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Clinical Trial Results:
An open-label, multi-center, expanded access study for postmenopausal women with hormone receptor-positive locally advanced or metastatic breast cancer who have progressed following prior endocrine therapy, investigating the treatment of everolimus (RAD001) in combination with exemestane

Summary
EudraCT number	2012-000073-23
Trial protocol	AT NL SE NO ES DK FI BE CZ IT HU IE SK BG
Global end of trial date	01 Sep 2014

Results information
Results version number	v1(current)
This version publication date	27 Nov 2019
First version publication date	27 Nov 2019
Other versions

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

CRAD001YIC04

ISRCTN number

-

US NCT number

-

WHO universal trial number (UTN)

-

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharmaceuticals AG, +41 613241111,

Scientific contact

Clinical Disclosure Office, Novartis Pharmaceuticals AG, +41 613241111,

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

Final

Date of interim/final analysis

01 Sep 2014

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

01 Sep 2014

Was the trial ended prematurely?

No

Main objective of the trial

To evaluate safety of everolimus in postmenopausal women with hormone receptor-positive locally advanced or metastatic breast cancer after recurrence or progression following Non-steroidal aromatase inhibitors (NSAIs) treatment.

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

16 May 2012

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 71

Country: Number of subjects enrolled

Norway: 20

Country: Number of subjects enrolled

Poland: 47

Country: Number of subjects enrolled

Slovakia: 20

Country: Number of subjects enrolled

Spain: 429

Country: Number of subjects enrolled

Sweden: 6

Country: Number of subjects enrolled

Austria: 4

Country: Number of subjects enrolled

Belgium: 237

Country: Number of subjects enrolled

Bulgaria: 35

Country: Number of subjects enrolled

Denmark: 8

Country: Number of subjects enrolled

Finland: 10

Country: Number of subjects enrolled

Hungary: 67

Country: Number of subjects enrolled

Italy: 1153

Country: Number of subjects enrolled

Romania: 26

Worldwide total number of subjects

2133

EEA total number of subjects

2133

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)

1171

From 65 to 84 years

950

85 years and over

12

Subject disposition

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Recruitment details

This was a multi-center, open-label, single arm, Phase III b, expanded access study. In this study up to 2500 patients from up to 500 centers were to be recruited.

Screening details

A total of 2133 postmenopausal female subjects with advanced or metastatic breast cancer were enrolled in the study, out of which, 2131 were included in the safety population.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Everolimus + Exemestane

Arm description

Subjects received everolimus 10 mg (2x5mg) in combination with exemestane 25 mg, orally, once daily.

Arm type

Experimental

Investigational medicinal product name

Everolimus

Investigational medicinal product code

RAD001

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Two everolimus tablets 5 mg or one everolimus tablet 10 mg, orally, once daily.

Investigational medicinal product name

Exemestane

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Exemestane 25 mg tablet, orally, once daily.

Number of subjects in period 1	Everolimus + Exemestane
Started	2133
Completed	82
Not completed	2051
Abnormal laboratory value(s)	11
Disease progression	786
Unsatisfactory therapeutic effect	6
Administrative problems	2
Adverse event(s)	338
Abnormal test procedure result(s)	1
Subject withdrew consent	72
Everolimus locally reimbursed	713
Protocol violation	35
Death	32
Other	28
Subject's condition no longer requires study drug	14
Lost to follow-up	13

Baseline characteristics

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Reporting group title

Everolimus + Exemestane

Reporting group description

Subjects received everolimus 10 mg (2x5mg) in combination with exemestane 25 mg, orally, once daily.

Reporting group values	Everolimus + Exemestane	Total
Number of subjects	2133	2133
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	1171	1171
From 65-84 years	950	950
85 years and over	12	12
Age continuous
Units: years
arithmetic mean (standard deviation)	62.7 ( 9.86 )	-
Gender categorical
Units: Subjects
Female	2133	2133
Male	0	0

End points

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Reporting group title

Everolimus + Exemestane

Reporting group description

Subjects received everolimus 10 mg (2x5mg) in combination with exemestane 25 mg, orally, once daily.

Primary: Number of Subjects with Adverse Events (AEs)

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End point title

Number of Subjects with Adverse Events (AEs) ^[1]

End point description

An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. An AE includes any noxious, pathological, or unintended change in anatomical, physiological, or metabolic functions as indicated by physical signs or symptoms occurring in any phase of the clinical study whether or not considered related to the study medication. Safety population included all subjects who received at least one dose of everolimus or exemestane and had at least one post-baseline safety assessment.

End point type

Primary

End point timeframe

From first dose of study treatment through 28 days after last dose of study treatment (Up to approximately 24 months)

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: No statistical hypothesis was planned for this endpoint.

End point values	Everolimus + Exemestane
Number of subjects analysed	2131
Units: Subjects
number (not applicable)	2018

No statistical analyses for this end point

Secondary: Number of Subjects with Grade 3/4 AEs

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End point title

Number of Subjects with Grade 3/4 AEs

End point description

Subjects with grade 3 and 4 severity AE were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, unless otherwise specified. If CTCAE grading did not exist for an adverse event, the severity of mild, moderate, severe, and life-threatening, corresponding to grade 1 to grade 4, was used. Safety population included all subjects who received at least one dose of everolimus or exemestane and had at least one post-baseline safety assessment.

End point type

Secondary

End point timeframe

From first dose of study treatment through 28 days after last dose of study treatment (Up to approximately 24 months)

End point values	Everolimus + Exemestane
Number of subjects analysed	2131
Units: Subjects
number (not applicable)	214

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit

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

17.1

Reporting group title

Without Chemo in Metastatic Setting

Reporting group description

Without Chemo in Metastatic Setting

Reporting group title

With Chemo in Metastatic Setting

Reporting group description

With Chemo in Metastatic Setting

Serious adverse events	Without Chemo in Metastatic Setting	With Chemo in Metastatic Setting
Total subjects affected by serious adverse events
subjects affected / exposed	163 / 847 (19.24%)	288 / 1284 (22.43%)
number of deaths (all causes)	24	97
number of deaths resulting from adverse events	1	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive lobular breast carcinoma
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphangiosis carcinomatosa
subjects affected / exposed	0 / 847 (0.00%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant ascites
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to meninges
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metastatic pain
subjects affected / exposed	1 / 847 (0.12%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour of ampulla of Vater
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Blood pressure fluctuation
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Circulatory collapse
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 847 (0.12%)	5 / 1284 (0.39%)
occurrences causally related to treatment / all	0 / 1	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Embolism
subjects affected / exposed	0 / 847 (0.00%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypovolaemic shock
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphoedema
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant hypertension
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic venous thrombosis
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Shock
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombophlebitis
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombophlebitis superficial
subjects affected / exposed	2 / 847 (0.24%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	1 / 847 (0.12%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Venous thrombosis limb
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 847 (0.12%)	9 / 1284 (0.70%)
occurrences causally related to treatment / all	0 / 1	4 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Death
subjects affected / exposed	1 / 847 (0.12%)	3 / 1284 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 3
deaths causally related to treatment / all	1 / 1	0 / 3
Disease progression
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Face oedema
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fatigue
subjects affected / exposed	4 / 847 (0.47%)	7 / 1284 (0.55%)
occurrences causally related to treatment / all	4 / 4	3 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	4 / 847 (0.47%)	12 / 1284 (0.93%)
occurrences causally related to treatment / all	0 / 4	2 / 12
deaths causally related to treatment / all	0 / 0	1 / 2
Hyperpyrexia
subjects affected / exposed	0 / 847 (0.00%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperthermia malignant
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 847 (0.00%)	3 / 1284 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	3 / 847 (0.35%)	6 / 1284 (0.47%)
occurrences causally related to treatment / all	1 / 3	7 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 847 (0.12%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Performance status decreased
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	8 / 847 (0.94%)	26 / 1284 (2.02%)
occurrences causally related to treatment / all	3 / 8	9 / 26
deaths causally related to treatment / all	0 / 0	0 / 0
Sense of oppression
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Reproductive system and breast disorders
Breast ulceration
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vaginal inflammation
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema
subjects affected / exposed	1 / 847 (0.12%)	3 / 1284 (0.23%)
occurrences causally related to treatment / all	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Chylothorax
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cough
subjects affected / exposed	1 / 847 (0.12%)	6 / 1284 (0.47%)
occurrences causally related to treatment / all	0 / 1	3 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphonia
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	17 / 847 (2.01%)	35 / 1284 (2.73%)
occurrences causally related to treatment / all	7 / 18	13 / 35
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea at rest
subjects affected / exposed	0 / 847 (0.00%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	5 / 847 (0.59%)	5 / 1284 (0.39%)
occurrences causally related to treatment / all	5 / 5	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Orthopnoea
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	12 / 847 (1.42%)	14 / 1284 (1.09%)
occurrences causally related to treatment / all	3 / 12	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	14 / 847 (1.65%)	33 / 1284 (2.57%)
occurrences causally related to treatment / all	14 / 14	29 / 33
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 847 (0.12%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	4 / 847 (0.47%)	4 / 1284 (0.31%)
occurrences causally related to treatment / all	1 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	2 / 847 (0.24%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Respiratory failure
subjects affected / exposed	2 / 847 (0.24%)	6 / 1284 (0.47%)
occurrences causally related to treatment / all	0 / 2	3 / 6
deaths causally related to treatment / all	0 / 0	0 / 1
Psychiatric disorders
Confusional state
subjects affected / exposed	1 / 847 (0.12%)	3 / 1284 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Disorientation
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Social avoidant behaviour
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 847 (0.00%)	4 / 1284 (0.31%)
occurrences causally related to treatment / all	0 / 0	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 847 (0.00%)	4 / 1284 (0.31%)
occurrences causally related to treatment / all	0 / 0	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	3 / 847 (0.35%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	3 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood electrolytes decreased
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood urea increased
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eastern cooperative oncology group performance status worsened
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ejection fraction decreased
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 847 (0.00%)	4 / 1284 (0.31%)
occurrences causally related to treatment / all	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sputum abnormal
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	1 / 847 (0.12%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Acetabulum fracture
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 847 (0.00%)	4 / 1284 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Hand fracture
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	1 / 847 (0.12%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Joint injury
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis chemical
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post-traumatic pain
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Radiation pneumonitis
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Traumatic intracranial haemorrhage
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Arrhythmia
subjects affected / exposed	1 / 847 (0.12%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	3 / 847 (0.35%)	5 / 1284 (0.39%)
occurrences causally related to treatment / all	0 / 3	2 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 847 (0.00%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiac failure
subjects affected / exposed	2 / 847 (0.24%)	8 / 1284 (0.62%)
occurrences causally related to treatment / all	1 / 2	5 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	1 / 847 (0.12%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiopulmonary failure
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiovascular insufficiency
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Palpitations
subjects affected / exposed	2 / 847 (0.24%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Tachyarrhythmia
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tachycardia paroxysmal
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Ataxia
subjects affected / exposed	0 / 847 (0.00%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral haematoma
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 847 (0.00%)	3 / 1284 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Cerebrovascular accident
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Coma hepatic
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Convulsion
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 847 (0.00%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dysarthria
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dysgeusia
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Facial paresis
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Headache
subjects affected / exposed	0 / 847 (0.00%)	3 / 1284 (0.23%)
occurrences causally related to treatment / all	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic encephalopathy
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Loss of consciousness
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myelopathy
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorder
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Somnolence
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	1 / 847 (0.12%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	1 / 847 (0.12%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Syncope
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	8 / 847 (0.94%)	19 / 1284 (1.48%)
occurrences causally related to treatment / all	6 / 8	11 / 21
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 847 (0.12%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 847 (0.00%)	5 / 1284 (0.39%)
occurrences causally related to treatment / all	0 / 0	4 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytosis
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Diplopia
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eyelid ptosis
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Periorbital oedema
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	3 / 847 (0.35%)	11 / 1284 (0.86%)
occurrences causally related to treatment / all	0 / 3	3 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 847 (0.12%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anal inflammation
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	3 / 847 (0.35%)	10 / 1284 (0.78%)
occurrences causally related to treatment / all	0 / 3	1 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 847 (0.12%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Crohn's disease
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	14 / 847 (1.65%)	6 / 1284 (0.47%)
occurrences causally related to treatment / all	10 / 14	5 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric disorder
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric perforation
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	1 / 847 (0.12%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis haemorrhagic
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal perforation
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 847 (0.00%)	3 / 1284 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	4 / 847 (0.47%)	3 / 1284 (0.23%)
occurrences causally related to treatment / all	5 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Obstruction gastric
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema mouth
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 847 (0.00%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 847 (0.12%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	6 / 847 (0.71%)	4 / 1284 (0.31%)
occurrences causally related to treatment / all	6 / 6	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Subileus
subjects affected / exposed	0 / 847 (0.00%)	3 / 1284 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	6 / 847 (0.71%)	7 / 1284 (0.55%)
occurrences causally related to treatment / all	3 / 6	2 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Biliary colic
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 847 (0.00%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	1 / 847 (0.12%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	2 / 847 (0.24%)	3 / 1284 (0.23%)
occurrences causally related to treatment / all	0 / 2	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Hepatic function abnormal
subjects affected / exposed	1 / 847 (0.12%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	0 / 847 (0.00%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice cholestatic
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver disorder
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Erythema
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rash pruritic
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Crush syndrome
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Polyuria
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Prerenal failure
subjects affected / exposed	1 / 847 (0.12%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal colic
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	4 / 847 (0.47%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	1 / 4	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	4 / 847 (0.47%)	7 / 1284 (0.55%)
occurrences causally related to treatment / all	4 / 4	4 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure chronic
subjects affected / exposed	1 / 847 (0.12%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	2 / 847 (0.24%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal tubular necrosis
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Hypercalcaemia of malignancy
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 847 (0.12%)	3 / 1284 (0.23%)
occurrences causally related to treatment / all	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Back pain
subjects affected / exposed	2 / 847 (0.24%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bone lesion
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bone pain
subjects affected / exposed	0 / 847 (0.00%)	5 / 1284 (0.39%)
occurrences causally related to treatment / all	0 / 0	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 847 (0.00%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Neck pain
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 847 (0.00%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 847 (0.00%)	3 / 1284 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	0 / 847 (0.00%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	2 / 847 (0.24%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridial infection
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cytomegalovirus mononucleosis
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	2 / 847 (0.24%)	4 / 1284 (0.31%)
occurrences causally related to treatment / all	1 / 2	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 847 (0.00%)	3 / 1284 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes virus infection
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster disseminated
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	1 / 847 (0.12%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Parotitis
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	4 / 847 (0.47%)	7 / 1284 (0.55%)
occurrences causally related to treatment / all	2 / 4	4 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyopneumothorax
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 847 (0.12%)	3 / 1284 (0.23%)
occurrences causally related to treatment / all	0 / 1	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Salmonellosis
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 847 (0.12%)	4 / 1284 (0.31%)
occurrences causally related to treatment / all	0 / 1	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 1
Staphylococcal sepsis
subjects affected / exposed	0 / 847 (0.00%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 847 (0.12%)	4 / 1284 (0.31%)
occurrences causally related to treatment / all	1 / 1	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 847 (0.12%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Vulval abscess
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Cachexia
subjects affected / exposed	2 / 847 (0.24%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2
Decreased appetite
subjects affected / exposed	3 / 847 (0.35%)	7 / 1284 (0.55%)
occurrences causally related to treatment / all	2 / 3	2 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	2 / 847 (0.24%)	3 / 1284 (0.23%)
occurrences causally related to treatment / all	2 / 2	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 847 (0.00%)	2 / 1284 (0.16%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Fluid retention
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Food intolerance
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	1 / 847 (0.12%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercholesterolaemia
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	8 / 847 (0.94%)	7 / 1284 (0.55%)
occurrences causally related to treatment / all	8 / 8	4 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperlipidaemia
subjects affected / exposed	0 / 847 (0.00%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	2 / 847 (0.24%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	4 / 847 (0.47%)	5 / 1284 (0.39%)
occurrences causally related to treatment / all	2 / 4	3 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	5 / 847 (0.59%)	1 / 1284 (0.08%)
occurrences causally related to treatment / all	2 / 5	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Polydipsia
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Type 1 diabetes mellitus
subjects affected / exposed	1 / 847 (0.12%)	0 / 1284 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	Without Chemo in Metastatic Setting	With Chemo in Metastatic Setting
Total subjects affected by non serious adverse events
subjects affected / exposed	770 / 847 (90.91%)	1153 / 1284 (89.80%)
Vascular disorders
Hypertension
subjects affected / exposed	38 / 847 (4.49%)	28 / 1284 (2.18%)
occurrences all number	43	29
Lymphoedema
subjects affected / exposed	23 / 847 (2.72%)	22 / 1284 (1.71%)
occurrences all number	24	22
General disorders and administration site conditions
Asthenia
subjects affected / exposed	193 / 847 (22.79%)	284 / 1284 (22.12%)
occurrences all number	215	323
Fatigue
subjects affected / exposed	126 / 847 (14.88%)	163 / 1284 (12.69%)
occurrences all number	140	169
Oedema peripheral
subjects affected / exposed	115 / 847 (13.58%)	138 / 1284 (10.75%)
occurrences all number	129	169
Pyrexia
subjects affected / exposed	96 / 847 (11.33%)	176 / 1284 (13.71%)
occurrences all number	117	213
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	108 / 847 (12.75%)	142 / 1284 (11.06%)
occurrences all number	117	158
Dyspnoea
subjects affected / exposed	71 / 847 (8.38%)	111 / 1284 (8.64%)
occurrences all number	75	118
Epistaxis
subjects affected / exposed	58 / 847 (6.85%)	88 / 1284 (6.85%)
occurrences all number	59	97
Pneumonitis
subjects affected / exposed	63 / 847 (7.44%)	104 / 1284 (8.10%)
occurrences all number	69	108
Psychiatric disorders
Insomnia
subjects affected / exposed	25 / 847 (2.95%)	40 / 1284 (3.12%)
occurrences all number	25	41
Investigations
Alanine aminotransferase increased
subjects affected / exposed	47 / 847 (5.55%)	66 / 1284 (5.14%)
occurrences all number	49	75
Aspartate aminotransferase increased
subjects affected / exposed	41 / 847 (4.84%)	69 / 1284 (5.37%)
occurrences all number	43	76
Blood cholesterol increased
subjects affected / exposed	16 / 847 (1.89%)	43 / 1284 (3.35%)
occurrences all number	18	43
Blood creatinine increased
subjects affected / exposed	28 / 847 (3.31%)	26 / 1284 (2.02%)
occurrences all number	28	32
Blood lactate dehydrogenase increased
subjects affected / exposed	17 / 847 (2.01%)	31 / 1284 (2.41%)
occurrences all number	17	31
Gamma-glutamyltransferase increased
subjects affected / exposed	41 / 847 (4.84%)	84 / 1284 (6.54%)
occurrences all number	42	87
Weight decreased
subjects affected / exposed	80 / 847 (9.45%)	135 / 1284 (10.51%)
occurrences all number	83	140
Nervous system disorders
Dizziness
subjects affected / exposed	23 / 847 (2.72%)	19 / 1284 (1.48%)
occurrences all number	24	19
Dysgeusia
subjects affected / exposed	84 / 847 (9.92%)	92 / 1284 (7.17%)
occurrences all number	89	93
Headache
subjects affected / exposed	54 / 847 (6.38%)	84 / 1284 (6.54%)
occurrences all number	55	97
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	107 / 847 (12.63%)	179 / 1284 (13.94%)
occurrences all number	130	204
Leukopenia
subjects affected / exposed	19 / 847 (2.24%)	22 / 1284 (1.71%)
occurrences all number	23	25
Neutropenia
subjects affected / exposed	24 / 847 (2.83%)	51 / 1284 (3.97%)
occurrences all number	27	68
Thrombocytopenia
subjects affected / exposed	35 / 847 (4.13%)	88 / 1284 (6.85%)
occurrences all number	42	123
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	27 / 847 (3.19%)	30 / 1284 (2.34%)
occurrences all number	29	31
Abdominal pain upper
subjects affected / exposed	28 / 847 (3.31%)	37 / 1284 (2.88%)
occurrences all number	29	39
Aphthous stomatitis
subjects affected / exposed	17 / 847 (2.01%)	25 / 1284 (1.95%)
occurrences all number	17	27
Constipation
subjects affected / exposed	37 / 847 (4.37%)	70 / 1284 (5.45%)
occurrences all number	39	76
Diarrhoea
subjects affected / exposed	158 / 847 (18.65%)	187 / 1284 (14.56%)
occurrences all number	183	225
Dry mouth
subjects affected / exposed	25 / 847 (2.95%)	34 / 1284 (2.65%)
occurrences all number	25	35
Nausea
subjects affected / exposed	94 / 847 (11.10%)	156 / 1284 (12.15%)
occurrences all number	103	167
Stomatitis
subjects affected / exposed	474 / 847 (55.96%)	649 / 1284 (50.55%)
occurrences all number	608	850
Vomiting
subjects affected / exposed	73 / 847 (8.62%)	94 / 1284 (7.32%)
occurrences all number	79	106
Hepatobiliary disorders
Hypertransaminasaemia
subjects affected / exposed	6 / 847 (0.71%)	28 / 1284 (2.18%)
occurrences all number	6	31
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	27 / 847 (3.19%)	19 / 1284 (1.48%)
occurrences all number	27	19
Dry skin
subjects affected / exposed	36 / 847 (4.25%)	39 / 1284 (3.04%)
occurrences all number	38	41
Erythema
subjects affected / exposed	30 / 847 (3.54%)	33 / 1284 (2.57%)
occurrences all number	35	36
Pruritus
subjects affected / exposed	76 / 847 (8.97%)	90 / 1284 (7.01%)
occurrences all number	82	96
Rash
subjects affected / exposed	161 / 847 (19.01%)	190 / 1284 (14.80%)
occurrences all number	177	213
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	63 / 847 (7.44%)	96 / 1284 (7.48%)
occurrences all number	71	101
Back pain
subjects affected / exposed	47 / 847 (5.55%)	50 / 1284 (3.89%)
occurrences all number	48	52
Bone pain
subjects affected / exposed	52 / 847 (6.14%)	71 / 1284 (5.53%)
occurrences all number	53	81
Myalgia
subjects affected / exposed	27 / 847 (3.19%)	36 / 1284 (2.80%)
occurrences all number	30	37
Pain in extremity
subjects affected / exposed	37 / 847 (4.37%)	52 / 1284 (4.05%)
occurrences all number	39	54
Infections and infestations
Bronchitis
subjects affected / exposed	17 / 847 (2.01%)	12 / 1284 (0.93%)
occurrences all number	17	13
Cystitis
subjects affected / exposed	23 / 847 (2.72%)	33 / 1284 (2.57%)
occurrences all number	24	36
Nasopharyngitis
subjects affected / exposed	18 / 847 (2.13%)	21 / 1284 (1.64%)
occurrences all number	18	24
Urinary tract infection
subjects affected / exposed	37 / 847 (4.37%)	23 / 1284 (1.79%)
occurrences all number	39	29
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	134 / 847 (15.82%)	200 / 1284 (15.58%)
occurrences all number	136	220
Hypercholesterolaemia
subjects affected / exposed	71 / 847 (8.38%)	144 / 1284 (11.21%)
occurrences all number	76	151
Hyperglycaemia
subjects affected / exposed	118 / 847 (13.93%)	142 / 1284 (11.06%)
occurrences all number	128	167
Hypertriglyceridaemia
subjects affected / exposed	49 / 847 (5.79%)	74 / 1284 (5.76%)
occurrences all number	53	79
Hypocalcaemia
subjects affected / exposed	22 / 847 (2.60%)	21 / 1284 (1.64%)
occurrences all number	25	22
Hypokalaemia
subjects affected / exposed	27 / 847 (3.19%)	33 / 1284 (2.57%)
occurrences all number	32	39

More information

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Were there any global substantial amendments to the protocol? Yes

10 Oct 2012

The protocol was amended to reflect the indication granted by European Commission in Jul 2012, i.e. “Afinitor is indicated for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2/neu) negative advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor” • Inclusion criteria 1 updated to “Adult women (≥ 18 years of age) with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy, whose disease recurred or progressed following a Non-steroidal aromatase inhibitor (NSAI) treatment • The wording “refractory to NSAIs” has been changed to “after recurrence or progression following NSAIs treatment” • Addition of only PgR-positive breast cancer and the deletion of disease refractory to NSAIs • Exclusion criteria was updated to for Delete criteria regarding previous treatment with exemestane or mammalian target of rapamycin (mTOR) inhibitors, bilateral diffuse lymphangitic carcinomatosis, and subjects who test positive for hepatitis B or C • Added criteria regarding pre-menopausal, pregnant or lactating women, the known hypersensitivity to exemestane or any excipients, the rare hereditary problems of galactose intolerance and subject with positive baseline hepatitis B or C results the Screening period was extended to 28 days to allow time for prophylactic treatment • Management guidelines for specific toxicities were updated.

20 Dec 2012

The protocol was updated to better clarify the subject population. “Radiological or clinical evidence of recurrence or progression on last therapy prior to enrollment” has been added to inclusion criteria in order to make sure that subjects have relapsed on the last therapy prior to enrollment • A local sub-study was planned in two countries (Italy and Belgium) in 110 subjects newly enrolled in the core study with the aim of evaluating if Caphosol® is more effective than “standard care” (good mouth hygiene and mouth washes with normal saline) in reduction of incidence and severity of oral mucositis (OM) due to everolimus combination with exemestane.

10 Sep 2013

The protocol was updated to extend the study duration from 31 Jan 2014 till 30 June 2014 and to increase the number of subjects from 2200 to 2500 • The local sub-study that was planned to be performed in two countries (Italy and Belgium) in 110 subjects newly enrolled in the core study was dropped with this amendment.

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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