Download PDF

Clinical Trial Results:
A double-blind, placebo-controlled, three arm randomised multi-centre Gynaecologic Cancer InterGroup trial of AZD2171, in combination with platinum-based chemotherapy and as a single agent maintenance therapy, in women with ovarian cancer relapsing more than 6 months following completion of first line platinum-based treatment.

Summary
EudraCT number	2007-001346-41
Trial protocol	GB ES
Global end of trial date	01 Oct 2018

Results information
Results version number	v1(current)
This version publication date	26 Dec 2020
First version publication date	26 Dec 2020
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

ICON6

ISRCTN number

ISRCTN68510403

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Medical Research Council

Sponsor organisation address

58 Victoria Embankment, London, United Kingdom,

Public contact

ICON6 Trial Manager, Medical Research Council, icon6@ctu.mrc.ac.uk

Scientific contact

ICON6 Trial Manager, Medical Research Council, icon6@ctu.mrc.ac.uk

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

27 Mar 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

01 Oct 2018

Was the trial ended prematurely?

Main objective of the trial

to assess the safety and efficacy of AZD2171 in combination with platinum-based chemotherapy and as a single agent maintenance therapy, in women with ovarian cancer relapsing more than 6 months following completion of first line platinum based treatment. The main outcome measure is Progression Free Survival (PFS)

Protection of trial subjects

Not applicable.

Background therapy

Evidence for comparator

Actual start date of recruitment

05 Dec 2007

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 2

Country: Number of subjects enrolled

United Kingdom: 380

Country: Number of subjects enrolled

Canada: 87

Country: Number of subjects enrolled

Australia: 17

Worldwide total number of subjects

486

EEA total number of subjects

382

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)

274

From 65 to 84 years

210

85 years and over

Subject disposition

Top of page

Recruitment details

Screening details

Number of subjects started

486

Number of subjects completed

456

Reason: Number of subjects

Lower dose, not in final analysis: 30

Period 1 title

Main Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Reference

Arm description

6 cycles of platinum-based chemotherapy plus Placebo during chemotherapy

Arm type

Placebo

Investigational medicinal product name

Carboplatin/Paclitaxel + Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion, Capsule

Routes of administration

Oral use, Intravenous use

Dosage and administration details

carboplatin AUC 6b over 30-60 minutes, in combination with paclitaxel 175 mg/m2 over three hours, three weekly for six cycles.

Concurrent

Arm description

6 cycles of platinum-based chemotherapy plus Cediranib during chemotherapy; then an oral daily placebo tablet up to 18 months from randomisation or until progression

Arm type

Experimental

Investigational medicinal product name

Cediranib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

20mg; 15mg were allowed if there were toxic effects.

Maintenance

Arm description

6 cycles of platinum-based chemotherapy plus Cediranib during chemotherapy; plus oral cediranib daily during chemotherapy and then continued up to 18 months from randomisation or until progression.

Arm type

Experimental

Investigational medicinal product name

Cediranib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

20mg; 15mg were allowed if there were toxic effects.

Number of subjects in period 1 ^[1]	Reference	Concurrent	Maintenance
Started	118	174	164
Completed	118	174	164

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The thirty participants who completed 30mg of drug are not included in the final analysis.

Baseline characteristics

Top of page

Reporting group title

Reference

Reporting group description

6 cycles of platinum-based chemotherapy plus Placebo during chemotherapy

Reporting group title

Concurrent

Reporting group description

6 cycles of platinum-based chemotherapy plus Cediranib during chemotherapy; then an oral daily placebo tablet up to 18 months from randomisation or until progression

Reporting group title

Maintenance

Reporting group description

6 cycles of platinum-based chemotherapy plus Cediranib during chemotherapy; plus oral cediranib daily during chemotherapy and then continued up to 18 months from randomisation or until progression.

Reporting group values	Reference	Concurrent	Maintenance	Total
Number of subjects	118	174	164	456
Age categorical
Units: Subjects
In utero				0
Preterm newborn infants (gestational age < 37 wks)				0
Newborns (0-27 days)				0
Infants and toddlers (28 days-23 months)				0
Children (2-11 years)				0
Adolescents (12-17 years)				0
Adults (18-64 years)				0
From 65-84 years				0
85 years and over				0
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	62 (53 to 67)	62 (54 to 69)	62 (54 to 68)	-
Gender categorical
Units: Subjects
Female	118	174	164	456
Male	0	0	0	0
ECOG Status
Units: Subjects
Zero	69	109	95	273
One	47	64	67	178
Two	1	0	0	1
Three	0	0	1	1
Not available	1	1	1	3
Primary tumour type
Units: Subjects
Ovary	98	139	131	368
Fallopian	1	6	6	13
Peritoneal	19	29	27	75
Histology
Units: Subjects
Serous	87	129	116	332
Endometrioid	3	7	9	19
Clear cell	3	8	5	16
Mucinous	0	3	1	4
Mixed or other	21	26	30	77
Undifferentiated	3	0	2	5
Not available	1	1	1	3
Tumour grade
Units: Subjects
Well differentiated	1	6	5	12
Moderately differentiated	18	20	24	62
Poorly differentiated	97	132	117	346
Not assessable or missing	2	16	18	36
First-line chemotherapy included paclitaxel
Units: Subjects
Yes	104	151	149	404
No	13	20	15	48
Not available	1	3	0	4
Previous bevacizumab
Units: Subjects
Yes	6	9	9	24
No	112	165	155	432
Time since last chemotherapy
Units: Subjects
6-12 months	43	59	50	152
>12 months	75	115	114	304
Planned chemotherapy
Units: Subjects
Carboplatin alone	12	19	18	49
Carboplatin plus paclitaxel	89	130	121	340
Carboplatin plus gemcitabine	17	25	25	67
Time from fi rst histological diagnosis to randomisation
Units: weeks
median (inter-quartile range (Q1-Q3))	82.6 (60 to 117)	82.9 (64 to 135)	87.4 (65 to 117)	-

Subject analysis set title

Reference + Concurrent

Subject analysis set type

Intention-to-treat

Subject analysis set description

This entry was created to accommodate a secondary analysis of Quality of Life outcomes.

Subject analysis set title

Concurrent + Maintenance

Subject analysis set type

Intention-to-treat

Subject analysis set description

This entry was created to accommodate a secondary analysis of Quality of Life outcomes.

Subject analysis sets values	Reference + Concurrent	Concurrent + Maintenance
Number of subjects	292	338
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))
Gender categorical
Units: Subjects
Female
Male
ECOG Status
Units: Subjects
Zero
One
Two
Three
Not available
Primary tumour type
Units: Subjects
Ovary
Fallopian
Peritoneal
Histology
Units: Subjects
Serous
Endometrioid
Clear cell
Mucinous
Mixed or other
Undifferentiated
Not available
Tumour grade
Units: Subjects
Well differentiated
Moderately differentiated
Poorly differentiated
Not assessable or missing
First-line chemotherapy included paclitaxel
Units: Subjects
Yes
No
Not available
Previous bevacizumab
Units: Subjects
Yes
No
Time since last chemotherapy
Units: Subjects
6-12 months	83	109
>12 months	189	229
Planned chemotherapy
Units: Subjects
Carboplatin alone
Carboplatin plus paclitaxel
Carboplatin plus gemcitabine
Time from fi rst histological diagnosis to randomisation
Units: weeks
median (inter-quartile range (Q1-Q3))

End points

Top of page

Reporting group title

Reference

Reporting group description

6 cycles of platinum-based chemotherapy plus Placebo during chemotherapy

Reporting group title

Concurrent

Reporting group description

6 cycles of platinum-based chemotherapy plus Cediranib during chemotherapy; then an oral daily placebo tablet up to 18 months from randomisation or until progression

Reporting group title

Maintenance

Reporting group description

6 cycles of platinum-based chemotherapy plus Cediranib during chemotherapy; plus oral cediranib daily during chemotherapy and then continued up to 18 months from randomisation or until progression.

Subject analysis set title

Reference + Concurrent

Subject analysis set type

Intention-to-treat

Subject analysis set description

This entry was created to accommodate a secondary analysis of Quality of Life outcomes.

Subject analysis set title

Concurrent + Maintenance

Subject analysis set type

Intention-to-treat

Subject analysis set description

This entry was created to accommodate a secondary analysis of Quality of Life outcomes.

Primary: Progression-Free Survival (PFS)

Top of page

End point title

Progression-Free Survival (PFS)

End point description

End point type

Primary

End point timeframe

Progression-free survival was defi ned as time from randomisation to disease progression or death from any cause

End point values	Reference	Concurrent	Maintenance
Number of subjects analysed	118	174	164
Units: month
median (inter-quartile range (Q1-Q3))	8.7 (7.7 to 9.4)	9.9 (9.4 to 10.5)	11 (10.4 to 11.7)

PFS ; HR

Comparison groups

Maintenance v Reference

Number of subjects included in analysis

282

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.00001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.56

Confidence interval

level

95%

sides

2-sided

lower limit

0.44

upper limit

0.72

Restricted Mean Survival

Statistical analysis description

Analysis unit is months.

Comparison groups

Reference v Maintenance

Number of subjects included in analysis

282

Analysis specification

Pre-specified

Analysis type

superiority

Method

Restricted Mean Survival Time Difference

Parameter type

Restricted Mean Survival Time Difference

Point estimate

3.1

Confidence interval

level

95%

sides

2-sided

lower limit

1.9

upper limit

4.4

Primary: Progression Free Survival (PFS)

Top of page

End point title

Progression Free Survival (PFS) ^[1]

End point description

End point type

Primary

End point timeframe

Progression-free survival was defined as time from randomisation to disease progression or death from any cause

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The outcome is reported for Arms A and B. Baseline statistics for Arm C are presented in a different outcome.

End point values	Reference	Concurrent
Number of subjects analysed	118	174
Units: months
median (inter-quartile range (Q1-Q3))	8.7 (7.7 to 9.4)	9.9 (9.4 to 10.5)

PFS ; HR

Comparison groups

Reference v Concurrent

Number of subjects included in analysis

292

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0036

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.69

Confidence interval

level

95%

sides

2-sided

lower limit

0.55

upper limit

0.89

Secondary: Overall Survival (OS)

Top of page

End point title

Overall Survival (OS)

End point description

End point type

Secondary

End point timeframe

Overall survival (OS) is calculated from the date of randomisation to date of death from any cause

End point values	Reference	Concurrent	Maintenance
Number of subjects analysed	118	174	164
Units: months
median (inter-quartile range (Q1-Q3))	19.9 (17.4 to 26.5)	26.6 (22.6 to 29.1)	27.3 (24.8 to 33.0)

OS; HR

Comparison groups

Reference v Maintenance

Number of subjects included in analysis

282

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.24

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.86

Confidence interval

level

95%

sides

2-sided

lower limit

0.67

upper limit

1.11

Restricted Mean Survival; OS

Statistical analysis description

Analysis unit is months.

Comparison groups

Reference v Maintenance

Number of subjects included in analysis

282

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Restricted Mean Survival Time Difference

Point estimate

4.24

Confidence interval

level

95%

sides

2-sided

lower limit

-1.9

upper limit

10.3

Secondary: QLQ C30

Top of page

End point title

QLQ C30

End point description

End point type

Secondary

End point timeframe

Baseline to 1 year of enrollment.

End point values	Reference	Concurrent	Maintenance
Number of subjects analysed	82	126	132
Units: points
arithmetic mean (standard deviation)	-6.4 ± 28.0	-0.7 ± 21.7	-4.6 ± 20.9

ANCOVA

Comparison groups

Reference v Maintenance

Number of subjects included in analysis

214

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.18

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

4.5

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Secondary: Improved Ascites Resolution During Chemotherapy

Top of page

End point title

Improved Ascites Resolution During Chemotherapy ^[2]

End point description

End point type

Secondary

End point timeframe

From baseline to the end of chemotherapy.

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Physical function was explored in arms A and B/C combined.

End point values	Reference	Concurrent + Maintenance
Number of subjects analysed	39	113
Units: points
arithmetic mean (standard deviation)
Baseline	37.1 ± 25.0	34.9 ± 22.0
End of chemotherapy	24.2 ± 19.9	21.4 ± 18.2

Difference in the area under the curve

Comparison groups

Reference v Concurrent + Maintenance

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.98 ^[3]

Method

Difference in the area under the curve

Confidence interval

Notes
[3] - Calculated using the difference in the area under the curve during chemotherapy adjusted for the baseline score

Secondary: Improved QoL: Global

Top of page

End point title

Improved QoL: Global ^[4]

End point description

End point type

Secondary

End point timeframe

Baseline to chemotherapy midpoint (Week 9).

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Physical function was explored in arms A and B/C combined.

End point values	Reference	Concurrent + Maintenance
Number of subjects analysed	87	176
Units: points
arithmetic mean (standard deviation)
Baseline	69.9 ± 20.2	69.1 ± 21.3
Midpoint	64.0 ± 19.9	65.8 ± 19.6

Interaction test

Statistical analysis description

Interaction test of the treatment group and whether or not the patient was symptomatic at enrollment

Comparison groups

Reference v Concurrent + Maintenance

Number of subjects included in analysis

263

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.88

Method

Interaction test

Confidence interval

Secondary: Improved QoL: Pain

Top of page

End point title

Improved QoL: Pain ^[5]

End point description

End point type

Secondary

End point timeframe

Baseline to chemotherapy midpoint (week 9).

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Physical function was explored in arms A and B/C combined.

End point values	Reference	Concurrent + Maintenance
Number of subjects analysed	87	176
Units: points
arithmetic mean (standard deviation)
Baseline	82.7 ± 19.6	84.0 ± 17.9
Midpoint	75.0 ± 20.0	78.0 ± 19.0

Interaction Test

Statistical analysis description

Interaction test of the treatment group and whether or not the patient was symptomatic at enrollment.

Comparison groups

Reference v Concurrent + Maintenance

Number of subjects included in analysis

263

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.92

Method

Interaction test

Confidence interval

Secondary: Improved QoL: Physical function

Top of page

End point title

Improved QoL: Physical function ^[6]

End point description

End point type

Secondary

End point timeframe

Baseline to chemotherapy midpoint (week 9).

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Physical function was explored in arms A and B/C combined.

End point values	Reference	Concurrent + Maintenance
Number of subjects analysed	87	176
Units: points
arithmetic mean (standard deviation)
Baseline	23.2 ± 23.2	22.0 ± 24.2
Midpoint	20.5 ± 23.9	17.8 ± 22.6

Interaction test

Statistical analysis description

Interaction test of the treatment group and whether or not the patient was symptomatic at enrollment.

Comparison groups

Reference v Concurrent + Maintenance

Number of subjects included in analysis

263

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.63

Method

Interaction test

Confidence interval

Secondary: Impaired fatigue during maintenance treatment

Top of page

End point title

Impaired fatigue during maintenance treatment ^[7]

End point description

End point type

Secondary

End point timeframe

End of chemotherapy to 1 year.

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Impaired fatigue was explored in arms A and B combined vs C.

End point values	Maintenance	Reference + Concurrent
Number of subjects analysed	84	140
Units: points
arithmetic mean (standard deviation)
End of chemotherapy	74.2 ± 22.0	72.0 ± 27.0
1 year	78.6 ± 27.3	72.5 ± 30.8

ANCOVA

Statistical analysis description

Analysis of covariance adjusted for the 18-week score

Comparison groups

Maintenance v Reference + Concurrent

Number of subjects included in analysis

224

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.17

Method

ANCOVA

Confidence interval

Secondary: Impaired social functioning during maintenance treatment

Top of page

End point title

Impaired social functioning during maintenance treatment ^[8]

End point description

End point type

Secondary

End point timeframe

End of chemotherapy to 1 year.

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Impaired social functioning was explored in arms A and B combined vs C.

End point values	Maintenance	Reference + Concurrent
Number of subjects analysed	84	140
Units: points
arithmetic mean (standard deviation)
End of chemotherapy	38.0 ± 22.6	37.6 ± 24.4
1 year	30.0 ± 25.2	31.0 ± 25.5

ANCOVA

Comparison groups

Maintenance v Reference + Concurrent

Number of subjects included in analysis

224

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.71

Method

ANCOVA

Confidence interval

Other pre-specified: Time to First Subsequent Treatment (TFST)

Top of page

End point title

Time to First Subsequent Treatment (TFST) ^[9]

End point description

End point type

Other pre-specified

End point timeframe

exploratory outcome given its emerging clinical relevance, and the fact that patients could continue trial drug beyond documented disease progression

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This was only evaluated in the arms specified.

End point values	Reference	Maintenance
Number of subjects analysed	118	164
Units: months
median (inter-quartile range (Q1-Q3))	11.5 (10.4 to 12.4)	13.2 (12.0 to 15.1)

Restricted Mean Survival; TFST

Statistical analysis description

Analysis unit is months.

Comparison groups

Reference v Maintenance

Number of subjects included in analysis

282

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Restricted Mean Survival Time Difference

Point estimate

5.2

Confidence interval

level

95%

sides

2-sided

lower limit

2.3

upper limit

8.8

Hazard Ratio

Comparison groups

Reference v Maintenance

Number of subjects included in analysis

282

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0014

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.64

Confidence interval

level

95%

sides

2-sided

lower limit

0.49

upper limit

0.85

Other pre-specified: QLQ C30 Arm B vs Arm A

Top of page

End point title

QLQ C30 Arm B vs Arm A

End point description

End point type

Other pre-specified

End point timeframe

Baseline to 1 year enrollment.

End point values	Reference	Concurrent	Maintenance
Number of subjects analysed	82	126	132
Units: points
arithmetic mean (standard deviation)	-6.4 ± 28.0	-0.7 ± 21.7	-4.6 ± 20.9

ANCOVA; Arm B vs Arm A

Comparison groups

Reference v Concurrent

Number of subjects included in analysis

208

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.01

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

8.3

Confidence interval

level

95%

sides

2-sided

lower limit

1.7

upper limit

14.9

Other pre-specified: QLQ C30 End of chemotherapy

Top of page

End point title

QLQ C30 End of chemotherapy

End point description

End point type

Other pre-specified

End point timeframe

Baseline to end of chemotherapy .

End point values	Reference	Concurrent	Maintenance
Number of subjects analysed	82	126	132
Units: points
arithmetic mean (confidence interval 95%)	-2.8 (-8.6 to 3.1)	-7.4 (-12.3 to -2.4)	-12.0 (-17.0 to -7.0)

ANCOVA

Comparison groups

Reference v Maintenance

Number of subjects included in analysis

214

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.01

Method

ANCOVA

Confidence interval

Other pre-specified: QLQ C30 End of chemotherapy Arm B vs Arm A

Top of page

End point title

QLQ C30 End of chemotherapy Arm B vs Arm A

End point description

End point type

Other pre-specified

End point timeframe

Baseline to end of chemotherapy .

End point values	Reference	Concurrent	Maintenance
Number of subjects analysed	82	126	132
Units: points
arithmetic mean (confidence interval 95%)	-2.8 (-8.6 to 3.1)	-7.4 (-12.3 to -2.4)	-12.0 (-17.0 to -7.0)

ANCOVA; Arm B vs Arm A

Comparison groups

Reference v Concurrent

Number of subjects included in analysis

208

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.22

Method

ANCOVA

Confidence interval

Other pre-specified: QLQ C30 End of chemotherapy to year 1

Top of page

End point title

QLQ C30 End of chemotherapy to year 1

End point description

End point type

Other pre-specified

End point timeframe

End of chemotherapy to 1 year.

End point values	Reference	Concurrent	Maintenance
Number of subjects analysed	82	126	132
Units: points
arithmetic mean (confidence interval 95%)	-1.0 (-5.4 to 3.5)	5.5 (1.6 to 9.3)	2.5 (-1.3 to 6.3)

ANCOVA

Comparison groups

Reference v Maintenance

Number of subjects included in analysis

214

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.14

Method

ANCOVA

Confidence interval

Other pre-specified: QLQ C30 End of chemotherapy to 1 year Arm B vs Arm A

Top of page

End point title

QLQ C30 End of chemotherapy to 1 year Arm B vs Arm A

End point description

End point type

Other pre-specified

End point timeframe

End of chemotherapy to 1 year.

End point values	Reference	Concurrent	Maintenance
Number of subjects analysed	82	126	132
Units: points
arithmetic mean (confidence interval 95%)	-1.0 (-5.4 to 3.5)	5.5 (1.6 to 9.3)	2.5 (-1.3 to 6.3)

ANCOVA; Arm B vs Arm A

Comparison groups

Reference v Concurrent

Number of subjects included in analysis

208

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.01

Method

ANCOVA

Confidence interval

Adverse events

Top of page

Timeframe for reporting adverse events

Timeframe for AE

Adverse event reporting additional description

AE additional description

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

CMaintenance

Reporting group description

Reporting group title

BConcurrent

Reporting group description

Reporting group title

AReference

Reporting group description

Serious adverse events	CMaintenance	BConcurrent	AReference
Total subjects affected by serious adverse events
subjects affected / exposed	53 / 164 (32.32%)	48 / 174 (27.59%)	34 / 118 (28.81%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Vascular disorders
Flushing
Additional description: Flushing
subjects affected / exposed	0 / 164 (0.00%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypotension
Additional description: Hypotension
subjects affected / exposed	1 / 164 (0.61%)	3 / 174 (1.72%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Edema - head and neck
Additional description: Edema - head and neck
subjects affected / exposed	1 / 164 (0.61%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fever
Additional description: Fever
subjects affected / exposed	2 / 164 (1.22%)	5 / 174 (2.87%)	4 / 118 (3.39%)
occurrences causally related to treatment / all	0 / 2	0 / 5	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Flu-like syndrome
Additional description: Flu-like syndrome
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain - Chest wall
Additional description: Pain - Chest wall
subjects affected / exposed	1 / 164 (0.61%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rigors/chills
Additional description: Rigors/chills
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Hemorrhage/Bleeding (tumour site)
Additional description: Hemorrhage/Bleeding (tumour site)
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Bronchospasm
Additional description: Bronchospasm
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cough
Additional description: Cough
subjects affected / exposed	2 / 164 (1.22%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnea
Additional description: Dyspnea
subjects affected / exposed	10 / 164 (6.10%)	8 / 174 (4.60%)	4 / 118 (3.39%)
occurrences causally related to treatment / all	0 / 15	0 / 8	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hemorrhage, Nose
Additional description: Hemorrhage, Nose
subjects affected / exposed	1 / 164 (0.61%)	3 / 174 (1.72%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoxia
Additional description: Hypoxia
subjects affected / exposed	4 / 164 (2.44%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
Additional description: Pleural effusion
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary - Other (chest tightness)
Additional description: Pulmonary - Other (chest tightness)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary/Upper Respiratory - other (nasal septal perforation)
Additional description: Pulmonary/Upper Respiratory - other (nasal septal perforation)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusion
Additional description: Confusion
subjects affected / exposed	0 / 164 (0.00%)	3 / 174 (1.72%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Insomnia
Additional description: Insomnia
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mood alteration
Additional description: Mood alteration
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mood alteration - Depression
Additional description: Mood alteration - Depression
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Creatinine
Additional description: Creatinine
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Creatinine; Hemoglobin
Additional description: Creatinine; Hemoglobin
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Bruising
Additional description: Bruising
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fracture
Additional description: Fracture
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombosis/embolism (vascular access-related)
Additional description: Thrombosis/embolism (vascular access-related)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound complication, non-infectious
Additional description: Wound complication, non-infectious
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac ischemia/infarction
Additional description: Cardiac ischemia/infarction
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain - Cardiac/heart
Additional description: Pain - Cardiac/heart
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sinus Tachycardia
Additional description: Sinus Tachycardia
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
CNS cerebrovascular ischemia
Additional description: CNS cerebrovascular ischemia
subjects affected / exposed	5 / 164 (3.05%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CNS ischemia
Additional description: CNS ischemia
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dizziness
Additional description: Dizziness
subjects affected / exposed	4 / 164 (2.44%)	2 / 174 (1.15%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 4	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neuropathy
Additional description: Neuropathy
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neuropathy: cranial
Additional description: Neuropathy: cranial
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain - Head/headache
Additional description: Pain - Head/headache
subjects affected / exposed	2 / 164 (1.22%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seizure
Additional description: Seizure
subjects affected / exposed	1 / 164 (0.61%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Somnolence
Additional description: Somnolence
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Somnolence/depressed level of consciousness
Additional description: Somnolence/depressed level of consciousness
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Speech impairment
Additional description: Speech impairment
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope (fainting)
Additional description: Syncope (fainting)
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	2 / 118 (1.69%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tremor
Additional description: Tremor
subjects affected / exposed	2 / 164 (1.22%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vasovagal episode
Additional description: Vasovagal episode
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Hemolysis
Additional description: Hemolysis
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Auditory/Ear - other (perforated ear drum)
Additional description: Auditory/Ear - other (perforated ear drum)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Ascites
Additional description: Ascites
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhea and Febrile neutropenia
Additional description: Diarrhea and Febrile neutropenia
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhea; Vomiting
Additional description: Diarrhea; Vomiting
subjects affected / exposed	0 / 164 (0.00%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Distension
Additional description: Distension
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Distension/bloating, abdominal
Additional description: Distension/bloating, abdominal
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dysphagia
Additional description: Dysphagia
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enteritis
Additional description: Enteritis
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fistula
Additional description: Fistula
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Flatulence
Additional description: Flatulence
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhage, Upper GI
Additional description: Haemorrhage, Upper GI
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Heartburn
Additional description: Heartburn
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hemorrhage, GI
Additional description: Hemorrhage, GI
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hemorrhage, GI - Stomach
Additional description: Hemorrhage, GI - Stomach
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hemorrhage, Rectum
Additional description: Hemorrhage, Rectum
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ileus
Additional description: Ileus
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mucositis/stomatitis
Additional description: Mucositis/stomatitis
subjects affected / exposed	4 / 164 (2.44%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mucositis/stomatitis - oral cavity
Additional description: Mucositis/stomatitis - oral cavity
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea and Vomiting
Additional description: Nausea and Vomiting
subjects affected / exposed	0 / 164 (0.00%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea; Vomiting
Additional description: Nausea; Vomiting
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Obstruction, GI
Additional description: Obstruction, GI
subjects affected / exposed	3 / 164 (1.83%)	2 / 174 (1.15%)	2 / 118 (1.69%)
occurrences causally related to treatment / all	0 / 4	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Obstruction, GI - ileum
Additional description: Obstruction, GI - ileum
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain - Gastrointestinal - Abdomen
Additional description: Pain - Gastrointestinal - Abdomen
subjects affected / exposed	4 / 164 (2.44%)	1 / 174 (0.57%)	2 / 118 (1.69%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain - Gastrointestinal - Abdomen NOS
Additional description: Pain - Gastrointestinal - Abdomen NOS
subjects affected / exposed	7 / 164 (4.27%)	10 / 174 (5.75%)	7 / 118 (5.93%)
occurrences causally related to treatment / all	0 / 7	0 / 12	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis
Additional description: Pancreatitis
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ulcer, GI - Anus
Additional description: Ulcer, GI - Anus
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ulcer, GI - Duodenum
Additional description: Ulcer, GI - Duodenum
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Liver dysfunction
Additional description: Liver dysfunction
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Pruritus
Additional description: Pruritus
subjects affected / exposed	1 / 164 (0.61%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rash; Vomiting
Additional description: Rash; Vomiting
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urticaria
Additional description: Urticaria
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Pain - Other (Dysuria)
Additional description: Pain - Other (Dysuria)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
Additional description: Renal failure
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthritis
Additional description: Arthritis
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscle weakness
Additional description: Muscle weakness
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain - Back
Additional description: Pain - Back
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain - Bone
Additional description: Pain - Bone
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain - Extremity-limb
Additional description: Pain - Extremity-limb
subjects affected / exposed	2 / 164 (1.22%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Infection - Bladder (urinary)
Additional description: Infection - Bladder (urinary)
subjects affected / exposed	1 / 164 (0.61%)	2 / 174 (1.15%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection - Bronchus
Additional description: Infection - Bronchus
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection - General - Catheter related
Additional description: Infection - General - Catheter related
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection - Lung
Additional description: Infection - Lung
subjects affected / exposed	2 / 164 (1.22%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection - Lung (pneumonia)
Additional description: Infection - Lung (pneumonia)
subjects affected / exposed	0 / 164 (0.00%)	3 / 174 (1.72%)	3 / 118 (2.54%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection - Other (abscess)
Additional description: Infection - Other (abscess)
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection - Pelvis NOS
Additional description: Infection - Pelvis NOS
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection - Peritoneal cavity
Additional description: Infection - Peritoneal cavity
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection - Skin (cellulitis)
Additional description: Infection - Skin (cellulitis)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection - Small bowel NOS
Additional description: Infection - Small bowel NOS
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection - Upper airway
Additional description: Infection - Upper airway
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection (documented clinically) with Grade 3 or 4 ANC
Additional description: Infection (documented clinically) with Grade 3 or 4 ANC
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection with unknown ANC
Additional description: Infection with unknown ANC
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypomagnesemia
Additional description: Hypomagnesemia
subjects affected / exposed	3 / 164 (1.83%)	2 / 174 (1.15%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 5	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyponatremia
Additional description: Hyponatremia
subjects affected / exposed	1 / 164 (0.61%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	CMaintenance	BConcurrent	AReference
Total subjects affected by non serious adverse events
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
Vascular disorders
Flushing
Additional description: Flushing
subjects affected / exposed	8 / 164 (4.88%)	7 / 174 (4.02%)	2 / 118 (1.69%)
occurrences all number	16	9	2
Haemmorhage/Bleeding
Additional description: Haemmorhage/Bleeding
subjects affected / exposed	6 / 164 (3.66%)	9 / 174 (5.17%)	2 / 118 (1.69%)
occurrences all number	7	20	2
Haemmorhage/Bleeding (1)
Additional description: Haemmorhage/Bleeding (1)
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1506	1565	1037
Haemmorhage/Bleeding (2)
Additional description: Haemmorhage/Bleeding (2)
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1506	1565	1037
Hematoma
Additional description: Hematoma
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	2	0	2
Hot flashes
Additional description: Hot flashes
subjects affected / exposed	8 / 164 (4.88%)	12 / 174 (6.90%)	14 / 118 (11.86%)
occurrences all number	30	27	69
Hypertension
Additional description: Hypertension
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1509	1568	1039
Hypotension
Additional description: Hypotension
subjects affected / exposed	5 / 164 (3.05%)	6 / 174 (3.45%)	3 / 118 (2.54%)
occurrences all number	6	7	6
Phlebitis
Additional description: Phlebitis
subjects affected / exposed	5 / 164 (3.05%)	2 / 174 (1.15%)	4 / 118 (3.39%)
occurrences all number	6	2	6
Thrombophlebitis
Additional description: Thrombophlebitis
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Thrombosis/thrombus/embolism
Additional description: Thrombosis/thrombus/embolism
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1515	1575	1039
Vascular - Other (insufficiency)
Additional description: Vascular - Other (insufficiency)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Vascular - Other (raynaud's disease)
Additional description: Vascular - Other (raynaud's disease)
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	11
General disorders and administration site conditions
Constitutional Symptoms - Other (cold extremities)
Additional description: Constitutional Symptoms - Other (cold extremities)
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	1	1	0
Constitutional Symptoms - Other (fall)
Additional description: Constitutional Symptoms - Other (fall)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Constitutional Symptoms - Other (Fear of going out)
Additional description: Constitutional Symptoms - Other (Fear of going out)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Constitutional Symptoms - Other (forgetfulness)
Additional description: Constitutional Symptoms - Other (forgetfulness)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Constitutional Symptoms - Other (Light headed)
Additional description: Constitutional Symptoms - Other (Light headed)
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Constitutional Symptoms - Other (psychological effects)
Additional description: Constitutional Symptoms - Other (psychological effects)
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Constitutional Symptoms - Other (restlessness)
Additional description: Constitutional Symptoms - Other (restlessness)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Constitutional Symptoms - Other (warm feet)
Additional description: Constitutional Symptoms - Other (warm feet)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Edema
Additional description: Edema
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	2 / 118 (1.69%)
occurrences all number	1	3	2
Edema: head and neck
Additional description: Edema: head and neck
subjects affected / exposed	2 / 164 (1.22%)	2 / 174 (1.15%)	1 / 118 (0.85%)
occurrences all number	2	3	2
Edema: limb
Additional description: Edema: limb
subjects affected / exposed	14 / 164 (8.54%)	22 / 174 (12.64%)	6 / 118 (5.08%)
occurrences all number	38	44	11
Edema: trunk/genital
Additional description: Edema: trunk/genital
subjects affected / exposed	2 / 164 (1.22%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences all number	6	3	0
Fatigue
Additional description: Fatigue
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1518	1577	1041
Fever
Additional description: Fever
subjects affected / exposed	6 / 164 (3.66%)	11 / 174 (6.32%)	5 / 118 (4.24%)
occurrences all number	7	11	9
Flu-like syndrome
Additional description: Flu-like syndrome
subjects affected / exposed	6 / 164 (3.66%)	3 / 174 (1.72%)	9 / 118 (7.63%)
occurrences all number	11	3	12
Gait/walking
Additional description: Gait/walking
subjects affected / exposed	2 / 164 (1.22%)	2 / 174 (1.15%)	3 / 118 (2.54%)
occurrences all number	2	4	16
Injection site reaction
Additional description: Injection site reaction
subjects affected / exposed	4 / 164 (2.44%)	5 / 174 (2.87%)	2 / 118 (1.69%)
occurrences all number	10	7	3
Injection site reaction/Extravasation
Additional description: Injection site reaction/Extravasation
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Pain
Additional description: Pain
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1513	1565	1040
Pain - Chest
Additional description: Pain - Chest
subjects affected / exposed	2 / 164 (1.22%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	4	1	0
Pain - Chest/thorax NOS
Additional description: Pain - Chest/thorax NOS
subjects affected / exposed	2 / 164 (1.22%)	1 / 174 (0.57%)	2 / 118 (1.69%)
occurrences all number	4	1	3
Pain - Face
Additional description: Pain - Face
subjects affected / exposed	3 / 164 (1.83%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	3	1	0
Pain - General
Additional description: Pain - General
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Pain - General - Foreign body
Additional description: Pain - General - Foreign body
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	2	2	0
Pain - NOS
Additional description: Pain - NOS
subjects affected / exposed	2 / 164 (1.22%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	3	0	0
Pain - Other (throat spasm)
Additional description: Pain - Other (throat spasm)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Pain NOS
Additional description: Pain NOS
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	2	0	0
Rigors/chills
Additional description: Rigors/chills
subjects affected / exposed	4 / 164 (2.44%)	3 / 174 (1.72%)	5 / 118 (4.24%)
occurrences all number	4	3	10
Immune system disorders
Allergic reaction
Additional description: Allergic reaction
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1537	1584	1056
Cytokine release syndrome
Additional description: Cytokine release syndrome
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Reproductive system and breast disorders
Haemorrhage, GU - Urinary NOS
Additional description: Haemorrhage, GU - Urinary NOS
subjects affected / exposed	2 / 164 (1.22%)	5 / 174 (2.87%)	0 / 118 (0.00%)
occurrences all number	4	5	0
Haemorrhage, GU - Vagina
Additional description: Haemorrhage, GU - Vagina
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	1	1	0
Infection - Sexual/reproductive function
Additional description: Infection - Sexual/reproductive function
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Irregular menses
Additional description: Irregular menses
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Pain - Breast
Additional description: Pain - Breast
subjects affected / exposed	1 / 164 (0.61%)	2 / 174 (1.15%)	3 / 118 (2.54%)
occurrences all number	1	12	5
Pain - Pelvis
Additional description: Pain - Pelvis
subjects affected / exposed	3 / 164 (1.83%)	3 / 174 (1.72%)	3 / 118 (2.54%)
occurrences all number	4	8	6
Pain - Perineum
Additional description: Pain - Perineum
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences all number	0	1	1
Sexual - Other (vaginal prolapse)
Additional description: Sexual - Other (vaginal prolapse)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	1	0	3
Sexual - Other (vulval irritation)
Additional description: Sexual - Other (vulval irritation)
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Vaginal discharge
Additional description: Vaginal discharge
subjects affected / exposed	2 / 164 (1.22%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences all number	3	5	0
Vaginal dryness
Additional description: Vaginal dryness
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	2 / 118 (1.69%)
occurrences all number	5	4	3
Respiratory, thoracic and mediastinal disorders
Airway obstruction - Bronchus
Additional description: Airway obstruction - Bronchus
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Apnea
Additional description: Apnea
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	7
Bronchospasm
Additional description: Bronchospasm
subjects affected / exposed	2 / 164 (1.22%)	1 / 174 (0.57%)	2 / 118 (1.69%)
occurrences all number	7	1	15
Bronchospasm, wheezing
Additional description: Bronchospasm, wheezing
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	2 / 118 (1.69%)
occurrences all number	1	0	2
Cough
Additional description: Cough
subjects affected / exposed	36 / 164 (21.95%)	32 / 174 (18.39%)	28 / 118 (23.73%)
occurrences all number	78	50	60
Dyspnea
Additional description: Dyspnea
subjects affected / exposed	59 / 164 (35.98%)	66 / 174 (37.93%)	34 / 118 (28.81%)
occurrences all number	209	189	123
Haemorrhage pulmonary - Bronchopulmonary NOS
Additional description: Haemorrhage pulmonary - Bronchopulmonary NOS
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Haemorrhage pulmonary - Nose
Additional description: Haemorrhage pulmonary - Nose
subjects affected / exposed	3 / 164 (1.83%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	3	0	0
Nasal/paranasal reactions
Additional description: Nasal/paranasal reactions
subjects affected / exposed	2 / 164 (1.22%)	2 / 174 (1.15%)	3 / 118 (2.54%)
occurrences all number	2	2	13
Pain - Oral cavity
Additional description: Pain - Oral cavity
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Pain - Pleura
Additional description: Pain - Pleura
subjects affected / exposed	0 / 164 (0.00%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences all number	0	2	0
Pain - Throat
Additional description: Pain - Throat
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Pain - Throat/pharynx/larynx
Additional description: Pain - Throat/pharynx/larynx
subjects affected / exposed	14 / 164 (8.54%)	13 / 174 (7.47%)	11 / 118 (9.32%)
occurrences all number	25	18	19
Pleural effusion
Additional description: Pleural effusion
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	2 / 118 (1.69%)
occurrences all number	6	0	2
Pulmonary - Other (chest tightness)
Additional description: Pulmonary - Other (chest tightness)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	2	0
Pulmonary - Other (throat irritation)
Additional description: Pulmonary - Other (throat irritation)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Pulmonary - Other (tonsillar erythema)
Additional description: Pulmonary - Other (tonsillar erythema)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Rhinitis
Additional description: Rhinitis
subjects affected / exposed	14 / 164 (8.54%)	13 / 174 (7.47%)	3 / 118 (2.54%)
occurrences all number	30	26	13
Voice changes
Additional description: Voice changes
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1548	1580	1045
Psychiatric disorders
Confusion
Additional description: Confusion
subjects affected / exposed	2 / 164 (1.22%)	5 / 174 (2.87%)	2 / 118 (1.69%)
occurrences all number	2	5	3
Insomnia
Additional description: Insomnia
subjects affected / exposed	25 / 164 (15.24%)	37 / 174 (21.26%)	20 / 118 (16.95%)
occurrences all number	99	142	127
Mood alteration
Additional description: Mood alteration
subjects affected / exposed	6 / 164 (3.66%)	5 / 174 (2.87%)	0 / 118 (0.00%)
occurrences all number	13	7	0
Mood alteration - Agitation
Additional description: Mood alteration - Agitation
subjects affected / exposed	2 / 164 (1.22%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences all number	2	2	0
Mood alteration - Anxiety
Additional description: Mood alteration - Anxiety
subjects affected / exposed	13 / 164 (7.93%)	16 / 174 (9.20%)	15 / 118 (12.71%)
occurrences all number	58	52	52
Mood alteration - Depression
Additional description: Mood alteration - Depression
subjects affected / exposed	19 / 164 (11.59%)	13 / 174 (7.47%)	13 / 118 (11.02%)
occurrences all number	50	38	44
Other - Vivid dreams
Additional description: Other - Vivid dreams
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Psychosis
Additional description: Psychosis
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	1	0	1
Investigations
Alkaline phosphatase
Additional description: Alkaline phosphatase
subjects affected / exposed	23 / 164 (14.02%)	28 / 174 (16.09%)	10 / 118 (8.47%)
occurrences all number	55	84	27
ALT or AST
Additional description: ALT or AST
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1509	1568	1037
APTT
Additional description: APTT
subjects affected / exposed	162 / 164 (98.78%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1420	1477	980
AST
Additional description: AST
subjects affected / exposed	3 / 164 (1.83%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences all number	3	1	1
Bilirubin
Additional description: Bilirubin
subjects affected / exposed	6 / 164 (3.66%)	4 / 174 (2.30%)	4 / 118 (3.39%)
occurrences all number	10	13	10
Cholesterol
Additional description: Cholesterol
subjects affected / exposed	2 / 164 (1.22%)	2 / 174 (1.15%)	4 / 118 (3.39%)
occurrences all number	11	6	17
Coagulation - Other (PT elevation)
Additional description: Coagulation - Other (PT elevation)
subjects affected / exposed	0 / 164 (0.00%)	2 / 174 (1.15%)	1 / 118 (0.85%)
occurrences all number	0	2	1
CPK
Additional description: CPK
subjects affected / exposed	163 / 164 (99.39%)	174 / 174 (100.00%)	115 / 118 (97.46%)
occurrences all number	1448	1501	991
Creatinine
Additional description: Creatinine
subjects affected / exposed	11 / 164 (6.71%)	17 / 174 (9.77%)	7 / 118 (5.93%)
occurrences all number	22	26	7
Fibrinogen
Additional description: Fibrinogen
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
GGT
Additional description: GGT
subjects affected / exposed	7 / 164 (4.27%)	11 / 174 (6.32%)	2 / 118 (1.69%)
occurrences all number	13	35	5
INR
Additional description: INR
subjects affected / exposed	163 / 164 (99.39%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1439	1493	993
Leukocytes
Additional description: Leukocytes
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1552	1614	1079
Lymphopenia
Additional description: Lymphopenia
subjects affected / exposed	1 / 164 (0.61%)	2 / 174 (1.15%)	3 / 118 (2.54%)
occurrences all number	1	4	3
Metabolic/Laboratory - Other (glycosuria)
Additional description: Metabolic/Laboratory - Other (glycosuria)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	2	0
Metabolic/Laboratory - Other (high bicarbonate)
Additional description: Metabolic/Laboratory - Other (high bicarbonate)
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	1	2	0
Metabolic/Laboratory - Other (high chloride)
Additional description: Metabolic/Laboratory - Other (high chloride)
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	1	2	0
Metabolic/Laboratory - Other (high CRP)
Additional description: Metabolic/Laboratory - Other (high CRP)
subjects affected / exposed	2 / 164 (1.22%)	3 / 174 (1.72%)	1 / 118 (0.85%)
occurrences all number	2	3	1
Metabolic/Laboratory - Other (high globulins)
Additional description: Metabolic/Laboratory - Other (high globulins)
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	1	1	0
Metabolic/Laboratory - Other (high LDH)
Additional description: Metabolic/Laboratory - Other (high LDH)
subjects affected / exposed	1 / 164 (0.61%)	3 / 174 (1.72%)	1 / 118 (0.85%)
occurrences all number	1	4	7
Metabolic/Laboratory - Other (high urea)
Additional description: Metabolic/Laboratory - Other (high urea)
subjects affected / exposed	4 / 164 (2.44%)	7 / 174 (4.02%)	6 / 118 (5.08%)
occurrences all number	7	9	13
Metabolic/Laboratory - Other (hyperphosphatemia)
Additional description: Metabolic/Laboratory - Other (hyperphosphatemia)
subjects affected / exposed	5 / 164 (3.05%)	4 / 174 (2.30%)	1 / 118 (0.85%)
occurrences all number	9	4	2
Metabolic/Laboratory - Other (ketonuria)
Additional description: Metabolic/Laboratory - Other (ketonuria)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Metabolic/Laboratory - Other (low chloride)
Additional description: Metabolic/Laboratory - Other (low chloride)
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	1	2	0
Metabolic/Laboratory - Other (low GFR)
Additional description: Metabolic/Laboratory - Other (low GFR)
subjects affected / exposed	1 / 164 (0.61%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences all number	1	2	0
Metabolic/Laboratory - Other (low protein)
Additional description: Metabolic/Laboratory - Other (low protein)
subjects affected / exposed	0 / 164 (0.00%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences all number	0	7	0
Neutrophils
Additional description: Neutrophils
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1516	1571	1039
Platelets
Additional description: Platelets
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1513	1572	1038
Weight gain
Additional description: Weight gain
subjects affected / exposed	1 / 164 (0.61%)	3 / 174 (1.72%)	1 / 118 (0.85%)
occurrences all number	1	11	1
Weight loss
Additional description: Weight loss
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1519	1582	1038
Injury, poisoning and procedural complications
Bruising
Additional description: Bruising
subjects affected / exposed	7 / 164 (4.27%)	8 / 174 (4.60%)	1 / 118 (0.85%)
occurrences all number	10	8	1
Fracture
Additional description: Fracture
subjects affected / exposed	2 / 164 (1.22%)	0 / 174 (0.00%)	3 / 118 (2.54%)
occurrences all number	2	0	5
Infection - Wound
Additional description: Infection - Wound
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	2
Intra-op injury
Additional description: Intra-op injury
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1506	1565	1037
Intraop Injury - Eye NOS
Additional description: Intraop Injury - Eye NOS
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Intraop Injury - Teeth
Additional description: Intraop Injury - Teeth
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Vein injury - Extremity-lower
Additional description: Vein injury - Extremity-lower
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Wound complications
Additional description: Wound complications
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1506	1565	1037
Cardiac disorders
Cardiac Arrhythmia
Additional description: Cardiac Arrhythmia
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1506	1565	1037
Cardiac Arrhythmia - Sinus bradycardia
Additional description: Cardiac Arrhythmia - Sinus bradycardia
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	2	0	0
Cardiac Arrhythmia - Sinus tachycardia
Additional description: Cardiac Arrhythmia - Sinus tachycardia
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	2	0	0
Cardiac Arrhythmia - Tachycardia
Additional description: Cardiac Arrhythmia - Tachycardia
subjects affected / exposed	1 / 164 (0.61%)	2 / 174 (1.15%)	2 / 118 (1.69%)
occurrences all number	1	2	2
Cardiac General - Other (ECG changes)
Additional description: Cardiac General - Other (ECG changes)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	6	0	1
Cardiac ischaemia/infarction
Additional description: Cardiac ischaemia/infarction
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1506	1566	1047
LVSD
Additional description: LVSD
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1506	1565	1037
Pain - Cardiac/heart
Additional description: Pain - Cardiac/heart
subjects affected / exposed	2 / 164 (1.22%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	3	0	0
Palpitations
Additional description: Palpitations
subjects affected / exposed	4 / 164 (2.44%)	4 / 174 (2.30%)	3 / 118 (2.54%)
occurrences all number	6	10	3
Nervous system disorders
Cerebrovascular ischemia
Additional description: Cerebrovascular ischemia
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1509	1567	1037
CNS ischaemia
Additional description: CNS ischaemia
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Dizziness
Additional description: Dizziness
subjects affected / exposed	29 / 164 (17.68%)	23 / 174 (13.22%)	13 / 118 (11.02%)
occurrences all number	58	53	23
Encephalopathy
Additional description: Encephalopathy
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1506	1565	1037
Involuntary movement
Additional description: Involuntary movement
subjects affected / exposed	1 / 164 (0.61%)	3 / 174 (1.72%)	2 / 118 (1.69%)
occurrences all number	1	15	2
Leukoencephalopathy
Additional description: Leukoencephalopathy
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1506	1566	1037
Memory impairment
Additional description: Memory impairment
subjects affected / exposed	4 / 164 (2.44%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences all number	7	5	0
Neurology - Other (Bell's palsy)
Additional description: Neurology - Other (Bell's palsy)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	3	0
Neurology - other (dysthesia)
Additional description: Neurology - other (dysthesia)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	2	0	0
Neurology - Other (Impaired concentration)
Additional description: Neurology - Other (Impaired concentration)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Neurology - Other (Oral cavity dysthesia)
Additional description: Neurology - Other (Oral cavity dysthesia)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Neurology - Other (Parkinsonism)
Additional description: Neurology - Other (Parkinsonism)
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Neuropathy-sensory
Additional description: Neuropathy-sensory
subjects affected / exposed	5 / 164 (3.05%)	9 / 174 (5.17%)	6 / 118 (5.08%)
occurrences all number	10	19	18
Neuropathy - motor
Additional description: Neuropathy - motor
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1507	1566	1037
Neuropathy - sensory
Additional description: Neuropathy - sensory
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1514	1566	1038
Neuropathy: Cranial
Additional description: Neuropathy: Cranial
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Neuropathy: cranial - Motor-jaw muscles; Sensory-facial
Additional description: Neuropathy: cranial - Motor-jaw muscles; Sensory-facial
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	2	0
Neuropathy:cranial III Palsy
Additional description: Neuropathy:cranial III Palsy
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Pain - Head/headache
Additional description: Pain - Head/headache
subjects affected / exposed	20 / 164 (12.20%)	25 / 174 (14.37%)	13 / 118 (11.02%)
occurrences all number	55	58	26
Pain - Neuralgia/peripheral nerve
Additional description: Pain - Neuralgia/peripheral nerve
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Pain - Neurology - headache
Additional description: Pain - Neurology - headache
subjects affected / exposed	0 / 164 (0.00%)	2 / 174 (1.15%)	1 / 118 (0.85%)
occurrences all number	0	2	2
Seizure
Additional description: Seizure
subjects affected / exposed	0 / 164 (0.00%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences all number	0	2	0
Somnolence
Additional description: Somnolence
subjects affected / exposed	2 / 164 (1.22%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences all number	2	2	0
Speech impairment
Additional description: Speech impairment
subjects affected / exposed	2 / 164 (1.22%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	2	0	0
Syncope (fainting)
Additional description: Syncope (fainting)
subjects affected / exposed	1 / 164 (0.61%)	3 / 174 (1.72%)	2 / 118 (1.69%)
occurrences all number	2	3	3
Taste alteration
Additional description: Taste alteration
subjects affected / exposed	27 / 164 (16.46%)	26 / 174 (14.94%)	11 / 118 (9.32%)
occurrences all number	87	86	33
Tremor
Additional description: Tremor
subjects affected / exposed	6 / 164 (3.66%)	3 / 174 (1.72%)	1 / 118 (0.85%)
occurrences all number	9	4	3
Vasovagal episode
Additional description: Vasovagal episode
subjects affected / exposed	0 / 164 (0.00%)	2 / 174 (1.15%)	3 / 118 (2.54%)
occurrences all number	0	2	3
Blood and lymphatic system disorders
Blood
Additional description: Blood
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Blood - Other (Basophils)
Additional description: Blood - Other (Basophils)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Blood - Other (Lymphocytes)
Additional description: Blood - Other (Lymphocytes)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Blood - Other (mean corpuscular hemoglobin)
Additional description: Blood - Other (mean corpuscular hemoglobin)
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Blood - Other (raising CA125)
Additional description: Blood - Other (raising CA125)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Blood/Bone marrow - Other (high mcv)
Additional description: Blood/Bone marrow - Other (high mcv)
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences all number	1	2	3
Blood/Bone marrow - Other (low iron)
Additional description: Blood/Bone marrow - Other (low iron)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	4	0	0
Blood/Bone marrow - Other (low pcv)
Additional description: Blood/Bone marrow - Other (low pcv)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Blood/Bone marrow - Other (low red cell count)
Additional description: Blood/Bone marrow - Other (low red cell count)
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	2	3	0
Blood/Bone marrow - Other (RDW)
Additional description: Blood/Bone marrow - Other (RDW)
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	2	3	0
Blood/Bone Marrow – other esoinophils
Additional description: Blood/Bone Marrow other esoinophils
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Blood/Bone Marrow – other RBC
Additional description: Blood/Bone Marrow other RBC
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	2
Febrile neutropenia
Additional description: Febrile neutropenia
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1521	1573	1041
Haemoglobin
Additional description: Haemoglobin
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1519	1576	1058
Lymphatics
Additional description: Lymphatics
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1506	1565	1037
Ear and labyrinth disorders
Auditory/Ear
Additional description: Auditory/Ear
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1506	1565	1038
Auditory/Ear - Hearing loss
Additional description: Auditory/Ear - Hearing loss
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	2 / 118 (1.69%)
occurrences all number	1	0	2
Auditory/Ear - Other (Blocked ear)
Additional description: Auditory/Ear - Other (Blocked ear)
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Auditory/Ear - Other (Muffled hearing)
Additional description: Auditory/Ear - Other (Muffled hearing)
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Pain - Ear
Additional description: Pain - Ear
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	2	0	3
Pain - External ear
Additional description: Pain - External ear
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Tinnitus
Additional description: Tinnitus
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences all number	0	7	3
Eye disorders
Blurred vision
Additional description: Blurred vision
subjects affected / exposed	10 / 164 (6.10%)	6 / 174 (3.45%)	8 / 118 (6.78%)
occurrences all number	21	17	19
Cataract
Additional description: Cataract
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences all number	4	1	1
Diplopia
Additional description: Diplopia
subjects affected / exposed	2 / 164 (1.22%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	3	1	0
Dry eye
Additional description: Dry eye
subjects affected / exposed	2 / 164 (1.22%)	3 / 174 (1.72%)	1 / 118 (0.85%)
occurrences all number	4	12	1
Flashing lights
Additional description: Flashing lights
subjects affected / exposed	2 / 164 (1.22%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	3	1	0
Glaucoma
Additional description: Glaucoma
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	15	0	0
Ocular - Other (impaired vision)
Additional description: Ocular - Other (impaired vision)
subjects affected / exposed	3 / 164 (1.83%)	1 / 174 (0.57%)	2 / 118 (1.69%)
occurrences all number	4	7	2
Ocular - Other (Itchy eyes)
Additional description: Ocular - Other (Itchy eyes)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Ocular - Other (pruritus)
Additional description: Ocular - Other (pruritus)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Ocular - Other (visual changes)
Additional description: Ocular - Other (visual changes)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	2 / 118 (1.69%)
occurrences all number	0	1	2
Ocular surface disease
Additional description: Ocular surface disease
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences all number	0	1	1
Retinal detachment
Additional description: Retinal detachment
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Watery eye
Additional description: Watery eye
subjects affected / exposed	2 / 164 (1.22%)	1 / 174 (0.57%)	2 / 118 (1.69%)
occurrences all number	19	1	2
Gastrointestinal disorders
Ascites
Additional description: Ascites
subjects affected / exposed	6 / 164 (3.66%)	2 / 174 (1.15%)	4 / 118 (3.39%)
occurrences all number	14	7	5
Cheilitis
Additional description: Cheilitis
subjects affected / exposed	2 / 164 (1.22%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences all number	3	1	1
Constipation
Additional description: Constipation
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1511	1568	1040
Dental
Additional description: Dental
subjects affected / exposed	2 / 164 (1.22%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	2	0	0
Dental: Teeth
Additional description: Dental: Teeth
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Diarrhea
Additional description: Diarrhea
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	1	3	0
Diarrhoea
Additional description: Diarrhoea
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1518	1595	1043
Distension
Additional description: Distension
subjects affected / exposed	17 / 164 (10.37%)	33 / 174 (18.97%)	25 / 118 (21.19%)
occurrences all number	40	84	58
Dry mouth
Additional description: Dry mouth
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1509	1569	1037
Dyspepsia
Additional description: Dyspepsia
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Dysphagia
Additional description: Dysphagia
subjects affected / exposed	3 / 164 (1.83%)	3 / 174 (1.72%)	1 / 118 (0.85%)
occurrences all number	6	3	2
Esophagitis
Additional description: Esophagitis
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences all number	1	1	1
Fistula, GI
Additional description: Fistula, GI
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1506	1565	1037
Fistula, GU - Vagina
Additional description: Fistula, GU - Vagina
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Flatulence
Additional description: Flatulence
subjects affected / exposed	11 / 164 (6.71%)	12 / 174 (6.90%)	7 / 118 (5.93%)
occurrences all number	32	41	14
Gastritis
Additional description: Gastritis
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences all number	0	1	1
Gastrointestinal - Other (Altered bowel function)
Additional description: Gastrointestinal - Other (Altered bowel function)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences all number	0	1	2
Gastrointestinal - Other (Increased appetite)
Additional description: Gastrointestinal - Other (Increased appetite)
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	3 / 118 (2.54%)
occurrences all number	0	0	5
Gastrointestinal - Other (Irritable bowel)
Additional description: Gastrointestinal - Other (Irritable bowel)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	6	0
Gastrointestinal - Other (Ructus)
Additional description: Gastrointestinal - Other (Ructus)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	3 / 118 (2.54%)
occurrences all number	5	0	4
GI - Other (hernia)
Additional description: GI - Other (hernia)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
GI - Other (Hiatus hernia)
Additional description: GI - Other (Hiatus hernia)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	4	0	4
GI - Other (Increased appetite)
Additional description: GI - Other (Increased appetite)
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
GI - Other (rectal urgency)
Additional description: GI - Other (rectal urgency)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Haemorrhage, GI - Upper GI
Additional description: Haemorrhage, GI - Upper GI
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	2	1	0
Heartburn
Additional description: Heartburn
subjects affected / exposed	25 / 164 (15.24%)	33 / 174 (18.97%)	24 / 118 (20.34%)
occurrences all number	59	68	58
Hemorrhoids
Additional description: Hemorrhoids
subjects affected / exposed	4 / 164 (2.44%)	3 / 174 (1.72%)	1 / 118 (0.85%)
occurrences all number	7	4	1
Ileum
Additional description: Ileum
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	2	0
Ileus
Additional description: Ileus
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences all number	0	1	1
Incontinence, anal
Additional description: Incontinence, anal
subjects affected / exposed	0 / 164 (0.00%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences all number	0	2	0
Mucositis
Additional description: Mucositis
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1528	1584	1044
Mucositis - Oral cavity
Additional description: Mucositis - Oral cavity
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Nausea
Additional description: Nausea
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1514	1575	1042
Obstruction, GI
Additional description: Obstruction, GI
subjects affected / exposed	3 / 164 (1.83%)	2 / 174 (1.15%)	4 / 118 (3.39%)
occurrences all number	4	3	4
Obstruction, GI - Colon
Additional description: Obstruction, GI - Colon
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	3	1	0
Pain - Abdomen NOS
Additional description: Pain - Abdomen NOS
subjects affected / exposed	36 / 164 (21.95%)	38 / 174 (21.84%)	27 / 118 (22.88%)
occurrences all number	81	68	67
Pain - Anus
Additional description: Pain - Anus
subjects affected / exposed	1 / 164 (0.61%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences all number	1	2	0
Pain - Dental/teeth/peridontal
Additional description: Pain - Dental/teeth/peridontal
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences all number	0	4	1
Pain - Gastrointestinal
Additional description: Pain - Gastrointestinal
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Pain - Lip
Additional description: Pain - Lip
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Pain - Oral-gums
Additional description: Pain - Oral-gums
subjects affected / exposed	2 / 164 (1.22%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	4	0	0
Pain - Oral cavity
Additional description: Pain - Oral cavity
subjects affected / exposed	5 / 164 (3.05%)	10 / 174 (5.75%)	1 / 118 (0.85%)
occurrences all number	14	21	1
Pain - Rectum
Additional description: Pain - Rectum
subjects affected / exposed	5 / 164 (3.05%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	6	4	0
Pain - Stomach
Additional description: Pain - Stomach
subjects affected / exposed	9 / 164 (5.49%)	2 / 174 (1.15%)	5 / 118 (4.24%)
occurrences all number	16	3	9
Perforation, GI
Additional description: Perforation, GI
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1506	1566	1037
Periodontal
Additional description: Periodontal
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Salivary gland changes
Additional description: Salivary gland changes
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	5	3	0
Ulcer, GI - Duodenum
Additional description: Ulcer, GI - Duodenum
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	2	0	0
Vomiting
Additional description: Vomiting
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1518	1587	1045
Hepatobiliary disorders
Cholecystitis
Additional description: Cholecystitis
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Hepatobiliary/Pancreas
Additional description: Hepatobiliary/Pancreas
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1506	1565	1037
Skin and subcutaneous tissue disorders
Acne
Additional description: Acne
subjects affected / exposed	2 / 164 (1.22%)	3 / 174 (1.72%)	0 / 118 (0.00%)
occurrences all number	2	10	0
Alopecia
Additional description: Alopecia
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1508	1565	1037
Decubitus
Additional description: Decubitus
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	1	2	0
Dermatology - other (furuncle)
Additional description: Dermatology - other (furuncle)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Dermatology - other (perineal nodule)
Additional description: Dermatology - other (perineal nodule)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Dermatology/Skin - other
Additional description: Dermatology/Skin - other
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Dermatology/Skin - other (Actinic keratosis)
Additional description: Dermatology/Skin - other (Actinic keratosis)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	2	0
Dermatology/Skin - Other (blister)
Additional description: Dermatology/Skin - Other (blister)
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	1	1	0
Dermatology/Skin - Other (cyst)
Additional description: Dermatology/Skin - Other (cyst)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	3	0	0
Dermatology/Skin - Other (exacerbation of solar keratosis)
Additional description: Dermatology/Skin - Other (exacerbation of solar keratosis)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	3	0
Dermatology/Skin - Other (Increase in facial hair)
Additional description: Dermatology/Skin - Other (Increase in facial hair)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Dermatology/Skin - Other (Skin pigmentation)
Additional description: Dermatology/Skin - Other (Skin pigmentation)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Dry skin
Additional description: Dry skin
subjects affected / exposed	17 / 164 (10.37%)	11 / 174 (6.32%)	5 / 118 (4.24%)
occurrences all number	37	33	23
Hand-foot
Additional description: Hand-foot
subjects affected / exposed	0 / 164 (0.00%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences all number	0	2	0
Hand-foot syndrome
Additional description: Hand-foot syndrome
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1506	1582	1038
Hyperpigmentation
Additional description: Hyperpigmentation
subjects affected / exposed	1 / 164 (0.61%)	4 / 174 (2.30%)	1 / 118 (0.85%)
occurrences all number	1	9	8
Infection - Skin
Additional description: Infection - Skin
subjects affected / exposed	9 / 164 (5.49%)	8 / 174 (4.60%)	9 / 118 (7.63%)
occurrences all number	13	12	12
Infection - Skin (cellulitis)
Additional description: Infection - Skin (cellulitis)
subjects affected / exposed	2 / 164 (1.22%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences all number	2	4	0
Nail changes
Additional description: Nail changes
subjects affected / exposed	5 / 164 (3.05%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences all number	8	1	5
Pain - Anus
Additional description: Pain - Anus
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Pain - Scalp
Additional description: Pain - Scalp
subjects affected / exposed	2 / 164 (1.22%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences all number	3	3	0
Petechiae
Additional description: Petechiae
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	8	2	0
Photosensitivity
Additional description: Photosensitivity
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Pruritus
Additional description: Pruritus
subjects affected / exposed	16 / 164 (9.76%)	20 / 174 (11.49%)	6 / 118 (5.08%)
occurrences all number	26	35	11
Rash
Additional description: Rash
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1539	1577	1047
Skin - Other (lump)
Additional description: Skin - Other (lump)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	2	0	0
Skin - Other (solar keratosis)
Additional description: Skin - Other (solar keratosis)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Sweating
Additional description: Sweating
subjects affected / exposed	6 / 164 (3.66%)	4 / 174 (2.30%)	5 / 118 (4.24%)
occurrences all number	13	11	11
Ulceration
Additional description: Ulceration
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	2 / 118 (1.69%)
occurrences all number	1	0	12
Renal and urinary disorders
Cystitis
Additional description: Cystitis
subjects affected / exposed	6 / 164 (3.66%)	4 / 174 (2.30%)	2 / 118 (1.69%)
occurrences all number	10	4	2
Haemolysis
Additional description: Haemolysis
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Hemoglobinuria
Additional description: Hemoglobinuria
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	5	0	0
Incontinence
Additional description: Incontinence
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences all number	1	1	1
Incontinence, urinary
Additional description: Incontinence, urinary
subjects affected / exposed	0 / 164 (0.00%)	2 / 174 (1.15%)	4 / 118 (3.39%)
occurrences all number	0	2	4
Obstruction, GU (renal)
Additional description: Obstruction, GU (renal)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	4	0
Pain - Bladder
Additional description: Pain - Bladder
subjects affected / exposed	2 / 164 (1.22%)	0 / 174 (0.00%)	2 / 118 (1.69%)
occurrences all number	2	0	7
Proteinuria
Additional description: Proteinuria
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1507	1570	1037
Renal - Other (dysuria)
Additional description: Renal - Other (dysuria)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Renal - Other (hematuria)
Additional description: Renal - Other (hematuria)
subjects affected / exposed	0 / 164 (0.00%)	3 / 174 (1.72%)	0 / 118 (0.00%)
occurrences all number	0	3	0
Renal - Other (hydronephrosis)
Additional description: Renal - Other (hydronephrosis)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	2	0
Renal - Other (microscopic haematuria)
Additional description: Renal - Other (microscopic haematuria)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	2	0
Renal - Other (polyuria)
Additional description: Renal - Other (polyuria)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Renal - Other (proteinuria)
Additional description: Renal - Other (proteinuria)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Renal/Genitourinary
Additional description: Renal/Genitourinary
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1506	1565	1037
Urinary frequency
Additional description: Urinary frequency
subjects affected / exposed	1 / 164 (0.61%)	2 / 174 (1.15%)	1 / 118 (0.85%)
occurrences all number	1	7	1
Endocrine disorders
Hyperparathyroidism
Additional description: Hyperparathyroidism
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Hyperthyroidism
Additional description: Hyperthyroidism
subjects affected / exposed	12 / 164 (7.32%)	8 / 174 (4.60%)	1 / 118 (0.85%)
occurrences all number	41	18	3
Hypothyroidism
Additional description: Hypothyroidism
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1533	1570	1040
Thyroid function
Additional description: Thyroid function
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Musculoskeletal and connective tissue disorders
Arthritis
Additional description: Arthritis
subjects affected / exposed	3 / 164 (1.83%)	5 / 174 (2.87%)	2 / 118 (1.69%)
occurrences all number	8	9	2
Auditory/Ear - Other (Muscle tearing in right ear)
Additional description: Auditory/Ear - Other (Muscle tearing in right ear)
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Infection - Joint
Additional description: Infection - Joint
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Joint-function
Additional description: Joint-function
subjects affected / exposed	2 / 164 (1.22%)	4 / 174 (2.30%)	1 / 118 (0.85%)
occurrences all number	2	15	3
Joint - effusion
Additional description: Joint - effusion
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Joint function
Additional description: Joint function
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	2
Muscle weakness
Additional description: Muscle weakness
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	1	1	0
Muscle weakness - Distal
Additional description: Muscle weakness - Distal
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1507	1565	1038
Muscle weakness - Extremity-lower
Additional description: Muscle weakness - Extremity-lower
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	1 / 118 (0.85%)
occurrences all number	0	1	2
Muscle weakness - Extremity-upper
Additional description: Muscle weakness - Extremity-upper
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Muscle weakness - Proximal
Additional description: Muscle weakness - Proximal
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1506	1565	1037
Muscle weakness - Whole body/generalized
Additional description: Muscle weakness - Whole body/generalized
subjects affected / exposed	6 / 164 (3.66%)	1 / 174 (0.57%)	2 / 118 (1.69%)
occurrences all number	13	1	8
Musculoskeletal - other (cyst on leg)
Additional description: Musculoskeletal - other (cyst on leg)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Musculoskeletal - Other (injury)
Additional description: Musculoskeletal - Other (injury)
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Musculoskeletal - Other (plantar fascitis)
Additional description: Musculoskeletal - Other (plantar fascitis)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Musculoskeletal - other (pulled muscle)
Additional description: Musculoskeletal - other (pulled muscle)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Musculoskeletal - Other (tennis elbow flare)
Additional description: Musculoskeletal - Other (tennis elbow flare)
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Musculoskeletal - Other (tennis elbow)
Additional description: Musculoskeletal - Other (tennis elbow)
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	3
Musculoskeletal - Other (tightness - chest)
Additional description: Musculoskeletal - Other (tightness - chest)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	2	0	0
Musculoskeletal - Other (tightness - upper back)
Additional description: Musculoskeletal - Other (tightness - upper back)
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	9
Musculoskeletal/Soft Tissue - Swelling of ankles
Additional description: Musculoskeletal/Soft Tissue - Swelling of ankles
subjects affected / exposed	1 / 164 (0.61%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences all number	1	2	0
Musculosketal - other (trigger finger)
Additional description: Musculosketal - other (trigger finger)
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	18	0	0
Myositis
Additional description: Myositis
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1506	1565	1037
Osteoporosis
Additional description: Osteoporosis
subjects affected / exposed	2 / 164 (1.22%)	3 / 174 (1.72%)	0 / 118 (0.00%)
occurrences all number	8	11	0
Pain - Back
Additional description: Pain - Back
subjects affected / exposed	17 / 164 (10.37%)	13 / 174 (7.47%)	10 / 118 (8.47%)
occurrences all number	52	30	35
Pain - Bone
Additional description: Pain - Bone
subjects affected / exposed	4 / 164 (2.44%)	7 / 174 (4.02%)	2 / 118 (1.69%)
occurrences all number	6	18	2
Pain - Buttock
Additional description: Pain - Buttock
subjects affected / exposed	1 / 164 (0.61%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences all number	1	5	0
Pain - Dental/teeth/peridontal
Additional description: Pain - Dental/teeth/peridontal
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Pain - Extremity-limb
Additional description: Pain - Extremity-limb
subjects affected / exposed	27 / 164 (16.46%)	17 / 174 (9.77%)	18 / 118 (15.25%)
occurrences all number	48	30	39
Pain - Hip
Additional description: Pain - Hip
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Pain - Joint
Additional description: Pain - Joint
subjects affected / exposed	35 / 164 (21.34%)	37 / 174 (21.26%)	26 / 118 (22.03%)
occurrences all number	90	93	110
Pain - Muscle
Additional description: Pain - Muscle
subjects affected / exposed	20 / 164 (12.20%)	36 / 174 (20.69%)	16 / 118 (13.56%)
occurrences all number	47	81	55
Pain - Musculoskeletal
Additional description: Pain - Musculoskeletal
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Pain - Neck
Additional description: Pain - Neck
subjects affected / exposed	2 / 164 (1.22%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	5	0	1
Infections and infestations
Infection
Additional description: Infection
subjects affected / exposed	5 / 164 (3.05%)	4 / 174 (2.30%)	2 / 118 (1.69%)
occurrences all number	5	4	2
Infection - Abdomen
Additional description: Infection - Abdomen
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Infection - Abdomen NOS
Additional description: Infection - Abdomen NOS
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	2	0
Infection - Bladder (urinary)
Additional description: Infection - Bladder (urinary)
subjects affected / exposed	5 / 164 (3.05%)	3 / 174 (1.72%)	1 / 118 (0.85%)
occurrences all number	5	3	1
Infection - Bronchus
Additional description: Infection - Bronchus
subjects affected / exposed	11 / 164 (6.71%)	19 / 174 (10.92%)	13 / 118 (11.02%)
occurrences all number	14	25	20
Infection - Catheter-related
Additional description: Infection - Catheter-related
subjects affected / exposed	3 / 164 (1.83%)	3 / 174 (1.72%)	0 / 118 (0.00%)
occurrences all number	3	3	0
Infection - Conjunctiva
Additional description: Infection - Conjunctiva
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	2 / 118 (1.69%)
occurrences all number	2	1	2
Infection - Dental-tooth
Additional description: Infection - Dental-tooth
subjects affected / exposed	2 / 164 (1.22%)	3 / 174 (1.72%)	0 / 118 (0.00%)
occurrences all number	2	3	0
Infection - Ear
Additional description: Infection - Ear
subjects affected / exposed	3 / 164 (1.83%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	6	0	0
Infection - Eye NOS
Additional description: Infection - Eye NOS
subjects affected / exposed	0 / 164 (0.00%)	3 / 174 (1.72%)	1 / 118 (0.85%)
occurrences all number	0	3	1
Infection - Gallbladder (cholecystitis)
Additional description: Infection - Gallbladder (cholecystitis)
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Infection - Gastrointestinal - Abdomen NOS
Additional description: Infection - Gastrointestinal - Abdomen NOS
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Infection - Inner ear
Additional description: Infection - Inner ear
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	2	0
Infection - Kidney
Additional description: Infection - Kidney
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Infection - Larynx
Additional description: Infection - Larynx
subjects affected / exposed	3 / 164 (1.83%)	1 / 174 (0.57%)	5 / 118 (4.24%)
occurrences all number	3	1	5
Infection - Lung
Additional description: Infection - Lung
subjects affected / exposed	2 / 164 (1.22%)	4 / 174 (2.30%)	1 / 118 (0.85%)
occurrences all number	2	4	1
Infection - Middle ear
Additional description: Infection - Middle ear
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Infection - Nose
Additional description: Infection - Nose
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	2	0	0
Infection - Oral cavity
Additional description: Infection - Oral cavity
subjects affected / exposed	0 / 164 (0.00%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences all number	0	2	0
Infection - Oral cavity-gums
Additional description: Infection - Oral cavity-gums
subjects affected / exposed	8 / 164 (4.88%)	4 / 174 (2.30%)	2 / 118 (1.69%)
occurrences all number	9	4	2
Infection - Other (herpes simplex)
Additional description: Infection - Other (herpes simplex)
subjects affected / exposed	3 / 164 (1.83%)	5 / 174 (2.87%)	1 / 118 (0.85%)
occurrences all number	4	8	3
Infection - Other (shingles)
Additional description: Infection - Other (shingles)
subjects affected / exposed	2 / 164 (1.22%)	3 / 174 (1.72%)	1 / 118 (0.85%)
occurrences all number	2	5	1
Infection - Other abscess
Additional description: Infection - Other abscess
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Infection - other catheter-related
Additional description: Infection - other catheter-related
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Infection - Perianal
Additional description: Infection - Perianal
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Infection - Peritoneal cavity
Additional description: Infection - Peritoneal cavity
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Infection - Sinus
Additional description: Infection - Sinus
subjects affected / exposed	4 / 164 (2.44%)	4 / 174 (2.30%)	4 / 118 (3.39%)
occurrences all number	8	5	6
Infection - Soft tissue
Additional description: Infection - Soft tissue
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Infection - Soft tissue NOS
Additional description: Infection - Soft tissue NOS
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	2	0	0
Infection - Ungual (nails)
Additional description: Infection - Ungual (nails)
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	1 / 118 (0.85%)
occurrences all number	0	0	1
Infection - Upper Airway NOS
Additional description: Infection - Upper Airway NOS
subjects affected / exposed	31 / 164 (18.90%)	30 / 174 (17.24%)	18 / 118 (15.25%)
occurrences all number	49	38	22
Infection - Upper respiratory
Additional description: Infection - Upper respiratory
subjects affected / exposed	4 / 164 (2.44%)	4 / 174 (2.30%)	2 / 118 (1.69%)
occurrences all number	4	4	2
Infection - Urinary tract NOS
Additional description: Infection - Urinary tract NOS
subjects affected / exposed	23 / 164 (14.02%)	31 / 174 (17.82%)	14 / 118 (11.86%)
occurrences all number	35	56	31
Infection - Vagina
Additional description: Infection - Vagina
subjects affected / exposed	5 / 164 (3.05%)	2 / 174 (1.15%)	2 / 118 (1.69%)
occurrences all number	5	2	2
Infection - Vulva
Additional description: Infection - Vulva
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	2 / 118 (1.69%)
occurrences all number	0	0	3
Infection with Grade 3 or 4 ANC
Additional description: Infection with Grade 3 or 4 ANC
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	1	0
Metabolism and nutrition disorders
Anorexia
Additional description: Anorexia
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1525	1583	1047
Bicarbonate, serum-low
Additional description: Bicarbonate, serum-low
subjects affected / exposed	1 / 164 (0.61%)	0 / 174 (0.00%)	0 / 118 (0.00%)
occurrences all number	1	0	0
Dehydration
Additional description: Dehydration
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1509	1573	1038
Diabetes
Additional description: Diabetes
subjects affected / exposed	1 / 164 (0.61%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	6	2	0
Hypercalcemia
Additional description: Hypercalcemia
subjects affected / exposed	3 / 164 (1.83%)	10 / 174 (5.75%)	3 / 118 (2.54%)
occurrences all number	3	12	13
Hyperglycemia
Additional description: Hyperglycemia
subjects affected / exposed	8 / 164 (4.88%)	9 / 174 (5.17%)	6 / 118 (5.08%)
occurrences all number	13	14	11
Hyperkalemia
Additional description: Hyperkalemia
subjects affected / exposed	1 / 164 (0.61%)	4 / 174 (2.30%)	2 / 118 (1.69%)
occurrences all number	2	9	4
Hypernatremia
Additional description: Hypernatremia
subjects affected / exposed	3 / 164 (1.83%)	2 / 174 (1.15%)	0 / 118 (0.00%)
occurrences all number	3	2	0
Hypertriglyceridemia
Additional description: Hypertriglyceridemia
subjects affected / exposed	0 / 164 (0.00%)	0 / 174 (0.00%)	2 / 118 (1.69%)
occurrences all number	0	0	11
Hyperuricemia
Additional description: Hyperuricemia
subjects affected / exposed	1 / 164 (0.61%)	5 / 174 (2.87%)	3 / 118 (2.54%)
occurrences all number	1	11	7
Hypoalbuminemia
Additional description: Hypoalbuminemia
subjects affected / exposed	13 / 164 (7.93%)	10 / 174 (5.75%)	8 / 118 (6.78%)
occurrences all number	21	22	15
Hypocalcemia
Additional description: Hypocalcemia
subjects affected / exposed	17 / 164 (10.37%)	21 / 174 (12.07%)	3 / 118 (2.54%)
occurrences all number	37	38	4
Hypoglycemia
Additional description: Hypoglycemia
subjects affected / exposed	4 / 164 (2.44%)	2 / 174 (1.15%)	1 / 118 (0.85%)
occurrences all number	6	4	1
Hypokalemia
Additional description: Hypokalemia
subjects affected / exposed	164 / 164 (100.00%)	174 / 174 (100.00%)	116 / 118 (98.31%)
occurrences all number	1510	1570	1040
Hypomagnesemia
Additional description: Hypomagnesemia
subjects affected / exposed	63 / 164 (38.41%)	63 / 174 (36.21%)	31 / 118 (26.27%)
occurrences all number	244	299	123
Hyponatremia
Additional description: Hyponatremia
subjects affected / exposed	16 / 164 (9.76%)	16 / 174 (9.20%)	8 / 118 (6.78%)
occurrences all number	30	30	22
Hypophosphatemia
Additional description: Hypophosphatemia
subjects affected / exposed	13 / 164 (7.93%)	5 / 174 (2.87%)	10 / 118 (8.47%)
occurrences all number	16	8	14
Obesity
Additional description: Obesity
subjects affected / exposed	0 / 164 (0.00%)	1 / 174 (0.57%)	0 / 118 (0.00%)
occurrences all number	0	2	0

More information

Top of page

Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
03 Oct 2011	ICON6 was an academic trial with a planned sample size of 2000 that opened to recruitment in December 2007. In October 2011, the Pharma partner (AstraZeneca) made the decision to terminate development of cediranib and discontinued manufacture of the agent. The resultant loss of drug supply led to recruitment being discontinued in December 2011, at which point 486 women had been randomised amongst the three arms.	-

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

None reported

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression-Free Survival (PFS)

Primary: Progression-Free Survival (PFS)

Primary: Progression Free Survival (PFS)

Primary: Progression Free Survival (PFS)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: QLQ C30

Secondary: QLQ C30

Secondary: Improved Ascites Resolution During Chemotherapy

Secondary: Improved Ascites Resolution During Chemotherapy

Secondary: Improved QoL: Global

Secondary: Improved QoL: Global

Secondary: Improved QoL: Pain

Secondary: Improved QoL: Pain

Secondary: Improved QoL: Physical function

Secondary: Improved QoL: Physical function

Secondary: Impaired fatigue during maintenance treatment

Secondary: Impaired fatigue during maintenance treatment

Secondary: Impaired social functioning during maintenance treatment

Secondary: Impaired social functioning during maintenance treatment

Other pre-specified: Time to First Subsequent Treatment (TFST)

Other pre-specified: Time to First Subsequent Treatment (TFST)

Other pre-specified: QLQ C30 Arm B vs Arm A

Other pre-specified: QLQ C30 Arm B vs Arm A

Other pre-specified: QLQ C30 End of chemotherapy

Other pre-specified: QLQ C30 End of chemotherapy

Other pre-specified: QLQ C30 End of chemotherapy Arm B vs Arm A

Other pre-specified: QLQ C30 End of chemotherapy Arm B vs Arm A

Other pre-specified: QLQ C30 End of chemotherapy to year 1

Other pre-specified: QLQ C30 End of chemotherapy to year 1

Other pre-specified: QLQ C30 End of chemotherapy to 1 year Arm B vs Arm A

Other pre-specified: QLQ C30 End of chemotherapy to 1 year Arm B vs Arm A

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information