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Clinical Trial Results:
A national phase IIIb, multi-center, open label study for women and men with hormone-receptor positive, HER2-negative locally advanced or metastatic breast cancer treated with ribociclib (LEE011) in combination with letrozole RIBECCA RIBociclib for the trEatment of advanCed breast CAncer

Summary
EudraCT number	2016-002556-24
Trial protocol	DE
Global end of trial date	06 Feb 2020

Results information
Results version number	v1
This version publication date	22 Feb 2021
First version publication date	22 Feb 2021
Other versions	v2

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

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Trial information

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Sponsor protocol code

CLEE011XDE01

ISRCTN number

US NCT number

NCT03096847

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharmaceuticals

Sponsor organisation address

Novartis Campus, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharmaceuticals, 41 613241111, Novartis.email@Novartis.com

Scientific contact

Study Director , Novartis Pharmaceuticals, 41 613241111, Novartis.email@Novartis.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

06 Feb 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

06 Feb 2020

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study was the assessment of the clinical benefit rate (CBR) after 24 weeks for the total population and for cohorts A and B separately: -To assess the CBR after 24 weeks for ribociclib (LEE011) in combination with letrozole among postmenopausal women and men with hormone receptor positive, HER2- negative, advanced breast cancer who received no prior treatment for advanced disease. (70% group) (Cohort A) -To assess the CBR after 24 weeks for ribociclib (LEE011) in combination with letrozole and goserelin among pre-, and perimenopausal women who received no prior treatment for advanced disease as well as pre-, peri- and postmenopausal women and men with hormone receptor positive, HER2- negative, advanced breast cancer who received no more than 1 prior chemotherapy and 2 prior lines of endocrine therapy for advanced disease (30% group) (Cohort B)

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

24 Oct 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 502

Worldwide total number of subjects

502

EEA total number of subjects

502

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

256

From 65 to 84 years

240

85 years and over

Subject disposition

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Recruitment details

Screening details

584 patients were screened and defined as Cohort A, 191 patients defined Cohort B. Cohort B was divided into Cohort B1 comprising 34 pre- or perimenopausal women without prior treatment (treatment naïve) and Cohort B2 comprising 157 women or men with prior treatment (pretreated).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

ribociclib + letrozole cohort A

Arm description

postmenopausal women, or men; naïve. All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily.

Arm type

Experimental

Investigational medicinal product name

ribociclib and letrozole

Investigational medicinal product code

ribociclib (LEE011)

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribociclib - 600 mg (3 x 200mg) - Once daily - Days 1-21 of each 28-day cycle; Letrozole - 2.5 mg - Once daily

ribociclib + letrozole cohort B1

Arm description

premenopausal women or perimenopausal women; naïve All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily. Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly

Arm type

Experimental

Investigational medicinal product name

Ribociclib and Letrozole and Goserelin (for premenopausal patients)

Investigational medicinal product code

ribociclib (LEE011)

Other name

Pharmaceutical forms

Tablet, Implant

Routes of administration

Oral use, Subcutaneous use

Dosage and administration details

Ribociclib - 600 mg (3 x 200mg) - Once daily - Days 1-21 of each 28-day cycle; Letrozole - 2.5 mg - Once daily; Goserelin (for premenopausal patients) - 3.6 mg - Day 1 of each cycle

ribociclib + letrozole cohort B2

Arm description

premenopausal women or perimenopausal women or postmenopausal women, or men; pre-treated. All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily. Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly

Arm type

Experimental

Investigational medicinal product name

Ribociclib and Letrozole and Goserelin (for premenopausal patients)

Investigational medicinal product code

ribociclib (LEE011)

Other name

Pharmaceutical forms

Tablet, Implant

Routes of administration

Oral use, Subcutaneous use

Dosage and administration details

Ribociclib - 600 mg (3 x 200mg) - Once daily - Days 1-21 of each 28-day cycle; Letrozole - 2.5 mg - Once daily; Goserelin (for premenopausal patients) - 3.6 mg - Day 1 of each cycle

Number of subjects in period 1	ribociclib + letrozole cohort A	ribociclib + letrozole cohort B1	ribociclib + letrozole cohort B2
Started	319	26	157
Completed	100	6	19
Not completed	219	20	138
Adverse event, serious fatal	6	-	2
Physician decision	12	2	8
Consent withdrawn by subject	24	1	12
Adverse event, non-fatal	72	6	28
Non-compliance with study medication	1	-	-
Lost to follow-up	1	-	1
Progressive disease	97	10	78
New therapy for study indication	1	-	1
not specified	2	1	2
Protocol deviation	3	-	6

Baseline characteristics

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Reporting group title

ribociclib + letrozole cohort A

Reporting group description

postmenopausal women, or men; naïve. All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily.

Reporting group title

ribociclib + letrozole cohort B1

Reporting group description

Reporting group title

ribociclib + letrozole cohort B2

Reporting group description

Reporting group values	ribociclib + letrozole cohort A	ribociclib + letrozole cohort B1	ribociclib + letrozole cohort B2	Total
Number of subjects	319	26	157	502
Age Categorical
Units: Participants
<=18 years	0	0	0	0
Between 18 and 65 years	143	26	87	256
>=65 years	176	0	70	246
Age Continuous
Units: Years
arithmetic mean (standard deviation)	65.7 ( 10.1 )	46.5 ( 4.9 )	62.8 ( 12.8 )	-
Sex: Female, Male
Units: Participants
Female	315	26	156	497
Male	4	0	1	5
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0
Asian	0	1	1	2
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	0	1	0	1
White	312	24	151	487
More than one race	1	0	3	4
Unknown or Not Reported	6	0	2	8

End points

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Reporting group title

ribociclib + letrozole cohort A

Reporting group description

postmenopausal women, or men; naïve. All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily.

Reporting group title

ribociclib + letrozole cohort B1

Reporting group description

Reporting group title

ribociclib + letrozole cohort B2

Reporting group description

Subject analysis set title

ribociclib + letrozole cohort A

Subject analysis set type

Safety analysis

Subject analysis set description

postmenopausal women, or men; naïve. All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily.

Subject analysis set title

ribociclib + letrozole cohort B

Subject analysis set type

Safety analysis

Subject analysis set description

premenopausal women or perimenopausal women or postmenopausal women, or men; naïve + pre-treated All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o.daily. Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly

Subject analysis set title

ribociclib + letrozole cohort B1

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

ribociclib + letrozole cohort B2

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Total

Subject analysis set type

Safety analysis

Subject analysis set description

Total

Primary: Clinical Benefit Rate (CBR) in women and men with hormone receptor positiv, HER-2 negative breast cancer treated with ribocilib and letrozole

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End point title

Clinical Benefit Rate (CBR) in women and men with hormone receptor positiv, HER-2 negative breast cancer treated with ribocilib and letrozole ^[1]

End point description

Clinical Benefit Rate (CBR) after 24 weeks of treatment as defined by RECIST 1.1 as percentage of patients with Complete Response (CR), Partial response (PR) or Stable disease (SD) lasting 24 weeks or longer as well as patients with NCRNPD >24 for patients with non-measurable disease

End point type

Primary

End point timeframe

At 24 weeks after last patient enrolled in trial

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Summary statistics is available although statistical analysis is not.

End point values	ribociclib + letrozole cohort A	ribociclib + letrozole cohort B	Total
Number of subjects analysed	307	180	487
Units: Percentage of Participants
number (confidence interval 95%)
CBR by week 24)(Confirmed BOR)	63.2 (57.5 to 68.6)	56.7 (49.1 to 64.0)	60.8 (56.3 to 65.1)
CBR by week 24(non-confirmed BOR)	71.7 (66.3 to 76.6)	65.0 (57.6 to 71.9)	69.2 (64.9 to 73.3)

No statistical analyses for this end point

Secondary: CBR

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End point title

CBR

End point description

To assess the CBR after 24 weeks among pre- and perimenopausal women without prior therapy for advanced disease (Cohort B1); To assess the CBR after 24 weeks for ribociclib among pre-, peri- and postmenopausal women and men who were pretreated for advanced disease (Cohort B2)

End point type

Secondary

End point timeframe

At 24 weeks

End point values	ribociclib + letrozole cohort A	ribociclib + letrozole cohort B1	ribociclib + letrozole cohort B2
Number of subjects analysed	0 ^[2]	26	154
Units: Percentage of Participants
number (confidence interval 95%)
CBR by week 24 – confirmed assessment	( to )	57.7 (36.9 to 76.6)	56.5 (48.3 to 64.5)
CBR by week 24 – unconfirmed assessment	( to )	69.2 (48.2 to 85.7)	64.3 (56.2 to 71.8)

Notes
[2] - measure not applicable for this arm.

No statistical analyses for this end point

Secondary: Progression free survival (PFS) for different populations - Kaplan-Meier estimates (%, 95% CI)

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End point title

Progression free survival (PFS) for different populations - Kaplan-Meier estimates (%, 95% CI)

End point description

PFS based on radiologic assessment by investigator using RECIST 1.1 criteria

End point type

Secondary

End point timeframe

At week 24 , week 48 and week 72

End point values	ribociclib + letrozole cohort A	ribociclib + letrozole cohort B1	ribociclib + letrozole cohort B2
Number of subjects analysed	307	26	154
Units: Percentage of Participants
number (confidence interval 95%)
Kaplan-Meier estimates (%, 95% CI) - Week 24	73.1 (67.3 to 77.9)	67.0 (44.7 to 82.0)	63.8 (55.2 to 71.3)
Kaplan-Meier estimates (%, 95% CI) - Week 48	61.9 (55.7 to 67.5)	58.7 (36.8 to 75.2)	47.5 (38.7 to 55.7)
Kaplan-Meier estimates (%, 95% CI) - week 72	54.5 (48.1 to 60.5)	49.6 (28.6 to 67.6)	39.3 (30.8 to 47.6)

No statistical analyses for this end point

Secondary: Progression free survival (PFS) for different populations - Median time to progression or death with 95% CI [months]

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End point title

Progression free survival (PFS) for different populations - Median time to progression or death with 95% CI [months]

End point description

PFS based on radiologic assessment by investigator using RECIST 1.1 criteria

End point type

Secondary

End point timeframe

Up to approximately month 25

End point values	ribociclib + letrozole cohort A	ribociclib + letrozole cohort B1	ribociclib + letrozole cohort B2
Number of subjects analysed	307	26	154
Units: Months
median (confidence interval 95%)	21.8 (13.9 to 25.3)	16.5 (3.2 to 999)	8.8 (8.1 to 16.3)

No statistical analyses for this end point

Secondary: Overall Survival (OS) - Kaplan-Meier estimates (%, 95% CI)

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End point title

Overall Survival (OS) - Kaplan-Meier estimates (%, 95% CI)

End point description

Overall survival (OS) defined as the time from date of start of treatment to date of death due to any cause.

End point type

Secondary

End point timeframe

At Week 24, Week 48 and Week 72

End point values	ribociclib + letrozole cohort A	ribociclib + letrozole cohort B1	ribociclib + letrozole cohort B2
Number of subjects analysed	307	26	154
Units: Percentage of Participants
number (confidence interval 95%)
Kaplan-Meier estimates (%, 95% CI) - Week 24	98.6 (96.4 to 99.5)	100.0 (100.0 to 100.0)	93.9 (88.5 to 96.8)
Kaplan-Meier estimates (%, 95% CI) - Week 48	93.3 (89.7 to 95.7)	87.5 (66.1 to 95.8)	86.1 (79.2 to 90.8)
Kaplan-Meier estimates (%, 95% CI) - Week 72	89.7 (85.5 to 92.7)	87.5 (66.1 to 95.8)	81.0 (73.5 to 86.6)

No statistical analyses for this end point

Secondary: Overall Survival (OS) - Median time to progression or death with 95% CI [months]

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End point title

Overall Survival (OS) - Median time to progression or death with 95% CI [months]

End point description

Overall survival (OS) defined as the time from date of start of treatment to date of death due to any cause.

End point type

Secondary

End point timeframe

Up to approximatley 38 months

End point values	ribociclib + letrozole cohort A	ribociclib + letrozole cohort B1	ribociclib + letrozole cohort B2
Number of subjects analysed	307	26	154
Units: Months
median (confidence interval 95%)	999 (999 to 999)	999 (30.9 to 999)	999 (31.0 to 999)

No statistical analyses for this end point

Secondary: Overall Survival (OS) - number of deaths

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End point title

Overall Survival (OS) - number of deaths

End point description

Overall survival (OS) defined as the time from date of start of treatment to date of death due to any cause.

End point type

Secondary

End point timeframe

Up to approximatley 38 months

End point values	ribociclib + letrozole cohort A	ribociclib + letrozole cohort B1	ribociclib + letrozole cohort B2
Number of subjects analysed	307	26	154
Units: Participants
No. of censored (no death), n	240	17	94
No. of events (deaths due to any cause), n	67	9	60

No statistical analyses for this end point

Secondary: Overall response rate (ORR) - Kaplan-Meier estimates (%, 95% CI)

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End point title

Overall response rate (ORR) - Kaplan-Meier estimates (%, 95% CI)

End point description

Overall response rate (ORR) defined as complete response or partial response as defined by RECIST 1.1

End point type

Secondary

End point timeframe

At week 24

End point values	ribociclib + letrozole cohort A	ribociclib + letrozole cohort B1	ribociclib + letrozole cohort B2
Number of subjects analysed	307	26	154
Units: Percentage of Participants
number (confidence interval 95%)
ORR by week 24 - (BOR of CR or PR) (confirmed)	22.8 (18.2 to 27.9)	23.1 (9.0 to 43.6)	11.7 (7.1 to 17.8)
ORR by week 24 - (BOR of CR or PR) (unconfirmed)	24.8 (20.0 to 30.0)	30.8 (14.3 to 51.8)	16.2 (10.8 to 23.0)

No statistical analyses for this end point

Secondary: Patient reported Quality of Life (QoL) via EORTC QLQ-C30

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End point title

Patient reported Quality of Life (QoL) via EORTC QLQ-C30

End point description

The QLQ-C30 is the core questionnaire of the EORTC QLQ, which has been developed for the assessment of the health-related QOL of cancer patients participating in international clinical trials (Aaronson et al. 1993). Using a linear transformation to standardize the raw scores, all scores finally range from 0 to 100, where a higher score represents a higher response level, e.g., a higher ("better") level of functioning, but a higher ("worse") level of symptoms (Fayers et al. 2001). There is no aggregated total score, i.e., all scale scores were analyzed separately.

End point type

Secondary

End point timeframe

Change from Baseline to Week 24

End point values	ribociclib + letrozole cohort A	ribociclib + letrozole cohort B
Number of subjects analysed	307	154
Units: Scores on a scale
arithmetic mean (standard deviation)
Global health status-Change from b/l to Wk 24	8.8 ( 23.7 )	5.0 ( 26.2 )
Physical Functioning-Change from b/l to Wk 24	-3.1 ( 19.9 )	-2.2 ( 17.7 )
Role Functioning-Change from b/l to Wk 24	-6.6 ( 31.9 )	-1.3 ( 34.7 )
Emotional Functioning-Change from b/l to Wk 24	-9.6 ( 24.2 )	-3.6 ( 21.8 )
Cognitive Functioning-Change from b/l to Wk 24	2.7 ( 23.7 )	1.1 ( 21.6 )
Social Functioning-Change from b/l to Wk 24	-6.9 ( 27.9 )	-5.3 ( 31.3 )
Fatigue - Change from baseline to Wk 24	6.3 ( 25.9 )	3.9 ( 27.1 )
Nausea / Vomiting-Change from b/l to Wk 24	0.1 ( 16.7 )	-4.9 ( 19.1 )
Pain-Change from baseline to Wk 24	13.2 ( 31.9 )	9.0 ( 27.6 )
Dyspnoea-Change from baseline to Wk 24	3.8 ( 32.4 )	-5.3 ( 30.5 )
Insomnia-Change from baseline to Wk 24	4.2 ( 33.2 )	4.9 ( 32.7 )
Appetite loss-Change from baseline to Wk 24	11.2 ( 33.7 )	1.4 ( 30.9 )
Constipation-Change from baseline to Wk 24	-2.7 ( 26.6 )	-3.6 ( 27.9 )
Diarrhea-Change from baseline to Wk 24	2.6 ( 24.6 )	2.3 ( 27.2 )
Financial Problems-Change from b/l to Wk 24	0.2 ( 27.7 )	-1.4 ( 25.1 )

No statistical analyses for this end point

Secondary: Patient reported Quality of Life (QoL) via EORTC BR-23 - change from baseline at Week 24 (Cycle 7)

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End point title

Patient reported Quality of Life (QoL) via EORTC BR-23 - change from baseline at Week 24 (Cycle 7)

End point description

To evaluate health related quality of life (QoL) via EORTC BR-23. The scoring approach for the QLQ-BR23 is identical in principle to that for the function and symptom scales / single items of the QLQ-C30, i.e., all scores finally range from 0 to 100, where a higher score represents a higher response level, e.g., a higher ("better") level of functioning, but a higher ("worse") level of symptoms (Fayers et al. 2001).

End point type

Secondary

End point timeframe

Baseline and Week 24 (Cycle 7)

End point values	ribociclib + letrozole cohort A	ribociclib + letrozole cohort B
Number of subjects analysed	307	154
Units: Scores on a scale
arithmetic mean (standard deviation)
BODY IMAGE - change from b/l at cycle 7	-1.5 ( 18.2 )	0.4 ( 22.7 )
SEXUAL FUNCTIONING - change from b/l at cycle 7	-1.1 ( 17.7 )	0.8 ( 18.0 )
SEXUAL ENJOYMENT - change from b/l at cycle 7	-1.9 ( 31.3 )	7.4 ( 26.9 )
FUTURE PERSPECTIVE - change from b/l at cycle 7	-20 ( 33.4 )	-12 ( 26.2 )
SYSTEMATIC THERAPY - change from b/l at cycle 7	-9.4 ( 16.6 )	-6.0 ( 14.9 )
BREAST SYMPTOMS - change from b/l at cycle 7	3.3 ( 15.7 )	0.9 ( 17.5 )
ARM SYMPTOMS - change from b/l at cycle 7	4.1 ( 21.1 )	-2.1 ( 18.1 )
HAIR LOSS - change from baseline at cycle 7	-22 ( 43.4 )	-14 ( 33.9 )

No statistical analyses for this end point

Secondary: To evaluate the safety and tolerability of ribociclib in combination with letrozole (and goserelin in premenopausal patients) - via collection of Treatment Emergent Adverse Events (TEAE)

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End point title

To evaluate the safety and tolerability of ribociclib in combination with letrozole (and goserelin in premenopausal patients) - via collection of Treatment Emergent Adverse Events (TEAE)

End point description

AEs were separated into TEAEs (defined as AEs occurring/worsening from first study drug treatment until 30 days after the last study drug treatment) and AEs in the pre-/post-treatment period.

End point type

Secondary

End point timeframe

Up to Week 72

End point values	ribociclib + letrozole cohort A	ribociclib + letrozole cohort B1	ribociclib + letrozole cohort B2
Number of subjects analysed	319	26	157
Units: Number of Participants
Total AEs	318	25	157
Serious AE	97	5	45
Non-serious AE	317	25	157
AE with suspected relationship to ribociclib	302	25	144
AE leading to discontinuation of ribociclib	76	7	38
AE with fatal outcome	6	0	6

No statistical analyses for this end point

Secondary: Time to 10% deterioration in the European Organisation for Research and Treatment of Cancer (EORTC) global health status

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End point title

Time to 10% deterioration in the European Organisation for Research and Treatment of Cancer (EORTC) global health status

End point description

Time to 10% deterioration in the European Organisation for Research and Treatment of Cancer (EORTC) global health status

End point type

Secondary

End point timeframe

up to approximately 10 months

End point values	ribociclib + letrozole cohort A	ribociclib + letrozole cohort B1	ribociclib + letrozole cohort B2	Total
Number of subjects analysed	307	26	154	487
Units: months
median (confidence interval 95%)	3.3 (2.8 to 4.6)	3.7 (1.8 to 10.1)	2.8 (1.8 to 4.6)	3.0 (2.8 to 4.6)

No statistical analyses for this end point

Post-hoc: All Collected Deaths

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End point title

All Collected Deaths

End point description

On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 1150 days (approx 3.15 years). (Treatment duration ranged from 2 days to 1120 days). Deaths post treatment survival follow up were collected after the on- treatment period, up to approx. 3.15 years. Patients who didn’t die during the on-treatment period and had not stopped study participation at the time of data cut-off (end of study) were censored.

End point type

Post-hoc

End point timeframe

on-treatment deaths: up to approx 3.15 years; all deaths: approx 3.15 years

End point values	ribociclib + letrozole cohort A	ribociclib + letrozole cohort B	Total
Number of subjects analysed	319 ^[3]	183 ^[4]	502 ^[5]
Units: Participants
on-treatment deaths	6	6	12
Total deaths	67	69	136

Notes
[3] - n = 319 for on-treatment deaths; n = 307 for total deaths
[4] - n = 183 for on-treatment deaths; n = 180 for total deaths
[5] - n = 502 for on-treatment deaths; n = 487 for total deaths

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days, up to a maximum duration of 1150 days (approx. 3.15 years).(Treatment duration ranged from 2 days to 1120 days.)

Adverse event reporting additional description

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.1

Reporting group title

ribociclib + letrozole cohort A

Reporting group description

postmenopausal women, or men; naïve. All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily.

Reporting group title

ribociclib + letrozole cohort B

Reporting group description

Reporting group title

ribociclib + letrozole cohort B1

Reporting group description

Reporting group title

ribociclib + letrozole cohort B2

Reporting group description

Reporting group title

Total

Reporting group description

Total

Serious adverse events	ribociclib + letrozole cohort A	ribociclib + letrozole cohort B	ribociclib + letrozole cohort B1	ribociclib + letrozole cohort B2	Total
Total subjects affected by serious adverse events
subjects affected / exposed	97 / 319 (30.41%)	50 / 183 (27.32%)	5 / 26 (19.23%)	45 / 157 (28.66%)	147 / 502 (29.28%)
number of deaths (all causes)	6	6	0	6	12
number of deaths resulting from adverse events	1	1	0	1	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BRONCHIAL CARCINOMA
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CANCER PAIN
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COLON CANCER
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MALIGNANT PLEURAL EFFUSION
subjects affected / exposed	2 / 319 (0.63%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
METASTASES TO BONE
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
METASTASES TO SPINE
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RENAL CELL CARCINOMA
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SQUAMOUS CELL CARCINOMA OF THE TONGUE
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	1 / 26 (3.85%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TUMOUR PAIN
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
CIRCULATORY COLLAPSE
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPERTENSION
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPERTENSIVE CRISIS
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPOTENSION
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
CHEST PAIN
subjects affected / exposed	1 / 319 (0.31%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COMPLICATION OF DEVICE INSERTION
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DEATH
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
FATIGUE
subjects affected / exposed	0 / 319 (0.00%)	2 / 183 (1.09%)	0 / 26 (0.00%)	2 / 157 (1.27%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GENERAL PHYSICAL HEALTH DETERIORATION
subjects affected / exposed	2 / 319 (0.63%)	5 / 183 (2.73%)	0 / 26 (0.00%)	5 / 157 (3.18%)	7 / 502 (1.39%)
occurrences causally related to treatment / all	1 / 3	2 / 5	0 / 0	2 / 5	3 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
IMPAIRED HEALING
subjects affected / exposed	1 / 319 (0.31%)	2 / 183 (1.09%)	0 / 26 (0.00%)	2 / 157 (1.27%)	3 / 502 (0.60%)
occurrences causally related to treatment / all	1 / 1	0 / 2	0 / 0	0 / 2	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OEDEMA PERIPHERAL
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PAIN
subjects affected / exposed	1 / 319 (0.31%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PYREXIA
subjects affected / exposed	6 / 319 (1.88%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	7 / 502 (1.39%)
occurrences causally related to treatment / all	3 / 6	0 / 1	0 / 0	0 / 1	3 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
PELVIC PAIN
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
ASTHMA
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DYSPNOEA
subjects affected / exposed	9 / 319 (2.82%)	3 / 183 (1.64%)	0 / 26 (0.00%)	3 / 157 (1.91%)	12 / 502 (2.39%)
occurrences causally related to treatment / all	3 / 10	0 / 3	0 / 0	0 / 3	3 / 13
deaths causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 1	1 / 2
DYSPNOEA EXERTIONAL
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPERVENTILATION
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PLEURAL EFFUSION
subjects affected / exposed	3 / 319 (0.94%)	3 / 183 (1.64%)	0 / 26 (0.00%)	3 / 157 (1.91%)	6 / 502 (1.20%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 0	0 / 4	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
PNEUMONITIS
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMOTHORAX
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PULMONARY EMBOLISM
subjects affected / exposed	7 / 319 (2.19%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	8 / 502 (1.59%)
occurrences causally related to treatment / all	1 / 7	0 / 1	0 / 0	0 / 1	1 / 8
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 2
PULMONARY FIBROSIS
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RESPIRATORY FAILURE
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
Psychiatric disorders
DEPRESSION
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PANIC ATTACK
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SOMATIC SYMPTOM DISORDER
subjects affected / exposed	2 / 319 (0.63%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
DEVICE LOOSENING
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	5 / 319 (1.57%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	6 / 502 (1.20%)
occurrences causally related to treatment / all	5 / 5	1 / 1	0 / 0	1 / 1	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ASPARTATE AMINOTRANSFERASE INCREASED
subjects affected / exposed	3 / 319 (0.94%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	4 / 502 (0.80%)
occurrences causally related to treatment / all	3 / 3	1 / 1	0 / 0	1 / 1	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BLOOD BILIRUBIN INCREASED
subjects affected / exposed	1 / 319 (0.31%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
C-REACTIVE PROTEIN INCREASED
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HAEMOGLOBIN DECREASED
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NEUTROPHIL COUNT DECREASED
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	1 / 26 (3.85%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
WHITE BLOOD CELL COUNT DECREASED
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	1 / 26 (3.85%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
ACCIDENT
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ANKLE FRACTURE
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	1 / 26 (3.85%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CERVICAL VERTEBRAL FRACTURE
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FALL
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FEMORAL NECK FRACTURE
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FEMUR FRACTURE
subjects affected / exposed	3 / 319 (0.94%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	3 / 502 (0.60%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HIP FRACTURE
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HUMERUS FRACTURE
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INCISIONAL HERNIA
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
JAW FRACTURE
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
POST PROCEDURAL HAEMORRHAGE
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	1 / 26 (3.85%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
POST-TRAUMATIC PAIN
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
POSTOPERATIVE ADHESION
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PROCEDURAL COMPLICATION
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RADIUS FRACTURE
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RIB FRACTURE
subjects affected / exposed	3 / 319 (0.94%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	3 / 502 (0.60%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TIBIA FRACTURE
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
UPPER LIMB FRACTURE
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
ATRIAL FIBRILLATION
subjects affected / exposed	2 / 319 (0.63%)	2 / 183 (1.09%)	0 / 26 (0.00%)	2 / 157 (1.27%)	4 / 502 (0.80%)
occurrences causally related to treatment / all	1 / 2	0 / 2	0 / 0	0 / 2	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BRADYARRHYTHMIA
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARDIAC ARREST
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARDIAC FAILURE
subjects affected / exposed	1 / 319 (0.31%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
MYOCARDIAL INFARCTION
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SUPRAVENTRICULAR TACHYCARDIA
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
CEREBRAL ISCHAEMIA
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CEREBROVASCULAR ACCIDENT
subjects affected / exposed	2 / 319 (0.63%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIZZINESS
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HEADACHE
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MONOPLEGIA
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NEUROPATHY PERIPHERAL
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PARAESTHESIA
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PERIPHERAL NERVE LESION
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SYNCOPE
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	4 / 319 (1.25%)	4 / 183 (2.19%)	0 / 26 (0.00%)	4 / 157 (2.55%)	8 / 502 (1.59%)
occurrences causally related to treatment / all	10 / 11	10 / 12	0 / 0	10 / 12	20 / 23
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DISSEMINATED INTRAVASCULAR COAGULATION
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FEBRILE NEUTROPENIA
subjects affected / exposed	0 / 319 (0.00%)	3 / 183 (1.64%)	1 / 26 (3.85%)	2 / 157 (1.27%)	3 / 502 (0.60%)
occurrences causally related to treatment / all	0 / 0	3 / 3	1 / 1	2 / 2	3 / 3
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	1 / 1
HYPERFIBRINOLYSIS
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LEUKOPENIA
subjects affected / exposed	2 / 319 (0.63%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NEUTROPENIA
subjects affected / exposed	2 / 319 (0.63%)	2 / 183 (1.09%)	0 / 26 (0.00%)	2 / 157 (1.27%)	4 / 502 (0.80%)
occurrences causally related to treatment / all	1 / 2	1 / 2	0 / 0	1 / 2	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PANCYTOPENIA
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
THROMBOCYTOPENIA
subjects affected / exposed	3 / 319 (0.94%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	3 / 502 (0.60%)
occurrences causally related to treatment / all	4 / 5	0 / 0	0 / 0	0 / 0	4 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	1 / 319 (0.31%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	1 / 2	0 / 3	0 / 0	0 / 3	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ABDOMINAL PAIN LOWER
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ANAL HAEMORRHAGE
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CONSTIPATION
subjects affected / exposed	2 / 319 (0.63%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIARRHOEA
subjects affected / exposed	3 / 319 (0.94%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	4 / 502 (0.80%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTRITIS
subjects affected / exposed	3 / 319 (0.94%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	3 / 502 (0.60%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTROOESOPHAGEAL REFLUX DISEASE
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ILEUS
subjects affected / exposed	1 / 319 (0.31%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
INTESTINAL STRANGULATION
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NAUSEA
subjects affected / exposed	7 / 319 (2.19%)	2 / 183 (1.09%)	0 / 26 (0.00%)	2 / 157 (1.27%)	9 / 502 (1.79%)
occurrences causally related to treatment / all	2 / 8	0 / 3	0 / 0	0 / 3	2 / 11
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
VOMITING
subjects affected / exposed	3 / 319 (0.94%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	3 / 502 (0.60%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
BILE DUCT STENOSIS
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BILIARY COLIC
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CHOLECYSTITIS
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CHOLECYSTITIS ACUTE
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CHOLELITHIASIS
subjects affected / exposed	2 / 319 (0.63%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DRUG-INDUCED LIVER INJURY
subjects affected / exposed	5 / 319 (1.57%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	6 / 502 (1.20%)
occurrences causally related to treatment / all	6 / 6	1 / 1	0 / 0	1 / 1	7 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HEPATIC CIRRHOSIS
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HEPATOTOXICITY
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
JAUNDICE
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
SKIN ULCER
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
ACUTE KIDNEY INJURY
subjects affected / exposed	5 / 319 (1.57%)	1 / 183 (0.55%)	1 / 26 (3.85%)	0 / 157 (0.00%)	6 / 502 (1.20%)
occurrences causally related to treatment / all	0 / 5	1 / 1	1 / 1	0 / 0	1 / 6
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
HAEMATURIA
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
KIDNEY CONGESTION
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RENAL DISORDER
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RENAL FAILURE
subjects affected / exposed	1 / 319 (0.31%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RENAL IMPAIRMENT
subjects affected / exposed	1 / 319 (0.31%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
URETERIC STENOSIS
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
URETEROLITHIASIS
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
URINARY INCONTINENCE
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
URINARY RETENTION
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
URINARY TRACT OBSTRUCTION
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
HYPERTHYROIDISM
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BACK PAIN
subjects affected / exposed	2 / 319 (0.63%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BONE LESION
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BONE PAIN
subjects affected / exposed	2 / 319 (0.63%)	2 / 183 (1.09%)	0 / 26 (0.00%)	2 / 157 (1.27%)	4 / 502 (0.80%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FLANK PAIN
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LUMBAR SPINAL STENOSIS
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MOBILITY DECREASED
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MUSCULOSKELETAL CHEST PAIN
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MUSCULOSKELETAL PAIN
subjects affected / exposed	1 / 319 (0.31%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OSTEITIS
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OSTEOARTHRITIS
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OSTEONECROSIS OF JAW
subjects affected / exposed	2 / 319 (0.63%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PAIN IN EXTREMITY
subjects affected / exposed	2 / 319 (0.63%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SPINAL PAIN
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
ABDOMINAL ABSCESS
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ABSCESS JAW
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
APPENDICITIS
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ATYPICAL PNEUMONIA
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BRONCHITIS
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CHOLECYSTITIS INFECTIVE
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CYSTITIS
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CYSTITIS ESCHERICHIA
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DEVICE RELATED INFECTION
subjects affected / exposed	0 / 319 (0.00%)	2 / 183 (1.09%)	0 / 26 (0.00%)	2 / 157 (1.27%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
DIVERTICULITIS
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
EMPHYSEMATOUS CHOLECYSTITIS
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ERYSIPELAS
subjects affected / exposed	3 / 319 (0.94%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	3 / 502 (0.60%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ESCHERICHIA INFECTION
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FEBRILE INFECTION
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTROENTERITIS
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL INFECTION
subjects affected / exposed	1 / 319 (0.31%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HELICOBACTER GASTRITIS
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INFECTIOUS PLEURAL EFFUSION
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INFLUENZA
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MASTITIS
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed	8 / 319 (2.51%)	2 / 183 (1.09%)	0 / 26 (0.00%)	2 / 157 (1.27%)	10 / 502 (1.99%)
occurrences causally related to treatment / all	2 / 8	1 / 2	0 / 0	1 / 2	3 / 10
deaths causally related to treatment / all	0 / 2	1 / 1	0 / 0	1 / 1	1 / 3
PROTEUS INFECTION
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PYELONEPHRITIS
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RESPIRATORY SYNCYTIAL VIRUS INFECTION
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SEPSIS
subjects affected / exposed	1 / 319 (0.31%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 2
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
URINARY TRACT INFECTION
subjects affected / exposed	3 / 319 (0.94%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	3 / 502 (0.60%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
UROSEPSIS
subjects affected / exposed	2 / 319 (0.63%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DEHYDRATION
subjects affected / exposed	1 / 319 (0.31%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	2 / 502 (0.40%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPERCALCAEMIA
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPERKALAEMIA
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPONATRAEMIA
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPOPHAGIA
subjects affected / exposed	1 / 319 (0.31%)	0 / 183 (0.00%)	0 / 26 (0.00%)	0 / 157 (0.00%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TUMOUR LYSIS SYNDROME
subjects affected / exposed	0 / 319 (0.00%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	1 / 502 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	ribociclib + letrozole cohort A	ribociclib + letrozole cohort B	ribociclib + letrozole cohort B1	ribociclib + letrozole cohort B2	Total
Total subjects affected by non serious adverse events
subjects affected / exposed	315 / 319 (98.75%)	181 / 183 (98.91%)	25 / 26 (96.15%)	156 / 157 (99.36%)	496 / 502 (98.80%)
Vascular disorders
HOT FLUSH
subjects affected / exposed	44 / 319 (13.79%)	30 / 183 (16.39%)	11 / 26 (42.31%)	19 / 157 (12.10%)	74 / 502 (14.74%)
occurrences all number	49	35	13	22	84
HYPERTENSION
subjects affected / exposed	36 / 319 (11.29%)	11 / 183 (6.01%)	4 / 26 (15.38%)	7 / 157 (4.46%)	47 / 502 (9.36%)
occurrences all number	38	13	4	9	51
General disorders and administration site conditions
FATIGUE
subjects affected / exposed	123 / 319 (38.56%)	74 / 183 (40.44%)	15 / 26 (57.69%)	59 / 157 (37.58%)	197 / 502 (39.24%)
occurrences all number	151	86	16	70	237
OEDEMA PERIPHERAL
subjects affected / exposed	35 / 319 (10.97%)	22 / 183 (12.02%)	5 / 26 (19.23%)	17 / 157 (10.83%)	57 / 502 (11.35%)
occurrences all number	37	31	7	24	68
PYREXIA
subjects affected / exposed	23 / 319 (7.21%)	14 / 183 (7.65%)	4 / 26 (15.38%)	10 / 157 (6.37%)	37 / 502 (7.37%)
occurrences all number	31	19	7	12	50
Immune system disorders
SEASONAL ALLERGY
subjects affected / exposed	4 / 319 (1.25%)	6 / 183 (3.28%)	3 / 26 (11.54%)	3 / 157 (1.91%)	10 / 502 (1.99%)
occurrences all number	4	6	3	3	10
Reproductive system and breast disorders
VULVOVAGINAL DRYNESS
subjects affected / exposed	4 / 319 (1.25%)	3 / 183 (1.64%)	3 / 26 (11.54%)	0 / 157 (0.00%)	7 / 502 (1.39%)
occurrences all number	5	3	3	0	8
Respiratory, thoracic and mediastinal disorders
COUGH
subjects affected / exposed	53 / 319 (16.61%)	22 / 183 (12.02%)	6 / 26 (23.08%)	16 / 157 (10.19%)	75 / 502 (14.94%)
occurrences all number	66	26	7	19	92
DYSPNOEA
subjects affected / exposed	49 / 319 (15.36%)	25 / 183 (13.66%)	4 / 26 (15.38%)	21 / 157 (13.38%)	74 / 502 (14.74%)
occurrences all number	58	26	4	22	84
OROPHARYNGEAL PAIN
subjects affected / exposed	11 / 319 (3.45%)	7 / 183 (3.83%)	5 / 26 (19.23%)	2 / 157 (1.27%)	18 / 502 (3.59%)
occurrences all number	12	9	7	2	21
Psychiatric disorders
DEPRESSION
subjects affected / exposed	7 / 319 (2.19%)	8 / 183 (4.37%)	2 / 26 (7.69%)	6 / 157 (3.82%)	15 / 502 (2.99%)
occurrences all number	9	8	2	6	17
INSOMNIA
subjects affected / exposed	31 / 319 (9.72%)	26 / 183 (14.21%)	4 / 26 (15.38%)	22 / 157 (14.01%)	57 / 502 (11.35%)
occurrences all number	34	28	5	23	62
SLEEP DISORDER
subjects affected / exposed	13 / 319 (4.08%)	10 / 183 (5.46%)	4 / 26 (15.38%)	6 / 157 (3.82%)	23 / 502 (4.58%)
occurrences all number	15	10	4	6	25
Investigations
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	75 / 319 (23.51%)	36 / 183 (19.67%)	6 / 26 (23.08%)	30 / 157 (19.11%)	111 / 502 (22.11%)
occurrences all number	93	43	10	33	136
ASPARTATE AMINOTRANSFERASE INCREASED
subjects affected / exposed	66 / 319 (20.69%)	36 / 183 (19.67%)	5 / 26 (19.23%)	31 / 157 (19.75%)	102 / 502 (20.32%)
occurrences all number	82	44	8	36	126
BLOOD BILIRUBIN INCREASED
subjects affected / exposed	16 / 319 (5.02%)	1 / 183 (0.55%)	0 / 26 (0.00%)	1 / 157 (0.64%)	17 / 502 (3.39%)
occurrences all number	17	1	0	1	18
BLOOD CREATININE INCREASED
subjects affected / exposed	27 / 319 (8.46%)	12 / 183 (6.56%)	2 / 26 (7.69%)	10 / 157 (6.37%)	39 / 502 (7.77%)
occurrences all number	38	13	2	11	51
BLOOD LACTATE DEHYDROGENASE INCREASED
subjects affected / exposed	17 / 319 (5.33%)	3 / 183 (1.64%)	1 / 26 (3.85%)	2 / 157 (1.27%)	20 / 502 (3.98%)
occurrences all number	22	4	1	3	26
BLOOD THYROID STIMULATING HORMONE INCREASED
subjects affected / exposed	0 / 319 (0.00%)	2 / 183 (1.09%)	2 / 26 (7.69%)	0 / 157 (0.00%)	2 / 502 (0.40%)
occurrences all number	0	2	2	0	2
ELECTROCARDIOGRAM QT PROLONGED
subjects affected / exposed	23 / 319 (7.21%)	14 / 183 (7.65%)	1 / 26 (3.85%)	13 / 157 (8.28%)	37 / 502 (7.37%)
occurrences all number	29	19	1	18	48
GAMMA-GLUTAMYLTRANSFERASE INCREASED
subjects affected / exposed	33 / 319 (10.34%)	18 / 183 (9.84%)	5 / 26 (19.23%)	13 / 157 (8.28%)	51 / 502 (10.16%)
occurrences all number	38	20	5	15	58
NEUTROPHIL COUNT DECREASED
subjects affected / exposed	40 / 319 (12.54%)	25 / 183 (13.66%)	2 / 26 (7.69%)	23 / 157 (14.65%)	65 / 502 (12.95%)
occurrences all number	164	75	2	73	239
WEIGHT DECREASED
subjects affected / exposed	16 / 319 (5.02%)	9 / 183 (4.92%)	0 / 26 (0.00%)	9 / 157 (5.73%)	25 / 502 (4.98%)
occurrences all number	17	12	0	12	29
WEIGHT INCREASED
subjects affected / exposed	7 / 319 (2.19%)	4 / 183 (2.19%)	2 / 26 (7.69%)	2 / 157 (1.27%)	11 / 502 (2.19%)
occurrences all number	7	5	3	2	12
WHITE BLOOD CELL COUNT DECREASED
subjects affected / exposed	27 / 319 (8.46%)	18 / 183 (9.84%)	2 / 26 (7.69%)	16 / 157 (10.19%)	45 / 502 (8.96%)
occurrences all number	56	21	2	19	77
Injury, poisoning and procedural complications
ARTHROPOD BITE
subjects affected / exposed	3 / 319 (0.94%)	3 / 183 (1.64%)	2 / 26 (7.69%)	1 / 157 (0.64%)	6 / 502 (1.20%)
occurrences all number	3	3	2	1	6
ARTHROPOD STING
subjects affected / exposed	0 / 319 (0.00%)	2 / 183 (1.09%)	2 / 26 (7.69%)	0 / 157 (0.00%)	2 / 502 (0.40%)
occurrences all number	0	2	2	0	2
Nervous system disorders
DIZZINESS
subjects affected / exposed	26 / 319 (8.15%)	12 / 183 (6.56%)	4 / 26 (15.38%)	8 / 157 (5.10%)	38 / 502 (7.57%)
occurrences all number	30	17	8	9	47
DYSGEUSIA
subjects affected / exposed	20 / 319 (6.27%)	11 / 183 (6.01%)	4 / 26 (15.38%)	7 / 157 (4.46%)	31 / 502 (6.18%)
occurrences all number	21	12	4	8	33
HEADACHE
subjects affected / exposed	56 / 319 (17.55%)	36 / 183 (19.67%)	10 / 26 (38.46%)	26 / 157 (16.56%)	92 / 502 (18.33%)
occurrences all number	90	55	20	35	145
HYPOAESTHESIA
subjects affected / exposed	3 / 319 (0.94%)	5 / 183 (2.73%)	3 / 26 (11.54%)	2 / 157 (1.27%)	8 / 502 (1.59%)
occurrences all number	3	5	3	2	8
POLYNEUROPATHY
subjects affected / exposed	16 / 319 (5.02%)	5 / 183 (2.73%)	1 / 26 (3.85%)	4 / 157 (2.55%)	21 / 502 (4.18%)
occurrences all number	17	5	1	4	22
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	46 / 319 (14.42%)	36 / 183 (19.67%)	7 / 26 (26.92%)	29 / 157 (18.47%)	82 / 502 (16.33%)
occurrences all number	60	60	19	41	120
LEUKOPENIA
subjects affected / exposed	76 / 319 (23.82%)	39 / 183 (21.31%)	8 / 26 (30.77%)	31 / 157 (19.75%)	115 / 502 (22.91%)
occurrences all number	183	108	45	63	291
LYMPHOPENIA
subjects affected / exposed	7 / 319 (2.19%)	2 / 183 (1.09%)	2 / 26 (7.69%)	0 / 157 (0.00%)	9 / 502 (1.79%)
occurrences all number	14	13	13	0	27
NEUTROPENIA
subjects affected / exposed	162 / 319 (50.78%)	88 / 183 (48.09%)	15 / 26 (57.69%)	73 / 157 (46.50%)	250 / 502 (49.80%)
occurrences all number	558	326	95	231	884
THROMBOCYTOPENIA
subjects affected / exposed	26 / 319 (8.15%)	18 / 183 (9.84%)	1 / 26 (3.85%)	17 / 157 (10.83%)	44 / 502 (8.76%)
occurrences all number	46	23	2	21	69
Ear and labyrinth disorders
VERTIGO
subjects affected / exposed	33 / 319 (10.34%)	17 / 183 (9.29%)	4 / 26 (15.38%)	13 / 157 (8.28%)	50 / 502 (9.96%)
occurrences all number	41	17	4	13	58
Eye disorders
DRY EYE
subjects affected / exposed	23 / 319 (7.21%)	10 / 183 (5.46%)	2 / 26 (7.69%)	8 / 157 (5.10%)	33 / 502 (6.57%)
occurrences all number	24	11	2	9	35
LACRIMATION INCREASED
subjects affected / exposed	34 / 319 (10.66%)	11 / 183 (6.01%)	2 / 26 (7.69%)	9 / 157 (5.73%)	45 / 502 (8.96%)
occurrences all number	38	11	2	9	49
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	15 / 319 (4.70%)	14 / 183 (7.65%)	5 / 26 (19.23%)	9 / 157 (5.73%)	29 / 502 (5.78%)
occurrences all number	21	17	7	10	38
ABDOMINAL PAIN UPPER
subjects affected / exposed	33 / 319 (10.34%)	13 / 183 (7.10%)	3 / 26 (11.54%)	10 / 157 (6.37%)	46 / 502 (9.16%)
occurrences all number	42	20	7	13	62
CONSTIPATION
subjects affected / exposed	62 / 319 (19.44%)	32 / 183 (17.49%)	4 / 26 (15.38%)	28 / 157 (17.83%)	94 / 502 (18.73%)
occurrences all number	71	43	4	39	114
DIARRHOEA
subjects affected / exposed	85 / 319 (26.65%)	40 / 183 (21.86%)	8 / 26 (30.77%)	32 / 157 (20.38%)	125 / 502 (24.90%)
occurrences all number	133	57	16	41	190
DRY MOUTH
subjects affected / exposed	28 / 319 (8.78%)	10 / 183 (5.46%)	1 / 26 (3.85%)	9 / 157 (5.73%)	38 / 502 (7.57%)
occurrences all number	30	10	1	9	40
DYSPEPSIA
subjects affected / exposed	25 / 319 (7.84%)	14 / 183 (7.65%)	2 / 26 (7.69%)	12 / 157 (7.64%)	39 / 502 (7.77%)
occurrences all number	28	14	2	12	42
NAUSEA
subjects affected / exposed	130 / 319 (40.75%)	77 / 183 (42.08%)	9 / 26 (34.62%)	68 / 157 (43.31%)	207 / 502 (41.24%)
occurrences all number	202	108	11	97	310
STOMATITIS
subjects affected / exposed	33 / 319 (10.34%)	27 / 183 (14.75%)	4 / 26 (15.38%)	23 / 157 (14.65%)	60 / 502 (11.95%)
occurrences all number	40	30	4	26	70
TOOTHACHE
subjects affected / exposed	9 / 319 (2.82%)	4 / 183 (2.19%)	2 / 26 (7.69%)	2 / 157 (1.27%)	13 / 502 (2.59%)
occurrences all number	10	4	2	2	14
VOMITING
subjects affected / exposed	66 / 319 (20.69%)	31 / 183 (16.94%)	5 / 26 (19.23%)	26 / 157 (16.56%)	97 / 502 (19.32%)
occurrences all number	93	63	10	53	156
Skin and subcutaneous tissue disorders
ALOPECIA
subjects affected / exposed	119 / 319 (37.30%)	57 / 183 (31.15%)	5 / 26 (19.23%)	52 / 157 (33.12%)	176 / 502 (35.06%)
occurrences all number	127	63	7	56	190
DRY SKIN
subjects affected / exposed	24 / 319 (7.52%)	15 / 183 (8.20%)	3 / 26 (11.54%)	12 / 157 (7.64%)	39 / 502 (7.77%)
occurrences all number	27	16	3	13	43
ERYTHEMA
subjects affected / exposed	9 / 319 (2.82%)	10 / 183 (5.46%)	1 / 26 (3.85%)	9 / 157 (5.73%)	19 / 502 (3.78%)
occurrences all number	9	10	1	9	19
PRURITUS
subjects affected / exposed	45 / 319 (14.11%)	18 / 183 (9.84%)	3 / 26 (11.54%)	15 / 157 (9.55%)	63 / 502 (12.55%)
occurrences all number	53	19	4	15	72
RASH
subjects affected / exposed	47 / 319 (14.73%)	19 / 183 (10.38%)	2 / 26 (7.69%)	17 / 157 (10.83%)	66 / 502 (13.15%)
occurrences all number	60	25	3	22	85
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	57 / 319 (17.87%)	39 / 183 (21.31%)	9 / 26 (34.62%)	30 / 157 (19.11%)	96 / 502 (19.12%)
occurrences all number	76	47	12	35	123
BACK PAIN
subjects affected / exposed	37 / 319 (11.60%)	24 / 183 (13.11%)	4 / 26 (15.38%)	20 / 157 (12.74%)	61 / 502 (12.15%)
occurrences all number	42	29	6	23	71
BONE PAIN
subjects affected / exposed	35 / 319 (10.97%)	15 / 183 (8.20%)	6 / 26 (23.08%)	9 / 157 (5.73%)	50 / 502 (9.96%)
occurrences all number	42	18	9	9	60
MUSCULOSKELETAL CHEST PAIN
subjects affected / exposed	12 / 319 (3.76%)	6 / 183 (3.28%)	2 / 26 (7.69%)	4 / 157 (2.55%)	18 / 502 (3.59%)
occurrences all number	13	7	2	5	20
MUSCULOSKELETAL PAIN
subjects affected / exposed	21 / 319 (6.58%)	14 / 183 (7.65%)	2 / 26 (7.69%)	12 / 157 (7.64%)	35 / 502 (6.97%)
occurrences all number	27	15	3	12	42
MYALGIA
subjects affected / exposed	18 / 319 (5.64%)	6 / 183 (3.28%)	0 / 26 (0.00%)	6 / 157 (3.82%)	24 / 502 (4.78%)
occurrences all number	18	7	0	7	25
PAIN IN EXTREMITY
subjects affected / exposed	52 / 319 (16.30%)	23 / 183 (12.57%)	3 / 26 (11.54%)	20 / 157 (12.74%)	75 / 502 (14.94%)
occurrences all number	68	35	5	30	103
Infections and infestations
BRONCHITIS
subjects affected / exposed	19 / 319 (5.96%)	5 / 183 (2.73%)	1 / 26 (3.85%)	4 / 157 (2.55%)	24 / 502 (4.78%)
occurrences all number	25	6	1	5	31
CYSTITIS
subjects affected / exposed	21 / 319 (6.58%)	9 / 183 (4.92%)	3 / 26 (11.54%)	6 / 157 (3.82%)	30 / 502 (5.98%)
occurrences all number	25	10	3	7	35
GASTROINTESTINAL INFECTION
subjects affected / exposed	2 / 319 (0.63%)	3 / 183 (1.64%)	2 / 26 (7.69%)	1 / 157 (0.64%)	5 / 502 (1.00%)
occurrences all number	2	3	2	1	5
NASOPHARYNGITIS
subjects affected / exposed	94 / 319 (29.47%)	49 / 183 (26.78%)	10 / 26 (38.46%)	39 / 157 (24.84%)	143 / 502 (28.49%)
occurrences all number	131	74	18	56	205
URINARY TRACT INFECTION
subjects affected / exposed	31 / 319 (9.72%)	17 / 183 (9.29%)	1 / 26 (3.85%)	16 / 157 (10.19%)	48 / 502 (9.56%)
occurrences all number	45	23	2	21	68
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	44 / 319 (13.79%)	19 / 183 (10.38%)	1 / 26 (3.85%)	18 / 157 (11.46%)	63 / 502 (12.55%)
occurrences all number	45	20	1	19	65
HYPERKALAEMIA
subjects affected / exposed	6 / 319 (1.88%)	4 / 183 (2.19%)	2 / 26 (7.69%)	2 / 157 (1.27%)	10 / 502 (1.99%)
occurrences all number	18	6	4	2	24
HYPOCALCAEMIA
subjects affected / exposed	8 / 319 (2.51%)	5 / 183 (2.73%)	2 / 26 (7.69%)	3 / 157 (1.91%)	13 / 502 (2.59%)
occurrences all number	10	5	2	3	15

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Were there any global substantial amendments to the protocol? Yes

30 Sep 2016

The purpose of this amendment was to include feedback received from BfArM and ECs during the assessment of the initial application.

03 May 2017

This amendment was intended to update the existing information about ribociclib, to clarify specific aspects of the original protocol and to introduce the option for treatment beyond radiologic progression at the investigators discretion.

14 Aug 2017

This amendment was intended to correct mistakes in the protocol

05 May 2019

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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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Clinical Benefit Rate (CBR) in women and men with hormone receptor positiv, HER-2 negative breast cancer treated with ribocilib and letrozole

Primary: Clinical Benefit Rate (CBR) in women and men with hormone receptor positiv, HER-2 negative breast cancer treated with ribocilib and letrozole

Secondary: CBR

Secondary: CBR

Secondary: Progression free survival (PFS) for different populations - Kaplan-Meier estimates (%, 95% CI)

Secondary: Progression free survival (PFS) for different populations - Kaplan-Meier estimates (%, 95% CI)

Secondary: Progression free survival (PFS) for different populations - Median time to progression or death with 95% CI [months]

Secondary: Progression free survival (PFS) for different populations - Median time to progression or death with 95% CI [months]

Secondary: Overall Survival (OS) - Kaplan-Meier estimates (%, 95% CI)

Secondary: Overall Survival (OS) - Kaplan-Meier estimates (%, 95% CI)

Secondary: Overall Survival (OS) - Median time to progression or death with 95% CI [months]

Secondary: Overall Survival (OS) - Median time to progression or death with 95% CI [months]

Secondary: Overall Survival (OS) - number of deaths

Secondary: Overall Survival (OS) - number of deaths

Secondary: Overall response rate (ORR) - Kaplan-Meier estimates (%, 95% CI)

Secondary: Overall response rate (ORR) - Kaplan-Meier estimates (%, 95% CI)

Secondary: Patient reported Quality of Life (QoL) via EORTC QLQ-C30

Secondary: Patient reported Quality of Life (QoL) via EORTC QLQ-C30

Secondary: Patient reported Quality of Life (QoL) via EORTC BR-23 - change from baseline at Week 24 (Cycle 7)

Secondary: Patient reported Quality of Life (QoL) via EORTC BR-23 - change from baseline at Week 24 (Cycle 7)

Secondary: To evaluate the safety and tolerability of ribociclib in combination with letrozole (and goserelin in premenopausal patients) - via collection of Treatment Emergent Adverse Events (TEAE)

Secondary: To evaluate the safety and tolerability of ribociclib in combination with letrozole (and goserelin in premenopausal patients) - via collection of Treatment Emergent Adverse Events (TEAE)

Secondary: Time to 10% deterioration in the European Organisation for Research and Treatment of Cancer (EORTC) global health status

Secondary: Time to 10% deterioration in the European Organisation for Research and Treatment of Cancer (EORTC) global health status

Post-hoc: All Collected Deaths

Post-hoc: All Collected Deaths

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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