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Clinical Trial Results:
An open-label, multicenter, Phase I/II dose escalation study of oral GW572016 in combination with docetaxel (Taxotere) plus trastuzumab (Herceptin) in subjects previously untreated for ErbB2-overexpressing metastatic breast cancer

Summary
EudraCT number	2005-000846-35
Trial protocol	IE
Global end of trial date	22 Jun 2022

Results information
Results version number	v1(current)
This version publication date	20 Mar 2023
First version publication date	20 Mar 2023
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

EGF100161

ISRCTN number

US NCT number

NCT00251433

WHO universal trial number (UTN)

Other trial identifiers

Novartis: CLAP016A2101

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

Novartis Campus, Basel, Switzerland, 4002

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 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

22 Jun 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

22 Jun 2022

Was the trial ended prematurely?

Yes

Main objective of the trial

The purpose of this Phase I/II dose escalation study, LAP016A2101/EGF100161, was to evaluate the tumor response rate, as well as the safety, tolerability, and efficacy of this combination in subjects with previously untreated metastatic breast cancer (MBC) whose tumors over-express Human epidermal growth factor receptor 2 (HER2)/ epidermal growth factor receptor 2 (ErbB2) receptors.

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

26 Sep 2005

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 22

Country: Number of subjects enrolled

Ireland: 28

Country: Number of subjects enrolled

United States: 3

Worldwide total number of subjects

EEA total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

This study was conducted in 5 centers in 3 countries: France (2), Ireland (2), United States (1)

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase I: Dose Level 0

Arm description

Lapatinib 500 mg once daily (OD) with Docetaxel 60 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Arm type

Experimental

Investigational medicinal product name

Lapatinib

Investigational medicinal product code

Other name

GW572016

Pharmaceutical forms

Film-coated tablet, Tablet

Routes of administration

Oral use

Dosage and administration details

500mg OD

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection, Solution for injection/infusion, Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

60mg/m2 q3weeks

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for infusion, Powder for concentrate, Powder for concentrate for solution for infusion, Powder for concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose: 4mg/kg during first week, 2mg/kg once a week

Phase I: Dose Level 1

Arm description

Lapatinib 500 mg once daily (OD) with Docetaxel 75 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Arm type

Experimental

Investigational medicinal product name

Lapatinib

Investigational medicinal product code

Other name

GW572016

Pharmaceutical forms

Film-coated tablet, Tablet

Routes of administration

Oral use

Dosage and administration details

500mg OD

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection, Solution for injection/infusion, Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

75mg/m2 q3weeks

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for infusion, Powder for concentrate, Powder for concentrate for solution for infusion, Powder for concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose: 4mg/kg during first week, 2mg/kg once a week

Phase I: Dose Level 1A

Arm description

Lapatinib 750 mg once daily (OD) with Docetaxel 75 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Arm type

Experimental

Investigational medicinal product name

Lapatinib

Investigational medicinal product code

Other name

GW572016

Pharmaceutical forms

Film-coated tablet, Tablet

Routes of administration

Oral use

Dosage and administration details

750mg OD

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection, Solution for injection/infusion, Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

75mg/m2 q3weeks

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for infusion, Powder for concentrate, Powder for concentrate for solution for infusion, Powder for concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose: 4mg/kg during first week, 2mg/kg once a week

Phase I: Dose Level 1B

Arm description

Lapatinib 1000 mg once daily (OD) with Docetaxel 75 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Arm type

Experimental

Investigational medicinal product name

Lapatinib

Investigational medicinal product code

Other name

GW572016

Pharmaceutical forms

Film-coated tablet, Tablet

Routes of administration

Oral use

Dosage and administration details

1000mg OD

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection, Solution for injection/infusion, Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

75mg/m2 q3weeks

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for infusion, Powder for concentrate, Powder for concentrate for solution for infusion, Powder for concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose: 4mg/kg during first week, 2mg/kg once a week

Phase I: Dose Level 1C

Arm description

Lapatinib 1250 mg once daily (OD) with Docetaxel 75 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Arm type

Experimental

Investigational medicinal product name

Lapatinib

Investigational medicinal product code

Other name

GW572016

Pharmaceutical forms

Film-coated tablet, Tablet

Routes of administration

Oral use

Dosage and administration details

1250mg OD

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection, Solution for injection/infusion, Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

75mg/m2 q3weeks

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for infusion, Powder for concentrate, Powder for concentrate for solution for infusion, Powder for concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose: 4mg/kg during first week, 2mg/kg once a week

Phase I: Dose Level 1D

Arm description

Lapatinib 1500 mg once daily (OD) with Docetaxel 75 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Arm type

Experimental

Investigational medicinal product name

Lapatinib

Investigational medicinal product code

Other name

GW572016

Pharmaceutical forms

Film-coated tablet, Tablet

Routes of administration

Oral use

Dosage and administration details

1500mg OD

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection, Solution for injection/infusion, Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

75mg/m2 q3weeks

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for infusion, Powder for concentrate, Powder for concentrate for solution for infusion, Powder for concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose: 4mg/kg during first week, 2mg/kg once a week

Phase I: Dose Level 2

Arm description

Lapatinib 500 mg once daily (OD) with Docetaxel 100 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Arm type

Experimental

Investigational medicinal product name

Lapatinib

Investigational medicinal product code

Other name

GW572016

Pharmaceutical forms

Film-coated tablet, Tablet

Routes of administration

Oral use

Dosage and administration details

500mg OD

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection, Solution for injection/infusion, Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

100mg/m2 q3weeks

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for infusion, Powder for concentrate, Powder for concentrate for solution for infusion, Powder for concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose: 4mg/kg during first week, 2mg/kg once a week

Phase I: Dose Level 3

Arm description

Lapatinib 750 mg once daily (OD) with Docetaxel 100 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Arm type

Experimental

Investigational medicinal product name

Lapatinib

Investigational medicinal product code

Other name

GW572016

Pharmaceutical forms

Film-coated tablet, Tablet

Routes of administration

Oral use

Dosage and administration details

750mg OD

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection, Solution for injection/infusion, Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

100mg/m2 q3weeks

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for infusion, Powder for concentrate, Powder for concentrate for solution for infusion, Powder for concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose: 4mg/kg during first week, 2mg/kg once a week

Phase I: Dose Level 4

Arm description

Lapatinib 1000 mg once daily (OD) with Docetaxel 100 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Arm type

Experimental

Investigational medicinal product name

Lapatinib

Investigational medicinal product code

Other name

GW572016

Pharmaceutical forms

Film-coated tablet, Tablet

Routes of administration

Oral use

Dosage and administration details

1000mg OD

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection, Solution for injection/infusion, Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

100mg/m2 q3weeks

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for infusion, Powder for concentrate, Powder for concentrate for solution for infusion, Powder for concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose: 4mg/kg during first week, 2mg/kg once a week

Phase I: Dose Level 5

Arm description

Lapatinib 1250 mg once daily (OD) with Docetaxel 100 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Arm type

Experimental

Investigational medicinal product name

Lapatinib

Investigational medicinal product code

Other name

GW572016

Pharmaceutical forms

Film-coated tablet, Tablet

Routes of administration

Oral use

Dosage and administration details

1250mg OD

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection, Solution for injection/infusion, Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

100mg/m2 q3weeks

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for infusion, Powder for concentrate, Powder for concentrate for solution for infusion, Powder for concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose: 4mg/kg during first week, 2mg/kg once a week

Number of subjects in period 1	Phase I: Dose Level 0	Phase I: Dose Level 1	Phase I: Dose Level 1A	Phase I: Dose Level 1B	Phase I: Dose Level 1C	Phase I: Dose Level 1D	Phase I: Dose Level 2	Phase I: Dose Level 3	Phase I: Dose Level 4	Phase I: Dose Level 5
Started	6	3	12	5	4	3	5	6	6	3
Completed	6	1	5	3	1	1	4	3	0	2
Not completed	0	2	7	2	3	2	1	3	6	1
Adverse event, non-fatal	-	-	-	-	1	-	1	1	1	-
Other pre-specified reasons defined in protocol	-	2	7	2	2	2	-	2	5	1

Baseline characteristics

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Reporting group title

Phase I: Dose Level 0

Reporting group description

Lapatinib 500 mg once daily (OD) with Docetaxel 60 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Reporting group title

Phase I: Dose Level 1

Reporting group description

Lapatinib 500 mg once daily (OD) with Docetaxel 75 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Reporting group title

Phase I: Dose Level 1A

Reporting group description

Lapatinib 750 mg once daily (OD) with Docetaxel 75 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Reporting group title

Phase I: Dose Level 1B

Reporting group description

Lapatinib 1000 mg once daily (OD) with Docetaxel 75 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Reporting group title

Phase I: Dose Level 1C

Reporting group description

Lapatinib 1250 mg once daily (OD) with Docetaxel 75 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Reporting group title

Phase I: Dose Level 1D

Reporting group description

Lapatinib 1500 mg once daily (OD) with Docetaxel 75 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Reporting group title

Phase I: Dose Level 2

Reporting group description

Lapatinib 500 mg once daily (OD) with Docetaxel 100 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Reporting group title

Phase I: Dose Level 3

Reporting group description

Lapatinib 750 mg once daily (OD) with Docetaxel 100 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Reporting group title

Phase I: Dose Level 4

Reporting group description

Lapatinib 1000 mg once daily (OD) with Docetaxel 100 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Reporting group title

Phase I: Dose Level 5

Reporting group description

Lapatinib 1250 mg once daily (OD) with Docetaxel 100 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Reporting group values	Phase I: Dose Level 0	Phase I: Dose Level 1	Phase I: Dose Level 1A	Phase I: Dose Level 1B	Phase I: Dose Level 1C	Phase I: Dose Level 1D	Phase I: Dose Level 2	Phase I: Dose Level 3	Phase I: Dose Level 4	Phase I: Dose Level 5	Total
Number of subjects	6	3	12	5	4	3	5	6	6	3	53
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	0	0	0
Adults (18-64 years)	6	3	11	4	4	3	5	6	4	3	49
From 65-84 years	0	0	1	1	0	0	0	0	2	0	4
85 years and over	0	0	0	0	0	0	0	0	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	45.2 ( 11.92 )	49.7 ( 7.51 )	46.2 ( 9.43 )	54.4 ( 12.74 )	44.0 ( 10.03 )	53.0 ( 7.00 )	50.0 ( 10.70 )	53.7 ( 8.04 )	55.8 ( 10.93 )	43.3 ( 11.02 )	-
Sex: Female, Male
Units: Participants
Female	6	3	12	5	4	3	5	6	6	3	53
Male	0	0	0	0	0	0	0	0	0	0	0
Race/Ethnicity, Customized
Units: Subjects
White	6	3	12	5	4	3	5	5	6	3	52
Asian	0	0	0	0	0	0	0	1	0	0	1

End points

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Reporting group title

Phase I: Dose Level 0

Reporting group description

Lapatinib 500 mg once daily (OD) with Docetaxel 60 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Reporting group title

Phase I: Dose Level 1

Reporting group description

Lapatinib 500 mg once daily (OD) with Docetaxel 75 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Reporting group title

Phase I: Dose Level 1A

Reporting group description

Lapatinib 750 mg once daily (OD) with Docetaxel 75 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Reporting group title

Phase I: Dose Level 1B

Reporting group description

Lapatinib 1000 mg once daily (OD) with Docetaxel 75 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Reporting group title

Phase I: Dose Level 1C

Reporting group description

Lapatinib 1250 mg once daily (OD) with Docetaxel 75 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Reporting group title

Phase I: Dose Level 1D

Reporting group description

Lapatinib 1500 mg once daily (OD) with Docetaxel 75 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Reporting group title

Phase I: Dose Level 2

Reporting group description

Lapatinib 500 mg once daily (OD) with Docetaxel 100 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Reporting group title

Phase I: Dose Level 3

Reporting group description

Lapatinib 750 mg once daily (OD) with Docetaxel 100 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Reporting group title

Phase I: Dose Level 4

Reporting group description

Lapatinib 1000 mg once daily (OD) with Docetaxel 100 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Reporting group title

Phase I: Dose Level 5

Reporting group description

Lapatinib 1250 mg once daily (OD) with Docetaxel 100 mg/m2 once every 3 weekly (q3weeks) with Trastuzumab (Loading dose: 4mg/kg during first week, 2mg/kg once a week).

Primary: Phase I: Determination of the optimally tolerated regimen (OTR)

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End point title

Phase I: Determination of the optimally tolerated regimen (OTR) ^[1]

End point description

Enrollment to the Phase I part of the study was halted on 04 August 2010 after 3 subjects were enrolled into the cohort dose level 5 (lapatinib 1250 mg) that was opened for enrollment on 23 November 2009 and completed enrollment by 03 June 2010. No subjects experienced a DLT at this dose level, thus the optimally tolerated regimen (OTR) dose regimen of lapatinib with the higher docetaxel dose (100 mg/m2) was not determined. The Phase II part of the study did not proceed.

End point type

Primary

End point timeframe

From first initiated treatment on 19-Jan-2006 to the data cut-off date for primary CSR on 9 Dec 2009, assessed approximately up to 4 years.

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: Only descriptive analysis performed

End point values	Phase I: Dose Level 0	Phase I: Dose Level 1	Phase I: Dose Level 1A	Phase I: Dose Level 1B	Phase I: Dose Level 1C	Phase I: Dose Level 1D	Phase I: Dose Level 2	Phase I: Dose Level 3	Phase I: Dose Level 4	Phase I: Dose Level 5
Number of subjects analysed	0 ^[2]	0 ^[3]	0 ^[4]	0 ^[5]	0 ^[6]	0 ^[7]	0 ^[8]	0 ^[9]	0 ^[10]	0 ^[11]
Units: Participants

Notes
[2] - Not estimable due to early termination of the study
[3] - Not estimable due to early termination of the study
[4] - Not estimable due to early termination of the study
[5] - Not estimable due to early termination of the study
[6] - Not estimable due to early termination of the study
[7] - Not estimable due to early termination of the study
[8] - Not estimable due to early termination of the study
[9] - Not estimable due to early termination of the study
[10] - Not estimable due to early termination of the study
[11] - Not estimable due to early termination of the study

No statistical analyses for this end point

Secondary: Phase I: Overall Response Rate (ORR)

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End point title

Phase I: Overall Response Rate (ORR)

End point description

Overall response rate (ORR) was defined as the percentage of subjects achieving either a confirmed complete response (CR) or partial response (PR). This was based on confirmed responses from the Investigator assessment of best overall response (the best response from the start of the treatment until disease progression/recurrence).

End point type

Secondary

End point timeframe

From first initiated treatment on 19-Jan-2006 to the data cut-off date for primary CSR on 9 Dec 2009, assessed approximately up to 4 years.

End point values	Phase I: Dose Level 0	Phase I: Dose Level 1	Phase I: Dose Level 1A	Phase I: Dose Level 1B	Phase I: Dose Level 1C	Phase I: Dose Level 1D	Phase I: Dose Level 2	Phase I: Dose Level 3	Phase I: Dose Level 4	Phase I: Dose Level 5
Number of subjects analysed	6	2	10	4	3	3	3	5	6	3
Units: Percentage of Participants
number (confidence interval 95%)
Best Response with Bone Scan Confirmation	67 (22.3 to 95.7)	50 (1.3 to 98.7)	30 (6.7 to 65.2)	999 (999 to 999)	67 (9.4 to 99.2)	33 (0.8 to 90.6)	33 (0.8 to 90.6)	40 (5.3 to 85.3)	33 (4.3 to 77.7)	999 (999 to 999)
Best Response without Bone Scan Confirmation	67 (22.3 to 95.7)	100 (15.8 to 100.0)	60 (26.2 to 87.8)	25 (0.6 to 80.6)	100 (29.2 to 100.0)	67 (9.4 to 99.2)	33 (0.8 to 90.6)	100 (47.8 to 100.0)	83 (35.9 to 99.6)	67 (9.4 to 99.2)

No statistical analyses for this end point

Secondary: Phase I: Duration of Response (DoR)

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End point title

Phase I: Duration of Response (DoR)

End point description

For subjects who did show CR or PR, duration of response was defined to be the time from first documented evidence of PR or CR until the first documented sign of disease progression or death due to breast cancer. Disease progression was based on the assessments from the blinded, independent review of objective evidence (e.g., radiological scans and medical photographs). For subjects who did not progress, or die, duration of response was censored at the time of the last independently-assessed radiological scan preceding the initiation of any alternative anti-cancer therapy.

End point type

Secondary

End point timeframe

From first initiated treatment on 19-Jan-2006 to the data cut-off date for primary CSR on 9 Dec 2009, assessed approximately up to 4 years.

End point values	Phase I: Dose Level 0	Phase I: Dose Level 1	Phase I: Dose Level 1A	Phase I: Dose Level 1B	Phase I: Dose Level 1C	Phase I: Dose Level 1D	Phase I: Dose Level 2	Phase I: Dose Level 3	Phase I: Dose Level 4	Phase I: Dose Level 5
Number of subjects analysed	4	2	6	1	3	2	1	5	5	2
Units: Weeks
median (inter-quartile range (Q1-Q3))	31.1 (24.9 to 184.4)	117.0 (108.3 to 125.7)	203.9 (143.3 to 241.7)	999 (999 to 999)	54.1 (42.6 to 62.1)	77.1 (60.7 to 93.6)	64.3 (64.3 to 64.3)	61.6 (31.1 to 152.1)	999 (39.3 to 999)	999 (57.0 to 999)

No statistical analyses for this end point

Secondary: Phase I: Time to Response

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End point title

Phase I: Time to Response

End point description

Time to response was defined as the time from randomization until first documented evidence of partial or complete tumor response (whichever status is recorded first) and was based on responses confirmed at a repeat assessment, with the time to response taken as the first time the response was observed. For subjects who withdrew with no tumor response, the time was censored at the time of withdrawal from the study.

End point type

Secondary

End point timeframe

Week 8, Week 12, Week 16, Week 24, Week 32

End point values	Phase I: Dose Level 0	Phase I: Dose Level 1	Phase I: Dose Level 1A	Phase I: Dose Level 1B	Phase I: Dose Level 1C	Phase I: Dose Level 1D	Phase I: Dose Level 2	Phase I: Dose Level 3	Phase I: Dose Level 4	Phase I: Dose Level 5
Number of subjects analysed	4	2	6	1	3	2	1	5	5	2
Units: Participants
CR or PR by Week 8	2	0	3	1	2	1	1	3	4	1
CR or PR by Week 12	1	1	1	0	0	0	0	2	1	0
CR or PR by Week 16	1	1	1	0	1	1	0	0	0	0
CR or PR by Week 24	0	0	0	0	0	0	0	0	0	1
CR or PR by Week 32	0	0	1	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Phase I: Time to Progression

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End point title

Phase I: Time to Progression

End point description

Time to progression was defined as the interval between the date of randomization and the earliest date of disease progression or death due to breast cancer, if sooner. Disease progression was based on the assessments from the blinded, independent review of objective evidence (e.g., radiological scans and medical photographs). For subjects who withdrew without disease progression, it was censored at the time of last contact.

End point type

Secondary

End point timeframe

From first initiated treatment on 19-Jan-2006 to the data cut-off date for primary CSR on 9 Dec 2009, assessed approximately up to 4 years.

End point values	Phase I: Dose Level 0	Phase I: Dose Level 1	Phase I: Dose Level 1A	Phase I: Dose Level 1B	Phase I: Dose Level 1C	Phase I: Dose Level 1D	Phase I: Dose Level 2	Phase I: Dose Level 3	Phase I: Dose Level 4	Phase I: Dose Level 5
Number of subjects analysed	6	2	9	3	3	2	5	5	2	2
Units: Weeks
median (inter-quartile range (Q1-Q3))	34.1 (32.0 to 50.9)	137.9 (119.6 to 999)	148.5 (27.5 to 999)	54.9 (17.1 to 999)	67.1 (53.6 to 999)	86.6 (73.9 to 99.3)	71.4 (50.3 to 130.9)	113.7 (37.9 to 165.0)	999 (45.6 to 999)	66.0 (63.9 to 999)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From study treatment start date till 30 days safety follow-up, assessed approximately up to 17 years.

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

25.0

Reporting group title

Dose Level 0

Reporting group description

Dose Level 0

Reporting group title

Dose Level 1A

Reporting group description

Dose Level 1A

Reporting group title

Dose Level 1B

Reporting group description

Dose Level 1B

Reporting group title

Dose Level 5

Reporting group description

Dose Level 5

Reporting group title

Dose Level 1D

Reporting group description

Dose Level 1D

Reporting group title

Dose Level 2

Reporting group description

Dose Level 2

Reporting group title

Dose Level 3

Reporting group description

Dose Level 3

Reporting group title

Dose Level 4

Reporting group description

Dose Level 4

Reporting group title

Dose Level 1

Reporting group description

Dose Level 1

Reporting group title

Dose Level 1C

Reporting group description

Dose Level 1C

Serious adverse events	Dose Level 0	Dose Level 1A	Dose Level 1B	Dose Level 5	Dose Level 1D	Dose Level 2	Dose Level 3	Dose Level 4	Dose Level 1	Dose Level 1C
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 6 (16.67%)	6 / 12 (50.00%)	1 / 5 (20.00%)	2 / 3 (66.67%)	1 / 3 (33.33%)	4 / 5 (80.00%)	5 / 6 (83.33%)	3 / 6 (50.00%)	2 / 3 (66.67%)	0 / 4 (0.00%)
number of deaths (all causes)	0	0	0	0	1	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0	0	0
Investigations
Blood calcium increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ejection fraction decreased
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 3	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	6 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oxygen saturation decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Urinary retention postoperative
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac failure
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Transient ischaemic attack
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	0 / 6 (0.00%)	5 / 12 (41.67%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 5 (60.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	10 / 12	0 / 0	0 / 0	0 / 0	5 / 5	1 / 1	2 / 2	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 5 (40.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Emphysema
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Lower respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular device infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Dose Level 0	Dose Level 1A	Dose Level 1B	Dose Level 5	Dose Level 1D	Dose Level 2	Dose Level 3	Dose Level 4	Dose Level 1	Dose Level 1C
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 6 (100.00%)	12 / 12 (100.00%)	5 / 5 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	5 / 5 (100.00%)	6 / 6 (100.00%)	6 / 6 (100.00%)	3 / 3 (100.00%)	4 / 4 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	1	0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Hypertension
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	1	0
Hot flush
subjects affected / exposed	1 / 6 (16.67%)	2 / 12 (16.67%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	2	3	0	1	0	0	0	0	0	1
Hypovolaemic shock
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Thrombophlebitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Lymphoedema
subjects affected / exposed	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	1	0	0	0	1	0	0	0	0
Surgical and medical procedures
Cataract operation
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
General disorders and administration site conditions
Catheter site haematoma
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Asthenia
subjects affected / exposed	1 / 6 (16.67%)	7 / 12 (58.33%)	2 / 5 (40.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 5 (40.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	1 / 3 (33.33%)	2 / 4 (50.00%)
occurrences all number	4	20	5	0	1	2	2	4	7	7
Axillary pain
subjects affected / exposed	0 / 6 (0.00%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0
Catheter site bruise
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Catheter site erythema
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Chest discomfort
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0
Catheter site pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	0	1	0	1	0	2
Catheter site inflammation
subjects affected / exposed	2 / 6 (33.33%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0	0
Chest pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	1	0
Hypothermia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Fatigue
subjects affected / exposed	4 / 6 (66.67%)	3 / 12 (25.00%)	1 / 5 (20.00%)	3 / 3 (100.00%)	2 / 3 (66.67%)	3 / 5 (60.00%)	5 / 6 (83.33%)	3 / 6 (50.00%)	3 / 3 (100.00%)	2 / 4 (50.00%)
occurrences all number	9	5	1	11	3	3	13	10	5	8
General physical health deterioration
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Granuloma
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Face oedema
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	1	0	0	0
Injection site erythema
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Infusion site vesicles
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Influenza like illness
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 3 (66.67%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	0
Injection site haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Nodule
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Mucosal inflammation
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1	0	0	1	0	1
Mucosal dryness
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
Injection site rash
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
Non-cardiac chest pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Oedema
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	1	1	0	0
Oedema peripheral
subjects affected / exposed	0 / 6 (0.00%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	3	0	0	0	0	2	1	0	2
Xerosis
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	1	0
Pyrexia
subjects affected / exposed	0 / 6 (0.00%)	5 / 12 (41.67%)	2 / 5 (40.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	2 / 4 (50.00%)
occurrences all number	0	5	2	1	0	1	0	2	2	3
Peripheral swelling
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	1	0	0	1	3	0	1
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	2	1	0	1	1	0	0	0
Hypersensitivity
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Social circumstances
Menopause
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Reproductive system and breast disorders
Intermenstrual bleeding
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0
Genital haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Breast pain
subjects affected / exposed	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	4	0	0	0	0	1	0	1	0
Breast oedema
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Amenorrhoea
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Vulvovaginal pruritus
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Vulvovaginal dryness
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Vaginal haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Pelvic pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Menopausal symptoms
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 6 (0.00%)	4 / 12 (33.33%)	3 / 5 (60.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 5 (20.00%)	5 / 6 (83.33%)	1 / 6 (16.67%)	2 / 3 (66.67%)	2 / 4 (50.00%)
occurrences all number	0	7	3	0	1	2	6	1	5	4
Allergic sinusitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Dysphonia
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	1	0	0	1	0	0	0
Dyspnoea
subjects affected / exposed	1 / 6 (16.67%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	3 / 6 (50.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	1	2	0	0	0	1	3	2	0	2
Dyspnoea exertional
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0	0
Emphysema
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Epistaxis
subjects affected / exposed	2 / 6 (33.33%)	6 / 12 (50.00%)	2 / 5 (40.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	3 / 5 (60.00%)	3 / 6 (50.00%)	2 / 6 (33.33%)	2 / 3 (66.67%)	3 / 4 (75.00%)
occurrences all number	3	8	2	1	1	4	4	6	3	3
Nasal dryness
subjects affected / exposed	0 / 6 (0.00%)	2 / 12 (16.67%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	1 / 4 (25.00%)
occurrences all number	0	3	1	0	0	0	0	1	1	1
Nasal discomfort
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Nasal obstruction
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Nasal inflammation
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	1	1	2	0	0
Nasal congestion
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Sinus congestion
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Rhinorrhoea
subjects affected / exposed	1 / 6 (16.67%)	7 / 12 (58.33%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	2 / 3 (66.67%)	2 / 4 (50.00%)
occurrences all number	4	13	2	0	0	2	1	2	2	3
Pulmonary fibrosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0
Productive cough
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Pharyngeal erythema
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Pharyngeal oedema
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Pleural effusion
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Oropharyngeal pain
subjects affected / exposed	1 / 6 (16.67%)	2 / 12 (16.67%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 5 (40.00%)	3 / 6 (50.00%)	2 / 6 (33.33%)	1 / 3 (33.33%)	2 / 4 (50.00%)
occurrences all number	1	3	0	1	0	2	7	2	3	2
Tachypnoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Psychiatric disorders
Abnormal dreams
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Tearfulness
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Anxiety
subjects affected / exposed	1 / 6 (16.67%)	3 / 12 (25.00%)	1 / 5 (20.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	6	1	2	0	0	1	1	2	0
Confusional state
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Depression
subjects affected / exposed	1 / 6 (16.67%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	2	0	0	0	0	1	0	0	0
Insomnia
subjects affected / exposed	5 / 6 (83.33%)	3 / 12 (25.00%)	0 / 5 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 5 (20.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)
occurrences all number	8	7	0	3	0	1	2	0	1	1
Mood altered
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	1
Investigations
Alanine aminotransferase
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	1	1	0	0	0	1	1	2	0
Alanine aminotransferase increased
subjects affected / exposed	0 / 6 (0.00%)	2 / 12 (16.67%)	2 / 5 (40.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	2	2	0	0	1	4	1	0	0
Aspartate aminotransferase
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	1	4	1	0	0
Blood albumin decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	1	1	1	0	0	0
Blood bilirubin increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Blood calcium decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0
Blood glucose increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Blood magnesium decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Ejection fraction decreased
subjects affected / exposed	0 / 6 (0.00%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	3	0	0	0
Haemoglobin decreased
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 5 (0.00%)	2 / 3 (66.67%)	1 / 3 (33.33%)	0 / 5 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	3	1	0	3	1	0	0
Weight decreased
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	1	1	2	0	0	1	2	1	0
White blood cell count decreased
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Fall
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Radiation skin injury
subjects affected / exposed	0 / 6 (0.00%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0
Procedural pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	3 / 6 (50.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0	0	0	3	0	0
Post procedural complication
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
Pelvic fracture
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Skin laceration
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	1	0	0	1	0	0	0	0	0	3
Thermal burn
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	7	0	0	0	0	0	0
Wound secretion
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Tachycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Intracardiac mass
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Nervous system disorders
Ageusia
subjects affected / exposed	0 / 6 (0.00%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	3	0	0	0	0	0	0	0	0
Allodynia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Headache
subjects affected / exposed	4 / 6 (66.67%)	6 / 12 (50.00%)	1 / 5 (20.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 5 (20.00%)	2 / 6 (33.33%)	2 / 6 (33.33%)	2 / 3 (66.67%)	3 / 4 (75.00%)
occurrences all number	5	9	1	2	1	1	2	4	4	8
Dizziness
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 5 (20.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)
occurrences all number	0	0	0	1	1	1	3	0	1	2
Dysgeusia
subjects affected / exposed	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 3 (33.33%)	2 / 4 (50.00%)
occurrences all number	1	2	0	0	1	0	1	0	3	2
Electric shock sensation
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Coma
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Hypoaesthesia
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0	0	0
Hyperaesthesia
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Horner's syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Memory impairment
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
Neuropathy peripheral
subjects affected / exposed	3 / 6 (50.00%)	3 / 12 (25.00%)	1 / 5 (20.00%)	2 / 3 (66.67%)	2 / 3 (66.67%)	2 / 5 (40.00%)	2 / 6 (33.33%)	5 / 6 (83.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	5	3	1	5	2	4	2	12	0	0
Neuralgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Motor dysfunction
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0
Migraine
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2
Paraesthesia
subjects affected / exposed	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 5 (40.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	1	0	0	0	2	1	1	1	0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Presyncope
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
Restless legs syndrome
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Syncope
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Taste disorder
subjects affected / exposed	4 / 6 (66.67%)	0 / 12 (0.00%)	2 / 5 (40.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	2 / 5 (40.00%)	1 / 6 (16.67%)	3 / 6 (50.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)
occurrences all number	9	0	2	2	0	5	1	5	0	2
Sciatica
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
Seizure
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Blood and lymphatic system disorders
Leukopenia
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	3	0	0	1	0
Anaemia
subjects affected / exposed	2 / 6 (33.33%)	5 / 12 (41.67%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	6	9	2	0	0	0	0	1	0	0
Thrombocytopenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0	0
Splenic vein thrombosis
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Neutropenia
subjects affected / exposed	4 / 6 (66.67%)	6 / 12 (50.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	3 / 3 (100.00%)	0 / 4 (0.00%)
occurrences all number	13	18	1	0	0	1	1	0	8	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	1	0	0	2	1	0
Ear disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Ear pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0	0	0
Eye disorders
Conjunctival irritation
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Conjunctival haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Dry eye
subjects affected / exposed	0 / 6 (0.00%)	3 / 12 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	4	0	0	1	0	1	0	1	0
Lacrimation increased
subjects affected / exposed	2 / 6 (33.33%)	2 / 12 (16.67%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	4 / 6 (66.67%)	2 / 3 (66.67%)	2 / 4 (50.00%)
occurrences all number	3	3	0	1	0	0	2	4	3	3
Foreign body sensation in eyes
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Eyelid oedema
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	0
Eye pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	1	2	0	0	0
Erythema of eyelid
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Ocular hyperaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Orbital oedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Visual impairment
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Visual acuity reduced
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
Vision blurred
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	3	0	0	0
Scintillating scotoma
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Photopsia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	1
Aerophagia
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Abdominal pain upper
subjects affected / exposed	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	1	0	1	0	0	0	0	0	0
Abdominal pain
subjects affected / exposed	4 / 6 (66.67%)	4 / 12 (33.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	1 / 3 (33.33%)	1 / 4 (25.00%)
occurrences all number	5	5	0	0	0	0	4	2	1	1
Anal fissure
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	2	0	0	0	0	0	0
Diarrhoea
subjects affected / exposed	5 / 6 (83.33%)	11 / 12 (91.67%)	5 / 5 (100.00%)	2 / 3 (66.67%)	3 / 3 (100.00%)	3 / 5 (60.00%)	5 / 6 (83.33%)	5 / 6 (83.33%)	3 / 3 (100.00%)	4 / 4 (100.00%)
occurrences all number	27	43	10	15	5	4	27	33	16	32
Constipation
subjects affected / exposed	3 / 6 (50.00%)	3 / 12 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 5 (40.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	7	4	0	0	1	2	0	4	0	0
Breath odour
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Aphthous ulcer
subjects affected / exposed	1 / 6 (16.67%)	4 / 12 (33.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	5	0	0	1	0	0	0	1	0
Anal haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Dysphagia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	1	0
Dyspepsia
subjects affected / exposed	1 / 6 (16.67%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 5 (40.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	2	0	0	1	2	2	1	0	0
Dyschezia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Dry mouth
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Gastritis
subjects affected / exposed	1 / 6 (16.67%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	2	0	0	0	3	1	2	1	0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 6 (16.67%)	4 / 12 (33.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	4	0	0	0	1	0	2	0	0
Gingival bleeding
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0
Gingival pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
Hypoaesthesia oral
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Hiatus hernia
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Haemorrhoids
subjects affected / exposed	1 / 6 (16.67%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	3	0	0	1	0	0	5	0	0
Haematochezia
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Intestinal obstruction
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Nausea
subjects affected / exposed	3 / 6 (50.00%)	7 / 12 (58.33%)	4 / 5 (80.00%)	3 / 3 (100.00%)	2 / 3 (66.67%)	3 / 5 (60.00%)	5 / 6 (83.33%)	5 / 6 (83.33%)	2 / 3 (66.67%)	4 / 4 (100.00%)
occurrences all number	13	14	7	11	3	12	8	14	12	14
Mouth ulceration
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Mesenteric vein thrombosis
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Lip pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Noninfective gingivitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Odynophagia
subjects affected / exposed	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	1	0	0	0	0	2	0	1	0
Rectal haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Oesophagitis
subjects affected / exposed	0 / 6 (0.00%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	1	0
Oral mucosal blistering
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Oral pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0
Periodontal disease
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Stomatitis
subjects affected / exposed	3 / 6 (50.00%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 5 (60.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	1 / 3 (33.33%)	3 / 4 (75.00%)
occurrences all number	7	2	0	0	0	4	2	2	3	7
Tongue ulceration
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Toothache
subjects affected / exposed	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	1	0	1	0	0	0	2	0	0
Vomiting
subjects affected / exposed	2 / 6 (33.33%)	5 / 12 (41.67%)	1 / 5 (20.00%)	3 / 3 (100.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	4 / 6 (66.67%)	2 / 6 (33.33%)	2 / 3 (66.67%)	3 / 4 (75.00%)
occurrences all number	2	9	2	6	0	1	4	11	5	7
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	1 / 6 (16.67%)	3 / 12 (25.00%)	1 / 5 (20.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 5 (40.00%)	4 / 6 (66.67%)	1 / 6 (16.67%)	2 / 3 (66.67%)	2 / 4 (50.00%)
occurrences all number	1	7	1	3	0	4	9	7	2	6
Drug eruption
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0	0	0
Dermatitis allergic
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Dermatitis acneiform
subjects affected / exposed	0 / 6 (0.00%)	5 / 12 (41.67%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	7	0	3	0	1	0	1	0	1
Blister
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
Alopecia
subjects affected / exposed	4 / 6 (66.67%)	6 / 12 (50.00%)	3 / 5 (60.00%)	3 / 3 (100.00%)	2 / 3 (66.67%)	5 / 5 (100.00%)	4 / 6 (66.67%)	4 / 6 (66.67%)	2 / 3 (66.67%)	4 / 4 (100.00%)
occurrences all number	4	6	3	4	2	5	4	4	2	4
Acne
subjects affected / exposed	1 / 6 (16.67%)	3 / 12 (25.00%)	2 / 5 (40.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 3 (0.00%)	3 / 4 (75.00%)
occurrences all number	3	8	2	0	0	0	4	1	0	3
Onycholysis
subjects affected / exposed	1 / 6 (16.67%)	2 / 12 (16.67%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 3 (66.67%)	0 / 4 (0.00%)
occurrences all number	2	3	0	1	0	1	0	1	2	0
Onychoclasis
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0	1	0
Onychalgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	1	0
Nail toxicity
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	1	0
Eczema
subjects affected / exposed	1 / 6 (16.67%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	1	2	0	0	0	0	0	0	0	1
Nail disorder
subjects affected / exposed	2 / 6 (33.33%)	6 / 12 (50.00%)	1 / 5 (20.00%)	1 / 3 (33.33%)	2 / 3 (66.67%)	1 / 5 (20.00%)	3 / 6 (50.00%)	4 / 6 (66.67%)	2 / 3 (66.67%)	4 / 4 (100.00%)
occurrences all number	2	11	1	1	3	1	3	9	2	10
Nail ridging
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0	1	0	1	0	0
Erythema
subjects affected / exposed	1 / 6 (16.67%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	2	0	0	3	0	1	3	1	0
Ecchymosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Onychomadesis
subjects affected / exposed	0 / 6 (0.00%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0
Rash erythematous
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	1
Rash
subjects affected / exposed	4 / 6 (66.67%)	5 / 12 (41.67%)	1 / 5 (20.00%)	1 / 3 (33.33%)	2 / 3 (66.67%)	2 / 5 (40.00%)	4 / 6 (66.67%)	4 / 6 (66.67%)	2 / 3 (66.67%)	4 / 4 (100.00%)
occurrences all number	12	5	1	5	2	7	8	9	5	6
Purpura
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Pruritus allergic
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Pruritus
subjects affected / exposed	2 / 6 (33.33%)	4 / 12 (33.33%)	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	3 / 6 (50.00%)	1 / 6 (16.67%)	3 / 3 (100.00%)	1 / 4 (25.00%)
occurrences all number	2	5	1	0	1	0	5	2	9	1
Pain of skin
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	1
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 6 (0.00%)	3 / 12 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	3	0	0	0	1	1	0	0	0
Skin fissures
subjects affected / exposed	1 / 6 (16.67%)	3 / 12 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	2 / 3 (66.67%)	1 / 4 (25.00%)
occurrences all number	2	11	0	0	0	0	0	2	2	2
Skin exfoliation
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Skin disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0
Skin discolouration
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Rash macular
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	4
Rash pruritic
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	1
Scab
subjects affected / exposed	0 / 6 (0.00%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	2	0	0	0	0	0	1	0	0
Rash maculo-papular
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Rash papular
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Xeroderma
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	0
Vascular skin disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	1	0	0	1	0	0	0	0
Neurogenic bladder
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Pollakiuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 5 (40.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0
Renal failure
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Urinary retention
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Urinary incontinence
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 6 (33.33%)	7 / 12 (58.33%)	2 / 5 (40.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 5 (20.00%)	2 / 6 (33.33%)	4 / 6 (66.67%)	1 / 3 (33.33%)	2 / 4 (50.00%)
occurrences all number	3	9	3	4	2	4	3	9	1	3
Arthritis
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Back pain
subjects affected / exposed	1 / 6 (16.67%)	3 / 12 (25.00%)	1 / 5 (20.00%)	2 / 3 (66.67%)	2 / 3 (66.67%)	1 / 5 (20.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	3 / 3 (100.00%)	1 / 4 (25.00%)
occurrences all number	1	4	1	3	2	1	2	1	4	2
Bone pain
subjects affected / exposed	0 / 6 (0.00%)	3 / 12 (25.00%)	2 / 5 (40.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	3	2	2	0	0	1	3	0	2
Musculoskeletal chest pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	1	0	0	0	1	0	0	0	0	1
Muscular weakness
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Muscle spasms
subjects affected / exposed	0 / 6 (0.00%)	4 / 12 (33.33%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	4	3	0	0	0	1	1	0	1
Joint swelling
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	1	2	0	0	0	0
Musculoskeletal discomfort
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Osteonecrosis
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Neck pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	1	1	1	0	0	0
Myalgia
subjects affected / exposed	1 / 6 (16.67%)	4 / 12 (33.33%)	2 / 5 (40.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 3 (0.00%)	2 / 4 (50.00%)
occurrences all number	1	5	4	1	0	1	3	3	0	4
Musculoskeletal pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Osteopenia
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Spinal pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	2	0	0	0	0	0	0	0
Pain in jaw
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0
Pain in extremity
subjects affected / exposed	2 / 6 (33.33%)	2 / 12 (16.67%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 5 (40.00%)	4 / 6 (66.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	5	2	1	0	0	2	5	1	0	0
Systemic lupus erythematosus
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Infections and infestations
Eye infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Ear infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	2	2	0	0
Folliculitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	0	0	2	1	0	6
Bronchitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Cellulitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Conjunctivitis
subjects affected / exposed	0 / 6 (0.00%)	2 / 12 (16.67%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 5 (40.00%)	3 / 6 (50.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	2	1	0	0	2	3	0	0	0
Cystitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Dermatitis infected
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Infected cyst
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Hordeolum
subjects affected / exposed	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	2	0	0	0	0	0	0	0	0
Herpes zoster
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0
Herpes virus infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Gastroenteritis
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	0
Fungal skin infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	3	0	0	0	0	0
Fungal foot infection
subjects affected / exposed	0 / 6 (0.00%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0
Infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Nasopharyngitis
subjects affected / exposed	0 / 6 (0.00%)	7 / 12 (58.33%)	1 / 5 (20.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	2 / 3 (66.67%)	2 / 4 (50.00%)
occurrences all number	0	8	2	4	0	0	1	8	8	3
Nail infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Nail bed infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Mastitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Lower respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	3 / 6 (50.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	1	0	7	2	1	0
Localised infection
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	1 / 5 (20.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 5 (20.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	1 / 3 (33.33%)	1 / 4 (25.00%)
occurrences all number	2	0	1	1	1	1	1	2	1	2
Laryngitis
subjects affected / exposed	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	1	0	0	0	0	1	0	0	0
Influenza
subjects affected / exposed	1 / 6 (16.67%)	3 / 12 (25.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	2	5	1	0	0	0	1	0	0	0
Oral herpes
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	1	0	0	0	1	1	0	0
Rash pustular
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Pustule
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0	0	0
Pharyngitis
subjects affected / exposed	1 / 6 (16.67%)	1 / 12 (8.33%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)
occurrences all number	1	1	1	0	0	0	1	0	1	1
Paronychia
subjects affected / exposed	1 / 6 (16.67%)	2 / 12 (16.67%)	2 / 5 (40.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	2 / 3 (66.67%)	3 / 4 (75.00%)
occurrences all number	1	7	3	0	3	0	0	2	3	8
Respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0	1	0
Rhinitis
subjects affected / exposed	0 / 6 (0.00%)	3 / 12 (25.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	5	1	0	0	0	1	3	0	0
Sepsis
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Septic rash
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Tooth infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Tooth abscess
subjects affected / exposed	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	3	1	0	1	0	0	0	0	1	0
Skin infection
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
Sinusitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	2	0	0	0	2	0	0	0
Tracheitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Vascular device infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	2	0	0	0	1	0	0
Vaginal infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	1	0	0	0
Urinary tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 5 (60.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	0	3	0	0	1	1
Upper respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 5 (20.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	2	0	0	1	1	3	2	0	0
Vulvovaginal candidiasis
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	3	0	0	0
Metabolism and nutrition disorders
Hyperkalaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Hyperglycaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Dehydration
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Decreased appetite
subjects affected / exposed	0 / 6 (0.00%)	4 / 12 (33.33%)	2 / 5 (40.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	2 / 5 (40.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 3 (33.33%)	3 / 4 (75.00%)
occurrences all number	0	5	2	3	0	2	1	5	2	3
Hypocalcaemia
subjects affected / exposed	0 / 6 (0.00%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0
Hyponatraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Hypokalaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0	0	0
Hypoglycaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0

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Were there any global substantial amendments to the protocol? Yes

13 Jan 2006

Amendment 01: The protocol was amended to include pharmacokinetic sampling in the Phase I part of the study. Inclusion/exclusion criteria were amended to facilitate recruitment. The prohibited medication list was revised.

08 Dec 2006

Amendment 2: The protocol was amended to include additional cohorts in Phase I to investigate doses of lapatinib (750mg, 1000mg, 1250mg, 1500mg ) with 75mg/m 2 once every 3 weeks docetaxel plus standard weekly doses of trastuzumab with prophylactic use of growth factors in all subjects and two further additional cohorts of subjects in the Phase I design to investigate the safety and tolerability of once every 3 weeks trastuzumab in combination with once every 3 weeks docetaxel plus lapatinib and 3- weekly trastuzumab with lapatinib as maintenance therapy.

13 Jun 2008

Amendment 3: The protocol was amended to include information regarding hepatotoxicity associated with lapatinib treatment, the allowance of the use of once every 3 weeks trastuzumab post completion of docetaxel, removal of cohort Z (1000mg lapatinib once daily plus 3–weekly trastuzumab after chemotherapy (docetaxel) course), and addition of a 6th optional cohort.

14 Jul 2008

Amendment 4: As part of the liver toxicity update of GM2003/00455/003, inclusion of pharmacokinetics sample needing to be taken has been added to the follow up criteria in Section 7.2.1.2.

18 Nov 2008

Amendment 5: The protocol was amended to allow more subjects to be investigated at the doses used in cohort 1D following its successful completion with the first 3 subjects with no dose limiting toxicities. Amendment to the wording regarding the use of three weekly trastuzumab post completion of docetaxel administration. Amendment to exclusion criteria 6. Allowance for investigators to perform efficacy assessments every 12 weeks once they have completed 24 weeks of treatment rather than every 6 weeks.

28 Aug 2012

Amendment 6: Added Long Term Follow-Up Phase. Discontinuation of many specific efficacy and safety assessments. The study was stopped for subjects in post treatment follow up. Continued access to study treatment lapatinib was permitted for subjects ongoing at the time of implementation of this amendment. Subjects on post treatment follow up were withdrawn. Changed subject visit frequency to Investigator Discretion as per institutional/local standards of medical care.

20 Feb 2013

Amendment 7 (country specific amendment for France): New information regarding diarrhea and dermatological (rash) management added.

03 Oct 2016

Amendment 8: Deleted or replaced references to GSK or its staff with that of Novartis/Novartis and its authorized agents. Administrative changes to align with Novartis processes and procedures. Replaced reference to Investigational product from non-commercial sources with that of commercial supply.

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.

Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com for complete trial results.

http://www.ncbi.nlm.nih.gov/pubmed/23878115

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Clinical trials

Clinical Trial Results:
An open-label, multicenter, Phase I/II dose escalation study of oral GW572016 in combination with docetaxel (Taxotere) plus trastuzumab (Herceptin) in subjects previously untreated for ErbB2-overexpressing metastatic breast cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase I: Determination of the optimally tolerated regimen (OTR)

Primary: Phase I: Determination of the optimally tolerated regimen (OTR)

Secondary: Phase I: Overall Response Rate (ORR)

Secondary: Phase I: Overall Response Rate (ORR)

Secondary: Phase I: Duration of Response (DoR)

Secondary: Phase I: Duration of Response (DoR)

Secondary: Phase I: Time to Response

Secondary: Phase I: Time to Response

Secondary: Phase I: Time to Progression

Secondary: Phase I: Time to Progression

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Substantial protocol amendments (globally)

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Clinical trials

Clinical Trial Results: An open-label, multicenter, Phase I/II dose escalation study of oral GW572016 in combination with docetaxel (Taxotere) plus trastuzumab (Herceptin) in subjects previously untreated for ErbB2-overexpressing metastatic breast cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase I: Determination of the optimally tolerated regimen (OTR)

Primary: Phase I: Determination of the optimally tolerated regimen (OTR)

Secondary: Phase I: Overall Response Rate (ORR)

Secondary: Phase I: Overall Response Rate (ORR)

Secondary: Phase I: Duration of Response (DoR)

Secondary: Phase I: Duration of Response (DoR)

Secondary: Phase I: Time to Response

Secondary: Phase I: Time to Response

Secondary: Phase I: Time to Progression

Secondary: Phase I: Time to Progression

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
An open-label, multicenter, Phase I/II dose escalation study of oral GW572016 in combination with docetaxel (Taxotere) plus trastuzumab (Herceptin) in subjects previously untreated for ErbB2-overexpressing metastatic breast cancer