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Clinical Trial Results:
A phase III trial evaluating the role of ovarian function suppression and the role of exemestane as adjuvant therapies for premenopausal women with endocrine responsive breast cancer.

Summary
EudraCT number	2004-000166-13
Trial protocol	DK SE DE ES IE HU
Global end of trial date

Results information
Results version number	v1(current)
This version publication date	05 May 2021
First version publication date	05 May 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

IBCSG 24-02 BIG 2-02 SOFT

ISRCTN number

-

US NCT number

NCT00066690

WHO universal trial number (UTN)

-

Sponsor organisation name

IBCSG

Sponsor organisation address

Effingerstrasse 40, Bern, Switzerland, 3008

Public contact

IBCSG Coordinating Center, International Breast Cancer Study Group (IBCSG), +41 31 511 94 00, regulatoryoffice@ibcsg.org

Scientific contact

IBCSG Coordinating Center, International Breast Cancer Study Group (IBCSG), +41 31 511 94 00, regulatoryoffice@ibcsg.org

Is trial part of an agreed paediatric investigation plan (PIP)

No

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Analysis stage

Interim

Date of interim/final analysis

31 Mar 2014

Is this the analysis of the primary completion data?

Yes

Primary completion date

31 Mar 2014

Global end of trial reached?

No

Main objective of the trial

This trial will evaluate the worth of ovarian function suppression (achieved by either long-term use of GnRH analogue or surgical oophorectomy or ovarian irradiation) plus tamoxifen compared with tamoxifen alone for premenopausal women with steroid hormone receptor positive early invasive breast cancer who either receive no adjuvant chemotherapy or remain premenopausal following adjuvant and/or neoadjuvant chemotherapy. In addition, the worth of exemestane will be evaluated for this premenopausal patient population by comparing ovarian function suppression plus exemestane with tamoxifen alone and by comparing ovarian function suppression plus exemestane with ovarian function suppression plus tamoxifen.

Protection of trial subjects

In compliance with GDPR. Adverse events were reported and in case of adverse events and treatment-related toxicities management guidance was provided in the study protocol to treat trial subjects in adequately manner. The safety of the trial treatment was regularly reviewed by the IBCSG Data Safety Monitoring Committee (DSMC).

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

04 Aug 2003

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

11 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 74

Country: Number of subjects enrolled

Australia: 182

Country: Number of subjects enrolled

New Zealand: 58

Country: Number of subjects enrolled

Brazil: 6

Country: Number of subjects enrolled

Chile: 72

Country: Number of subjects enrolled

India: 52

Country: Number of subjects enrolled

Italy: 288

Country: Number of subjects enrolled

Peru: 53

Country: Number of subjects enrolled

Switzerland: 114

Country: Number of subjects enrolled

South Africa: 13

Country: Number of subjects enrolled

Belgium: 122

Country: Number of subjects enrolled

Israel: 8

Country: Number of subjects enrolled

Netherlands: 11

Country: Number of subjects enrolled

Turkey: 17

Country: Number of subjects enrolled

Poland: 2

Country: Number of subjects enrolled

Serbia: 9

Country: Number of subjects enrolled

United States: 1030

Country: Number of subjects enrolled

Portugal: 31

Country: Number of subjects enrolled

Spain: 451

Country: Number of subjects enrolled

Sweden: 62

Country: Number of subjects enrolled

France: 194

Country: Number of subjects enrolled

Germany: 54

Country: Number of subjects enrolled

Hungary: 150

Country: Number of subjects enrolled

Ireland: 13

Worldwide total number of subjects

3066

EEA total number of subjects

1452

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

3066

From 65 to 84 years

0

85 years and over

0

Subject disposition

Top of page

Recruitment details

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

Screening details

This trial used a web-based randomization system. Each Participating Group determined how its Participating Centers will access the randomization system, either through a Group Randomization Center, or directly from the Participating Center.

Period 1 title

Overall study

Is this the baseline period?

No

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Tamoxifen

Arm description

Tamoxifen 20mg orally daily for 5 years

Arm type

Active comparator

Investigational medicinal product name

Tamoxifen

Investigational medicinal product code

Other name

Apo-Tamox, Clonoxifen, Dignotamoxi, Ebefen, Emblon, Estroxyn, Fentamox, Gen-Tamoxifen, Genox, ICI 46.474, ICI-46474, Jenoxifen, Kessar, Ledertam, Lesporene

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tamoxifen 20mg orally daily for 5 years

T+OFS

Arm description

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)

Arm type

Experimental

Investigational medicinal product name

Tamoxifen

Investigational medicinal product code

Other name

Apo-Tamox, Clonoxifen, Dignotamoxi, Ebefen, Emblon, Estroxyn, Fentamox, Gen-Tamoxifen, Genox, ICI 46.474, ICI-46474, Jenoxifen, Kessar, Ledertam, Lesporene

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tamoxifen 20mg orally daily for 5 years

Investigational medicinal product name

Triptorelin

Investigational medicinal product code

Other name

6-D-Tryptophan-LH-RH, 6-D-Tryptophanluteinizing Hormone-releasing Factor, AY-25650, CL-118532, Decapeptyl, Detryptoreline, GnRH analogue, Trelstar Depot, Decape

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

3.75 mg by im injection q28 days for 5 years

E + OFS

Arm description

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)

Arm type

Experimental

Investigational medicinal product name

Exemestane

Investigational medicinal product code

Other name

Aromasin, FCE-24304

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

25mg orally daily for 5 years

Investigational medicinal product name

Triptorelin

Investigational medicinal product code

Other name

6-D-Tryptophan-LH-RH, 6-D-Tryptophanluteinizing Hormone-releasing Factor, AY-25650, CL-118532, Decapeptyl, Detryptoreline, GnRH analogue, Trelstar Depot, Decape

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

3.75 mg by im injection q28 days for 5 years

Number of subjects in period 1	Tamoxifen	T+OFS	E + OFS
Started	1021	1024	1021
Completed	1018	1015	1014
Not completed	3	9	7
Consent withdrawn by subject	3	9	7

Period 2 title

ITT analysis

Is this the baseline period?

Yes ^[1]

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Tamoxifen

Arm description

Tamoxifen 20mg orally daily for 5 years

Arm type

Active comparator

Investigational medicinal product name

Tamoxifen

Investigational medicinal product code

Other name

Apo-Tamox, Clonoxifen, Dignotamoxi, Ebefen, Emblon, Estroxyn, Fentamox, Gen-Tamoxifen, Genox, ICI 46.474, ICI-46474, Jenoxifen, Kessar, Ledertam, Lesporene

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tamoxifen 20mg orally daily for 5 years

T+OFS

Arm description

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)

Arm type

Experimental

Investigational medicinal product name

Tamoxifen

Investigational medicinal product code

Other name

Apo-Tamox, Clonoxifen, Dignotamoxi, Ebefen, Emblon, Estroxyn, Fentamox, Gen-Tamoxifen, Genox, ICI 46.474, ICI-46474, Jenoxifen, Kessar, Ledertam, Lesporene

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tamoxifen 20mg orally daily for 5 years

Investigational medicinal product name

Triptorelin

Investigational medicinal product code

Other name

6-D-Tryptophan-LH-RH, 6-D-Tryptophanluteinizing Hormone-releasing Factor, AY-25650, CL-118532, Decapeptyl, Detryptoreline, GnRH analogue, Trelstar Depot, Decape

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

3.75 mg by im injection q28 days for 5 years

E + OFS

Arm description

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)

Arm type

Experimental

Investigational medicinal product name

Exemestane

Investigational medicinal product code

Other name

Aromasin, FCE-24304

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

25mg orally daily for 5 years

Investigational medicinal product name

Triptorelin

Investigational medicinal product code

Other name

6-D-Tryptophan-LH-RH, 6-D-Tryptophanluteinizing Hormone-releasing Factor, AY-25650, CL-118532, Decapeptyl, Detryptoreline, GnRH analogue, Trelstar Depot, Decape

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

3.75 mg by im injection q28 days for 5 years

Notes
[1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: Baseline characteristics were only reported for Intention-to-treat population

Number of subjects in period 2 ^[2]	Tamoxifen	T+OFS	E + OFS
Started	1018	1015	1014
Completed	1018	1015	1014

Notes
[2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Intention-to-treat population, excludes 19 patients who immediately withdrew consent.

Baseline characteristics

Top of page

Reporting group title

Tamoxifen

Reporting group description

Tamoxifen 20mg orally daily for 5 years

Reporting group title

T+OFS

Reporting group description

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)

Reporting group title

E + OFS

Reporting group description

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)

Reporting group values	Tamoxifen	T+OFS	E + OFS	Total
Number of subjects	1018	1015	1014	3047
Age categorical
Units: Subjects
In utero				0
Preterm newborn infants (gestational age < 37 wks)				0
Newborns (0-27 days)				0
Infants and toddlers (28 days-23 months)				0
Children (2-11 years)				0
Adolescents (12-17 years)				0
Adults (18-64 years)				0
From 65-84 years				0
85 years and over				0
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	43 (38 to 46)	43 (38 to 47)	43 (38 to 47)	-
Gender categorical
Units: Subjects
Female	1018	1015	1014	3047
Male	0	0	0	0
Race/Ethnicity
Units: Subjects
American Indian/Alaskan native	1	5	3	9
Asian	36	34	33	103
Black/African American	32	27	34	93
Hawaiian/Pacific Islander	5	4	3	12
White/Caucasian	877	873	866	2616
Other	4	2	3	9
Unknown	19	22	22	63
Hispanic/Latino/South American native	44	48	50	142

End points

Top of page

Reporting group title

Tamoxifen

Reporting group description

Tamoxifen 20mg orally daily for 5 years

Reporting group title

T+OFS

Reporting group description

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)

Reporting group title

E + OFS

Reporting group description

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)

Reporting group title

Tamoxifen

Reporting group description

Tamoxifen 20mg orally daily for 5 years

Reporting group title

T+OFS

Reporting group description

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)

Reporting group title

E + OFS

Reporting group description

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)

Primary: Disease-free Survival

Top of page

End point title

Disease-free Survival

End point description

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.

End point type

Primary

End point timeframe

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

End point values	Tamoxifen	T+OFS	E + OFS
Number of subjects analysed	1018	1015	1014
Units: Percentage of participants
number (confidence interval 95%)	84.7 (82.2 to 86.9)	86.6 (84.2 to 88.7)	89 (86.8 to 90.9)

Statistical analysis 1

Statistical analysis description

Tamoxifen, T+OFS

Comparison groups

Tamoxifen v T+OFS

Number of subjects included in analysis

2033

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.83

Confidence interval

level

95%

sides

2-sided

lower limit

0.66

upper limit

1.04

Statistical analysis 2

Statistical analysis description

Tamoxifen, E+OFS

Comparison groups

Tamoxifen v E + OFS

Number of subjects included in analysis

2032

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.68

Confidence interval

level

95%

sides

2-sided

lower limit

0.53

upper limit

0.86

Secondary: Breast Cancer-free Interval

Top of page

End point title

Breast Cancer-free Interval

End point description

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.

End point type

Secondary

End point timeframe

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

End point values	Tamoxifen	T+OFS	E + OFS
Number of subjects analysed	1018	1015	1014
Units: Percentage of participants
number (confidence interval 85%)	86.4 (84.0 to 88.5)	88.4 (86.1 to 90.3)	90.9 (88.9 to 92.6)

Statistical analysis 1

Statistical analysis description

Tamoxifen, T+OFS

Comparison groups

Tamoxifen v T+OFS

Number of subjects included in analysis

2033

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.09

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.81

Confidence interval

level

95%

sides

2-sided

lower limit

0.3

upper limit

1.03

Statistical analysis 2

Statistical analysis description

Tamoxifen, E+OFS

Comparison groups

Tamoxifen v E + OFS

Number of subjects included in analysis

2032

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.64

Confidence interval

level

95%

sides

2-sided

lower limit

0.49

upper limit

0.83

Secondary: Distant Recurrence-free Interval

Top of page

End point title

Distant Recurrence-free Interval

End point description

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.

End point type

Secondary

End point timeframe

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

End point values	Tamoxifen	T+OFS	E + OFS
Number of subjects analysed	1018	1015	1014
Units: Percentage of participants
number (confidence interval 95%)	90.7 (88.6 to 92.4)	91.3 (89.2 to 92.9)	93.0 (91.2 to 94.5)

Statistical analysis 1

Statistical analysis description

Tamoxifen, T+OFS

Comparison groups

Tamoxifen v T+OFS

Number of subjects included in analysis

2033

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.66

upper limit

1.18

Statistical analysis 2

Statistical analysis description

Tamoxifen, E+OFS

Comparison groups

Tamoxifen v E + OFS

Number of subjects included in analysis

2032

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.71

Confidence interval

level

95%

sides

2-sided

lower limit

0.52

upper limit

0.96

Secondary: Overall Survival

Top of page

End point title

Overall Survival

End point description

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.

End point type

Secondary

End point timeframe

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

End point values	Tamoxifen	T+OFS	E + OFS
Number of subjects analysed	1018	1015	1014
Units: Percentage of participants
number (confidence interval 95%)	91.5 (89.4 to 93.2)	93.3 (91.4 to 94.8)	92.1 (90.0 to 93.7)

Statistical analysis 1

Statistical analysis description

Tamoxifen, T+OFS

Comparison groups

Tamoxifen v T+OFS

Number of subjects included in analysis

2033

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.01

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.48

upper limit

0.92

Statistical analysis 2

Comparison groups

Tamoxifen v E + OFS

Number of subjects included in analysis

2032

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.62

upper limit

1.15

Adverse events

Top of page

Timeframe for reporting adverse events

Assessed every 3 months for the first year, then every 6 month until year 6. Reported at a median follow-up of 67 months.

Adverse event reporting additional description

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.

Assessment type

Systematic

Dictionary name

NCI CTCAE

Dictionary version

3.0

Reporting group title

Tamoxifen

Reporting group description

The safety population EXCLUDES patients who never started protocol-assigned therapy.

Reporting group title

T+OFS

Reporting group description

The safety population EXCLUDES patients who never started protocol-assigned therapy.

Reporting group title

E+OFS

Reporting group description

-

Serious adverse events	Tamoxifen	T+OFS	E+OFS
Total subjects affected by serious adverse events
subjects affected / exposed	315 / 1007 (31.28%)	375 / 1007 (37.24%)	375 / 1001 (37.46%)
number of deaths (all causes)	3	0	3
number of deaths resulting from adverse events
Vascular disorders
Postoperative bleeding (breast reconstruction) leading to severe anemia
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Subarachnoidale hemorrhage
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Central vein thrombosis (L eye)
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Deep Vein Thrombosis
subjects affected / exposed	10 / 1007 (0.99%)	6 / 1007 (0.60%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	10 / 10	6 / 6	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Ischemic Necrosis of Ileum and Jejunum
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Peripheral arterial ischemia
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Pulmonary Embolism
subjects affected / exposed	1 / 1007 (0.10%)	3 / 1007 (0.30%)	3 / 1001 (0.30%)
occurrences causally related to treatment / all	1 / 1	3 / 3	2 / 3
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Superficial Vein Thrombosis
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	2 / 1001 (0.20%)
occurrences causally related to treatment / all	0 / 0	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Thrombosis
subjects affected / exposed	2 / 1007 (0.20%)	2 / 1007 (0.20%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	1 / 2	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Surgical and medical procedures
Induced/elective abortion 8 weeks in to pregnancy
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Pregnancy, puerperium and perinatal conditions
Pregnancy
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
General disorders and administration site conditions
Fatigue (asthenia, lethargy, malaise)
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Insomnia
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Obesity
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Postoperative fever (in the abscence of neutropenia)
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Immune system disorders
Allergic reaction
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	3 / 1001 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Reproductive system and breast disorders
Pain Left Breast
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Adnexal and Ovarian Lesion
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Cervical Polyp
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Cervical Dysplasia
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Endometrial Hyperplasia
subjects affected / exposed	15 / 1007 (1.49%)	6 / 1007 (0.60%)	5 / 1001 (0.50%)
occurrences causally related to treatment / all	15 / 15	5 / 6	4 / 5
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Endometrial Polyp
subjects affected / exposed	8 / 1007 (0.79%)	3 / 1007 (0.30%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	9 / 9	3 / 3	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
High grade squamous intraepithelial lesion
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Intramural leiomyoma leading to hemorrhage
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Irregular Menses
subjects affected / exposed	1 / 1007 (0.10%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Ovarian Cyst
subjects affected / exposed	24 / 1007 (2.38%)	2 / 1007 (0.20%)	2 / 1001 (0.20%)
occurrences causally related to treatment / all	26 / 26	2 / 2	0 / 2
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Uterine Adenomyosis
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Uterine Fibroma
subjects affected / exposed	5 / 1007 (0.50%)	3 / 1007 (0.30%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	3 / 5	3 / 3	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Uterine Myoma
subjects affected / exposed	2 / 1007 (0.20%)	2 / 1007 (0.20%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	2 / 2	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Uterine Polyp
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Uterine prolapse
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Vaginal Bleeding
subjects affected / exposed	8 / 1007 (0.79%)	2 / 1007 (0.20%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	6 / 8	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Atypical Ductal Hyperplasia and Fibroadenoma (R Breast)
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Benign fibroadenoma R breast
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Respiratory, thoracic and mediastinal disorders
Atypical pleuritic pain
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Chest Pain
subjects affected / exposed	3 / 1007 (0.30%)	4 / 1007 (0.40%)	6 / 1001 (0.60%)
occurrences causally related to treatment / all	0 / 3	1 / 4	1 / 6
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Pain Chest wall
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Acute respiratory insufficiency
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Dyspnea due to Enlarged Uvula
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Exacerbation of COPD
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Pleural Effusion (Left)
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Pulmonary Xanthofibroma
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Respiratory Failure
subjects affected / exposed	1 / 1007 (0.10%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Endometriosis
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Injury, poisoning and procedural complications
Death (cause unknown)
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	1 / 3
Death (mixed drug intoxication)
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 3	0 / 0	0 / 3
Dural leak after lumbar fusion surgery
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Post-operative hematoma after oophorectomy
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Cardiac disorders
Anemia post surgery
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
AV-Block Grade III
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Palpitations
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Prolonged QT and sinus bradycardia
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Sinus Carotis Syndrome requiring pacemaker implantation
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Cardiac Failure
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	1 / 3	0 / 0	0 / 3
Cardiac ischemia
subjects affected / exposed	1 / 1007 (0.10%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Congestive Heart Failure
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	2 / 1001 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Dilated cardiomyopathy in context of congenital abnormality
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Hypertension
subjects affected / exposed	0 / 1007 (0.00%)	2 / 1007 (0.20%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Left ventricular systolic dysfunction
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Myocardial Infarction
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Severe Mitral Insufficiency
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Nervous system disorders
Anxiety
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Carpal Tunnel Syndrome
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	3 / 1001 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Cerebrovascular Accident
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	2 / 1001 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Cerebrovascular Ischemia
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
CNS Cerebrovascular ischemia
subjects affected / exposed	3 / 1007 (0.30%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Concussion cerebri
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Depression
subjects affected / exposed	5 / 1007 (0.50%)	5 / 1007 (0.50%)	3 / 1001 (0.30%)
occurrences causally related to treatment / all	3 / 6	3 / 5	2 / 3
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Dizziness
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	3 / 1001 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Hot flushes leading to syncope
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Multiple Sclerosis
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 3	0 / 0	0 / 3
Neuromyelitis optica
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Neuropathy: sensory
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Partial Amnesia
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Personality/Behavioral
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Suicide attempt
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Syncope
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	2 / 1001 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Trigeminal neuralgia
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Vestibular neuropathy
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Eye disorders
Cataract and Retinal Detachment (R Eye)
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Intermittent blurred vision L eye
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Papilledema bilateral
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Retinal Detachment
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Gastrointestinal disorders
Abdominal Pain
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Acute Appendicitis
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Anal Fissure
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Colitis
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Dehydration due to vomiting and diarrhea
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Gastrointestinal Obstruction (small bowel)
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Inguinal Hernia
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Pyloric Ulcer
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Gastric ulcer
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Gastrointestinal Bleeding
subjects affected / exposed	2 / 1007 (0.20%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Pain Abdomen NOS
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Gastroenteritis
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Ischemic Colitis
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	2 / 1001 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	2 / 1007 (0.20%)	4 / 1007 (0.40%)	4 / 1001 (0.40%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 3	0 / 0	1 / 3
Cholecystolithiasis
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Cholecystolithiasis requiring surgery
subjects affected / exposed	3 / 1007 (0.30%)	1 / 1007 (0.10%)	2 / 1001 (0.20%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Choledocholithiasis
subjects affected / exposed	2 / 1007 (0.20%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Cholelithiasis
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Hepatic Adenoma
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Hepatic steatosis
subjects affected / exposed	1 / 1007 (0.10%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Liver dysfunction (ethylic hepatitis)
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	1 / 3
Pancreatitis
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	4 / 1001 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Cellulitis
subjects affected / exposed	4 / 1007 (0.40%)	10 / 1007 (0.99%)	7 / 1001 (0.70%)
occurrences causally related to treatment / all	0 / 4	0 / 11	0 / 7
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Skin and subcutaneous tissue disorders
Acute generalized pustular dermatosis
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Rash pustular
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Renal and urinary disorders
Hydronephrosis
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Nephrolithiasis
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Renal failure
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Ureteral Obstruction
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Ureteral stenosis (L)
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	2 / 1001 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Urinary Incontinence
subjects affected / exposed	2 / 1007 (0.20%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Endocrine disorders
Bilateral hyperplasia of adrenal glands
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Diabetes mellitus Type 1
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Diabetes mellitus type 2
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Follicular hyperplasia of thyroid gland
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Hyperparathyroidism
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Pheochromocytoma
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Schwannoma L benign requiring parotidectomy
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Struma nodosa
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Thyroid Nodule (R Thyroid)
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	2 / 1001 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Bone Fracture
subjects affected / exposed	16 / 1007 (1.59%)	10 / 1007 (0.99%)	24 / 1001 (2.40%)
occurrences causally related to treatment / all	2 / 16	4 / 10	20 / 28
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Diaphragmatic lesions (benign)
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Discus Hernia
subjects affected / exposed	1 / 1007 (0.10%)	1 / 1007 (0.10%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Dislocation of hip prosthesis R
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Meniscus Lesion
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Osteoarthritis
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Rheumatoid arthritis leading to R knee replacement
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Spondylolisthesis requiring surgery (lumbal fusion L4-5)
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Wound dehiscence
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Back pain
subjects affected / exposed	2 / 1007 (0.20%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Joint pain
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Polytrauma
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Breast implant infection
subjects affected / exposed	1 / 1007 (0.10%)	1 / 1007 (0.10%)	2 / 1001 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Breast Infection
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Bursitis and cellulitis (L Elbow)
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Chest Wall Infection
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
CMV Colitis, UTI and Pneumonia
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Colitis and Urinary Infection
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Erysipelas (R Arm)
subjects affected / exposed	0 / 1007 (0.00%)	2 / 1007 (0.20%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Infected ingrown toe nail
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Infection (MRSA)
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Infective endocarditis after mitral valve replacement
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Influenza A
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
L breast abscess
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Meningitis
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Peri-rectal abscess
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Pneumonia
subjects affected / exposed	2 / 1007 (0.20%)	4 / 1007 (0.40%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 2	0 / 8	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Pneumonia/Pleuritis
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Postoperative infection
subjects affected / exposed	0 / 1007 (0.00%)	3 / 1007 (0.30%)	4 / 1001 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Pyelonephritis
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Recurrent urinary tract infections
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Sepsis
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Septic Shock
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Skin infection
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Superinfection of Posttraumatic Hematoma (R Shank)
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Urinary tract infection
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Urosepsis
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Ventriculoperitoneal shunt infection
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Wound Infection
subjects affected / exposed	3 / 1007 (0.30%)	2 / 1007 (0.20%)	2 / 1001 (0.20%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Metabolism and nutrition disorders
Dyspnea and Fatigue
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Hypoglycemia
subjects affected / exposed	0 / 1007 (0.00%)	0 / 1007 (0.00%)	1 / 1001 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Hypokalemia
subjects affected / exposed	0 / 1007 (0.00%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3
Increased GGT Levels
subjects affected / exposed	1 / 1007 (0.10%)	0 / 1007 (0.00%)	0 / 1001 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Tamoxifen	T+OFS	E+OFS
Total subjects affected by non serious adverse events
subjects affected / exposed	951 / 1007 (94.44%)	982 / 1007 (97.52%)	980 / 1001 (97.90%)
Vascular disorders
Hot flashes/flushes
subjects affected / exposed	727 / 1007 (72.19%)	806 / 1007 (80.04%)	820 / 1001 (81.92%)
occurrences all number	727	806	820
Hypertension
subjects affected / exposed	119 / 1007 (11.82%)	158 / 1007 (15.69%)	165 / 1001 (16.48%)
occurrences all number	119	158	165
General disorders and administration site conditions
Fatigue (asthenia, lethargy, malaise)
subjects affected / exposed	571 / 1007 (56.70%)	595 / 1007 (59.09%)	591 / 1001 (59.04%)
occurrences all number	571	595	591
Injection site reaction/extravasation changes
subjects affected / exposed	4 / 1007 (0.40%)	88 / 1007 (8.74%)	84 / 1001 (8.39%)
occurrences all number	4	88	84
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)
subjects affected / exposed	31 / 1007 (3.08%)	42 / 1007 (4.17%)	46 / 1001 (4.60%)
occurrences all number	31	42	46
Reproductive system and breast disorders
Pain - Vagina
subjects affected / exposed	224 / 1007 (22.24%)	240 / 1007 (23.83%)	290 / 1001 (28.97%)
occurrences all number	224	240	290
Vaginal dryness
subjects affected / exposed	421 / 1007 (41.81%)	500 / 1007 (49.65%)	541 / 1001 (54.05%)
occurrences all number	421	500	541
Psychiatric disorders
Insomnia
subjects affected / exposed	437 / 1007 (43.40%)	529 / 1007 (52.53%)	549 / 1001 (54.85%)
occurrences all number	437	529	549
Libido
subjects affected / exposed	427 / 1007 (42.40%)	477 / 1007 (47.37%)	492 / 1001 (49.15%)
occurrences all number	427	477	492
Mood alteration - depression
subjects affected / exposed	431 / 1007 (42.80%)	478 / 1007 (47.47%)	476 / 1001 (47.55%)
occurrences all number	431	478	476
Injury, poisoning and procedural complications
Fracture
subjects affected / exposed	41 / 1007 (4.07%)	46 / 1007 (4.57%)	51 / 1001 (5.09%)
occurrences all number	41	46	51
Thrombosis/embolism (vascular access-related)
subjects affected / exposed	5 / 1007 (0.50%)	3 / 1007 (0.30%)	2 / 1001 (0.20%)
occurrences all number	5	3	2
Cardiac disorders
Cardiac-ischemia/infarction
subjects affected / exposed	1 / 1007 (0.10%)	2 / 1007 (0.20%)	5 / 1001 (0.50%)
occurrences all number	1	2	5
Nervous system disorders
Hemorrhage, CNS
subjects affected / exposed	14 / 1007 (1.39%)	9 / 1007 (0.89%)	8 / 1001 (0.80%)
occurrences all number	14	9	8
CNS cerebrovascular ischemia
subjects affected / exposed	2 / 1007 (0.20%)	1 / 1007 (0.10%)	0 / 1001 (0.00%)
occurrences all number	2	1	0
Gastrointestinal disorders
Nausea
subjects affected / exposed	239 / 1007 (23.73%)	215 / 1007 (21.35%)	228 / 1001 (22.78%)
occurrences all number	239	215	228
Skin and subcutaneous tissue disorders
Sweating (diaphoresis)
subjects affected / exposed	486 / 1007 (48.26%)	621 / 1007 (61.67%)	566 / 1001 (56.54%)
occurrences all number	486	621	566
Renal and urinary disorders
Incontinence, urinary
subjects affected / exposed	156 / 1007 (15.49%)	180 / 1007 (17.87%)	120 / 1001 (11.99%)
occurrences all number	156	180	120
Musculoskeletal and connective tissue disorders
Osteoporosis
subjects affected / exposed	123 / 1007 (12.21%)	198 / 1007 (19.66%)	316 / 1001 (31.57%)
occurrences all number	123	198	316
Pain - Joint
subjects affected / exposed	631 / 1007 (62.66%)	700 / 1007 (69.51%)	778 / 1001 (77.72%)
occurrences all number	631	700	778
Metabolism and nutrition disorders
Glucose, serum-high (hyperglycemia)
subjects affected / exposed	15 / 1007 (1.49%)	37 / 1007 (3.67%)	17 / 1001 (1.70%)
occurrences all number	15	37	17
Pancreatic endocrine: glucose intolerance
subjects affected / exposed	15 / 1007 (1.49%)	21 / 1007 (2.09%)	28 / 1001 (2.80%)
occurrences all number	15	21	28

More information

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Were there any global substantial amendments to the protocol? Yes

07 Oct 2005

1.Modifiedthe eligibility and other sections to include patients with bilateral breast cancer. 2.Increasedthe eligibility timeframe after chemotherapy from 6 months to 8 months. 3.Modified/clarifiedeligibility requirements including:a. Defining a premenopausal group that does not require estradiol testing;b. Clarifying definitions of surgical margins;c. Defining eligible prior malignancies. 4.Clarifiedtiming of randomization with respect to surgery, radiotherapy, and chemotherapy. 5.Clarifiedthat trastuzumab is allowed prior to and/or concurrent with protocol treatment. 6.Includednew findings about exemestane efficacy and side effects in postmenopausal women. 7.Addeddetails of treatment administration. 8.Clarifiedpathology requirements and central review. 9.Administrative corrections and updates.

24 Aug 2011

1. Modifiedthe statistical analysis plan to compare: a. OFS + tamoxifen versus tamoxifen alone for a primary analysis with a data cut-off anticipated for the third quarterof 2013 at a median follow-up of at least 5 years. b. OFS + exemestane versus OFS + tamoxifen in the originally-planned combined analysis of SOFT and TEXT with a data cut-off anticipated for the fall of 2013 at a median follow-up of approximately 5 years in the SOFT population. 2. Includedbreast cancer-free interval (BCFI) and distant recurrence-free interval (DRFI) assecondary endpoints replacing systemic disease-free survival. 3. Added targeted adverse event information on diabetes and collection of anti-diabetic concomitant medications. Increased risk of diabetes has been suggested by epidemiologicstudies in men being treated with GnRH agonists for prostate cancer. Glucose intolerance (diabetes) and hyperglycemia wereadded to the case report forms as targetedadverse events.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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