20% 2/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.50% 5/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.30% 3/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Metabolism and nutrition disorders Glucose, serum-high (hyperglycemia)	1.7% 17/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	1.5% 15/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	3.7% 37/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Metabolism and nutrition disorders Pancreatic endocrine: glucose intolerance	2.8% 28/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	1.5% 15/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	2.1% 21/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Musculoskeletal and connective tissue disorders Osteoporosis	31.6% 316/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	12.2% 123/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	19.7% 198/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Musculoskeletal and connective tissue disorders Pain - Joint	77.7% 778/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	62.7% 631/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	69.5% 700/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Nervous system disorders Hemorrhage, CNS	0.80% 8/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	1.4% 14/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.89% 9/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Nervous system disorders CNS cerebrovascular ischemia	0.00% 0/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.20% 2/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	0.10% 1/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Psychiatric disorders Insomnia	54.8% 549/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	43.4% 437/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	52.5% 529/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Psychiatric disorders Libido	49.2% 492/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	42.4% 427/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	47.4% 477/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Psychiatric disorders Mood alteration - depression	47.6% 476/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	42.8% 431/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	47.5% 478/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Renal and urinary disorders Incontinence, urinary	12.0% 120/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	15.5% 156/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	17.9% 180/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Reproductive system and breast disorders Pain - Vagina	29.0% 290/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	22.2% 224/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	23.8% 240/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Reproductive system and breast disorders Vaginal dryness	54.0% 541/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	41.8% 421/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	49.7% 500/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Skin and subcutaneous tissue disorders Sweating (diaphoresis)	56.5% 566/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	48.3% 486/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	61.7% 621/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Vascular disorders Hot flashes/flushes	81.9% 820/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	72.2% 727/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	80.0% 806/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Vascular disorders Hypertension	16.5% 165/1001 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	11.8% 119/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.	15.7% 158/1007 • Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months. Targeted AEs and other grade 3 or higher AEs were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.