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Clinical Trial Results:
A Randomised Phase II/III trial of peri-operative Chemotherapy with or without Bevacizumab in Operable Oesophagogastric Adenocarcinoma and A Feasibility Study Evaluating Lapatinib in HER-2 Positive Oesophagogastric Adenocarcinoma and (in selected centres) MRI and FDG-PET/CT Sub-studies

Summary
EudraCT number	2006-000811-12
Trial protocol	GB DE
Global end of trial date	30 Nov 2018

Results information
Results version number	v1(current)
This version publication date	29 Aug 2020
First version publication date	29 Aug 2020
Other versions

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

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Trial information

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Sponsor protocol code

ST03

ISRCTN number

ISRCTN46020948

US NCT number

NCT00450203

WHO universal trial number (UTN)

Sponsor organisation name

Medical Research Council

Sponsor organisation address

90 High Holborn, London, United Kingdom, WC1V 6LJ

Public contact

ST03 Trial Manager, Medical Research Council Clinical Trials Unit, +44 02076704801, mrcctu.st03@ucl.ac.uk

Scientific contact

ST03 Trial Manager, Medical Research Council Clinical Trials Unit, +44 02076704801, mrcctu.st03@ucl.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

10 May 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

25 Apr 2017

Global end of trial reached?

Yes

Global end of trial date

30 Nov 2018

Was the trial ended prematurely?

Main objective of the trial

To assess safety and overall survival of patients by adding the monoclonal antibody bevacizumab to Epirubicin, Cisplatin, Capecitabine (ECX) chemotherapy administered peri-operatively in patients with operable oesophagogastric adenocarcinoma and (in selected centres) a feasibility study evaluating the safety and feasibility of adding lapatinib, a small molecule tyrosine kinase inhibitor of HER-2 and epidermal growth factor receptor to peri-operative ECX chemotherapy in patients with HER-2 positive tumours.

Protection of trial subjects

Patients provided informed consent prior to entering the trial. All patients were followed and treated by qualified clinicians in specialised teams.

Background therapy

Evidence for comparator

Actual start date of recruitment

31 Oct 2007

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 1109

Worldwide total number of subjects

1109

EEA total number of subjects

1109

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)

617

From 65 to 84 years

492

85 years and over

Subject disposition

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Recruitment details

Patients recruited between 31st October 2007 and 21st April 2016.

Screening details

Patients were screened for eligibility by centres, but information on numbers were not recorded. From 25th February 2013, patients underwent HER2 testing prior to randomisation, to assess eligibility for the feasibility study. 441 patients were assessed during this period, 46 of whom were subsequently randomised into that part of the study.

Period 1 title

Main trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

ECX (Arm A)

Arm description

Epirubicin, cisplatin, capecitabine. Control arm for Bevacizumab comparison.

Arm type

Active comparator

Investigational medicinal product name

Epirubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

50mg/m2 given on day 1 on 21-day chemo cycle. Three cycles pre- and post-operatively.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

60mg/m2 given on day 1 on 21-day chemo cycle. Three cycles pre- and post-operatively.

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

1250mg/m2 taken orally on each day of 21-day cycle. Three cycles pre- and post-operatively.

ECX + Bev (arm B)

Arm description

Epirubicin, cisplatin, capecitabine, plus Bevacizumab. Experimental arm for Bev comparison.

Arm type

Experimental

Investigational medicinal product name

Epirubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

50mg/m2 given on day 1 on 21-day chemo cycle. Three cycles pre- and post-operatively.

Investigational medicinal product name

Bevacizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

7.5mg/kg on day 1 of each 21-day chemotherapy cycle. Three cycles pre- and post-operatively alongside other chemotherapy agents. Patients received a further six doses, once every 21 days, as maintenance treatment after post-operative chemotherapy.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

60mg/m2 given on day 1 on 21-day chemo cycle. Three cycles pre- and post-operatively.

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

1250mg/m2 taken orally on each day of 21-day cycle. Three cycles pre- and post-operatively.

ECX (Arm C)

Arm description

Epirubicin, cisplatin, capecitabine. Control arm for the Lapatinib comparison. HER2 positive patients.

Arm type

Active comparator

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

1250mg/m2 taken orally on each day of 21-day cycle. Three cycles pre- and post-operatively.

Investigational medicinal product name

Epirubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

50mg/m2 given on day 1 on 21-day chemo cycle. Three cycles pre- and post-operatively.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

60mg/m2 given on day 1 on 21-day chemo cycle. Three cycles pre- and post-operatively.

ECX + Lap (Arm D)

Arm description

Epirubicin, cisplatin, capecitabine. Experimental arm for the Lapatinib comparison. HER2 positive patients.

Arm type

Experimental

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

1000mg/m2 taken orally on each day of 21-day cycle. Three cycles pre- and post-operatively.

Investigational medicinal product name

Epirubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

50mg/m2 given on day 1 on 21-day chemo cycle. Three cycles pre- and post-operatively.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

60mg/m2 given on day 1 on 21-day chemo cycle. Three cycles pre- and post-operatively.

Investigational medicinal product name

Lapatinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

1250mg taken orally on each day of 21-day chemotherapy cycle. Three pre- and post-operative cycles alongside other chemotherapy agents. Patients further received a maintenance dose of 1500mg, taken daily for six 21-day cycles, following post-op chemotherapy.

Number of subjects in period 1	ECX (Arm A)	ECX + Bev (arm B)	ECX (Arm C)	ECX + Lap (Arm D)
Started	533	530	24	22
Completed	522	512	24	20
Not completed	11	18	0	2
Withdrew consent prior to surgery	11	18	-	2

Baseline characteristics

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Reporting group title

ECX (Arm A)

Reporting group description

Epirubicin, cisplatin, capecitabine. Control arm for Bevacizumab comparison.

Reporting group title

ECX + Bev (arm B)

Reporting group description

Epirubicin, cisplatin, capecitabine, plus Bevacizumab. Experimental arm for Bev comparison.

Reporting group title

ECX (Arm C)

Reporting group description

Epirubicin, cisplatin, capecitabine. Control arm for the Lapatinib comparison. HER2 positive patients.

Reporting group title

ECX + Lap (Arm D)

Reporting group description

Epirubicin, cisplatin, capecitabine. Experimental arm for the Lapatinib comparison. HER2 positive patients.

Reporting group values	ECX (Arm A)	ECX + Bev (arm B)	ECX (Arm C)	ECX + Lap (Arm D)	Total
Number of subjects	533	530	24	22	1109
Age categorical
Age at date of randomisation
Units: Subjects
Adults (18-64 years)	304	289	12	12	617
From 65-84 years	229	241	12	10	492
Age continuous
Age at date of randomisation
Units: years
median (inter-quartile range (Q1-Q3))	63 (56 to 68)	64 (56 to 69)	64 (57 to 68)	62 (54 to 71)	-
Gender categorical
Units: Subjects
Female	425	434	21	14	894
Male	108	96	3	8	215
WHO performance status
Units: Subjects
Normal activity	381	376	17	14	788
Restricted in physical activity	152	154	7	8	321
Site of tumour
Units: Subjects
Stomach	194	189	4	4	391
OGJ (Type II)	105	95	4	4	208
OGJ (Type III)	98	109	4	2	213
OGJ (Type I)	62	67	4	5	138
Lower oesophageal	74	70	8	7	159

End points

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Reporting group title

ECX (Arm A)

Reporting group description

Epirubicin, cisplatin, capecitabine. Control arm for Bevacizumab comparison.

Reporting group title

ECX + Bev (arm B)

Reporting group description

Epirubicin, cisplatin, capecitabine, plus Bevacizumab. Experimental arm for Bev comparison.

Reporting group title

ECX (Arm C)

Reporting group description

Epirubicin, cisplatin, capecitabine. Control arm for the Lapatinib comparison. HER2 positive patients.

Reporting group title

ECX + Lap (Arm D)

Reporting group description

Epirubicin, cisplatin, capecitabine. Experimental arm for the Lapatinib comparison. HER2 positive patients.

Primary: Overall survival at 3 years (Bev comparison)

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End point title

Overall survival at 3 years (Bev comparison) ^[1]

End point description

End point type

Primary

End point timeframe

Overall survival rate at 3 years post-randomisation

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: This outcome measure only applies to the Bavacizumab comparison, involving only arms A and B.

End point values	ECX (Arm A)	ECX + Bev (arm B)
Number of subjects analysed	533	530
Units: Percentage survival
number (confidence interval 95%)	50.3 (45.5 to 54.9)	48.1 (43.2 to 52.7)

Overall survival

Comparison groups

ECX (Arm A) v ECX + Bev (arm B)

Number of subjects included in analysis

1063

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.36

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

1.29

Primary: Rate of preoperative diarrhoea (Lapatinib comparison)

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End point title

Rate of preoperative diarrhoea (Lapatinib comparison) ^[2] ^[3]

End point description

Number (percentage) of patients experiencing grade 3/4 diarrhoea pre-operatively.

End point type

Primary

End point timeframe

Events from randomisation until surgery.

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to early termination of the trial, no formal statistical analyses were conducted.
[3] - 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: Pre-operative diarrhoea was an outcome measure for the Lapatinib feasibility aspect of the trial, and only involves arms C and D.

End point values	ECX (Arm C)	ECX + Lap (Arm D)
Number of subjects analysed	24	20
Units: Patients
Grade 3/4 diarrhoea	0	4
No grade 3/4 diarrhoea	24	15

No statistical analyses for this end point

Secondary: Progression free survival (Bev comparison)

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End point title

Progression free survival (Bev comparison) ^[4]

End point description

PFS calculated from randomisation until first occurremce of disease recurrence or death. Censored at date of last follow-up.

End point type

Secondary

End point timeframe

Progression free survival at 3 years post-randomisation

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: This outcome measure only applies to the Bavacizumab comparison, involving only arms A and B.

End point values	ECX (Arm A)	ECX + Bev (arm B)
Number of subjects analysed	533	530
Units: Percentage
number (confidence interval 95%)	0.43 (0.39 to 0.48)	0.41 (0.36 to 0.46)

Progression free survival

Comparison groups

ECX (Arm A) v ECX + Bev (arm B)

Number of subjects included in analysis

1063

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.56

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

1.23

Secondary: Disease free survival (Bev comparison)

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End point title

Disease free survival (Bev comparison) ^[5]

End point description

DFS measured from a landmark point of 6 months post-randomisation, to allow for any differences in timing of surgery, to the first occurrence of disease recurrence or death. Patients who had an event before the landmark point and those who had a macroscopically imcomplete (R2) resection or no resection were deemed to have had a DFS event at time zero. Censored at date of last follow-up.

End point type

Secondary

End point timeframe

DFS from 6 months post-randomisation.

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: This outcome measure only applies to the Bavacizumab comparison, involving only arms A and B.

End point values	ECX (Arm A)	ECX + Bev (arm B)
Number of subjects analysed	533	530
Units: Percent
number (confidence interval 95%)	0.40 (0.35 to 0.44)	0.38 (0.33 to 0.43)

Disease free survival

Comparison groups

ECX (Arm A) v ECX + Bev (arm B)

Number of subjects included in analysis

1063

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.62

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

1.22

Secondary: Response to chemotherapy (Bev comparison)

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End point title

Response to chemotherapy (Bev comparison) ^[6]

End point description

RECIST response to pre-operative chemotherapy. Response is a partial or complete response. Patients with stable disease, progressive disease, or who had died before the RECIST assessment were regarded as non-responders.

End point type

Secondary

End point timeframe

Response to chemotherapy assessed at surgery

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: This outcome measure only applies to the Bavacizumab comparison, involving only arms A and B.

End point values	ECX (Arm A)	ECX + Bev (arm B)
Number of subjects analysed	438	437
Units: Patients
Response	183	177
Non-response	255	260

Response to chemotherapy

Comparison groups

ECX (Arm A) v ECX + Bev (arm B)

Number of subjects included in analysis

875

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7

Method

Chi-squared

Confidence interval

Secondary: R0 resection rate (Bev comparison)

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End point title

R0 resection rate (Bev comparison) ^[7]

End point description

Proportion of patients undergoing R0 resection

End point type

Secondary

End point timeframe

Resection status assessed at surgery.

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: This outcome measure only applies to the Bavacizumab comparison, involving only arms A and B.

End point values	ECX (Arm A)	ECX + Bev (arm B)
Number of subjects analysed	505	497
Units: Patients
R0	321	305
R1+	184	192

R0 resection rate

Comparison groups

ECX (Arm A) v ECX + Bev (arm B)

Number of subjects included in analysis

1002

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.47

Method

Chi-squared

Confidence interval

Adverse events

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Timeframe for reporting adverse events

At any time following randomisation

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

ECX (Arm A)

Reporting group description

Epirubicin, cisplatin, capecitabine. Control arm for Bevacizumab comparison.

Reporting group title

ECX + Bev (arm B)

Reporting group description

Epirubicin, cisplatin, capecitabine, plus Bevacizumab. Experimental arm for Bev comparison.

Reporting group title

ECX (Arm C)

Reporting group description

Epirubicin, cisplatin, capecitabine. Control arm for the Lapatinib comparison. HER2 positive patients.

Reporting group title

ECX + Lap (Arm D)

Reporting group description

Epirubicin, cisplatin, capecitabine. Experimental arm for the Lapatinib comparison. HER2 positive patients.

Notes
[1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
Justification: Only serious adverse events were collected.

Serious adverse events	ECX (Arm A)	ECX + Bev (arm B)	ECX (Arm C)	ECX + Lap (Arm D)
Total subjects affected by serious adverse events
subjects affected / exposed	411 / 533 (77.11%)	511 / 530 (96.42%)	16 / 24 (66.67%)	22 / 22 (100.00%)
number of deaths (all causes)	301	308	12	9
number of deaths resulting from adverse events
Vascular disorders
Anastomotic haemorrhage
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aortic aneurysm
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Aortic thrombosis
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arterial thrombosis
subjects affected / exposed	0 / 533 (0.00%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Central nervous system haemorrhage
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	2 / 533 (0.38%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	3 / 533 (0.56%)	7 / 530 (1.32%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	3 / 3	7 / 7	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Embolism
subjects affected / exposed	3 / 533 (0.56%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	3 / 3	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Exsanguination
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	1 / 533 (0.19%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	3 / 533 (0.56%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	2 / 533 (0.38%)	4 / 530 (0.75%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	3 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 533 (0.00%)	3 / 530 (0.57%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	4 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 533 (0.19%)	1 / 530 (0.19%)	1 / 24 (4.17%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal infarction
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	1 / 533 (0.19%)	4 / 530 (0.75%)	0 / 24 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 1	1 / 4	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Intra-abdominal haemorrhage
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	3 / 533 (0.56%)	3 / 530 (0.57%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	3 / 3	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Phlebitis
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	39 / 533 (7.32%)	38 / 530 (7.17%)	3 / 24 (12.50%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	34 / 39	31 / 38	2 / 3	1 / 1
deaths causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
Renal vein thrombosis
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subclavian vein thrombosis
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	2 / 533 (0.38%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	4 / 533 (0.75%)	11 / 530 (2.08%)	1 / 24 (4.17%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 4	9 / 11	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Vascular pain
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Coronary arterial stent insertion
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal anastomosis
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	10 / 533 (1.88%)	11 / 530 (2.08%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	4 / 11	4 / 11	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Complication associated with device
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	2 / 533 (0.38%)	3 / 530 (0.57%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 3	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	4 / 533 (0.75%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 4	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Extravasation
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	2 / 533 (0.38%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 2	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Flank pain
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypothermia
subjects affected / exposed	0 / 533 (0.00%)	0 / 530 (0.00%)	1 / 24 (4.17%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	3 / 533 (0.56%)	3 / 530 (0.57%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 3	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lethargy
subjects affected / exposed	1 / 533 (0.19%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	2 / 533 (0.38%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 2	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 2	1 / 2	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	2 / 533 (0.38%)	3 / 530 (0.57%)	0 / 24 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	1 / 2	2 / 3	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral swelling
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	2 / 533 (0.38%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 2	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	0 / 533 (0.00%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aspiration
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchial fistula
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 533 (0.00%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 533 (0.00%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	4 / 533 (0.75%)	5 / 530 (0.94%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 5	2 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 533 (0.00%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	2 / 533 (0.38%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleuritic pain
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	3 / 533 (0.56%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 533 (0.19%)	2 / 530 (0.38%)	0 / 24 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Delirium
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	1 / 533 (0.19%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Anastomotic leak
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drain site complication
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal injury
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural complication
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	1 / 533 (0.19%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Procedural complication
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Procedural haemorrhage
subjects affected / exposed	2 / 533 (0.38%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound complication
subjects affected / exposed	4 / 533 (0.75%)	4 / 530 (0.75%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 4	3 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	3 / 533 (0.56%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	1 / 533 (0.19%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	2 / 533 (0.38%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arrhythmia supraventricular
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	7 / 533 (1.31%)	3 / 530 (0.57%)	1 / 24 (4.17%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 7	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 533 (0.00%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	2 / 533 (0.38%)	3 / 530 (0.57%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	1 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 3	0 / 0	0 / 0
Cardiac disorder
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	4 / 533 (0.75%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 4	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Coronary artery dissection
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Coronary artery thrombosis
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	2 / 533 (0.38%)	5 / 530 (0.94%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 2	4 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 533 (0.00%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinus tachycardia
subjects affected / exposed	0 / 533 (0.00%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	3 / 533 (0.56%)	3 / 530 (0.57%)	0 / 24 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	1 / 3	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Brain stem infarction
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 533 (0.00%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	1 / 533 (0.19%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	2 / 533 (0.38%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 2	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 533 (0.19%)	3 / 530 (0.57%)	0 / 24 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	1 / 1	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dystonia
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Facial paralysis
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 533 (0.00%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Leukoencephalopathy
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	1 / 533 (0.19%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral motor neuropathy
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 533 (0.19%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 533 (0.19%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 533 (0.56%)	5 / 530 (0.94%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 3	2 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphatic duct injury
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphatic fistula
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Microangiopathic haemolytic anaemia
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 533 (0.19%)	3 / 530 (0.57%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal adhesions
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	10 / 533 (1.88%)	14 / 530 (2.64%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	3 / 11	9 / 14	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Anal fistula
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aortoenteric fistula
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	6 / 533 (1.13%)	6 / 530 (1.13%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	3 / 6	3 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diaphragmatic hernia
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	9 / 533 (1.69%)	9 / 530 (1.70%)	1 / 24 (4.17%)	4 / 22 (18.18%)
occurrences causally related to treatment / all	9 / 9	8 / 9	1 / 1	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea haemorrhagic
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	12 / 533 (2.25%)	14 / 530 (2.64%)	2 / 24 (8.33%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	2 / 14	3 / 17	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enteritis infectious
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterocutaneous fistula
subjects affected / exposed	1 / 533 (0.19%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric perforation
subjects affected / exposed	2 / 533 (0.38%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	1 / 533 (0.19%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal anastomotic leak
subjects affected / exposed	30 / 533 (5.63%)	62 / 530 (11.70%)	2 / 24 (8.33%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 30	27 / 63	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	4 / 5	0 / 0	0 / 0
Gastrointestinal disorder
subjects affected / exposed	2 / 533 (0.38%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal fistula
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 533 (0.19%)	2 / 530 (0.38%)	0 / 24 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Gastrointestinal pain
subjects affected / exposed	0 / 533 (0.00%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal perforation
subjects affected / exposed	1 / 533 (0.19%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	3 / 533 (0.56%)	3 / 530 (0.57%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 3	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Incisional hernia
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	3 / 533 (0.56%)	4 / 530 (0.75%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Melaena
subjects affected / exposed	0 / 533 (0.00%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	4 / 533 (0.75%)	4 / 530 (0.75%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	3 / 4	3 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obstruction gastric
subjects affected / exposed	1 / 533 (0.19%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Odynophagia
subjects affected / exposed	2 / 533 (0.38%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal fistula
subjects affected / exposed	1 / 533 (0.19%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Oesophageal obstruction
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	2 / 22 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal perforation
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal stenosis
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyloric stenosis
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	2 / 533 (0.38%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	3 / 533 (0.56%)	0 / 530 (0.00%)	1 / 24 (4.17%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	3 / 533 (0.56%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 3	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tracheo-oesophageal fistula
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 533 (0.19%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	5 / 533 (0.94%)	10 / 530 (1.89%)	0 / 24 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	3 / 5	4 / 10	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Biliary tract disorder
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	2 / 533 (0.38%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin wound
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 533 (0.19%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prerenal failure
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hyperglycaemia
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Ankle fracture
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gout
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gouty arthritis
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 533 (0.00%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tendonitis
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal sepsis
subjects affected / exposed	2 / 533 (0.38%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal wall abscess
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	2 / 533 (0.38%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea infectious
subjects affected / exposed	1 / 533 (0.19%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Empyema
subjects affected / exposed	0 / 533 (0.00%)	2 / 530 (0.38%)	1 / 24 (4.17%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enteritis infectious
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	11 / 533 (2.06%)	17 / 530 (3.21%)	1 / 24 (4.17%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	11 / 12	10 / 19	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	16 / 533 (3.00%)	10 / 530 (1.89%)	0 / 24 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	3 / 16	5 / 10	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	28 / 533 (5.25%)	26 / 530 (4.91%)	1 / 24 (4.17%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	27 / 28	27 / 27	1 / 1	0 / 0
deaths causally related to treatment / all	3 / 3	4 / 4	0 / 0	0 / 0
Pleural infection
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	7 / 533 (1.31%)	10 / 530 (1.89%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 7	3 / 10	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0
Post procedural infection
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural pneumonia
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	1 / 533 (0.19%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 533 (0.19%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	3 / 533 (0.56%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	3 / 533 (0.56%)	3 / 530 (0.57%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Varicella
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	14 / 533 (2.63%)	10 / 530 (1.89%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 14	5 / 11	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Abnormal loss of weight
subjects affected / exposed	1 / 533 (0.19%)	1 / 530 (0.19%)	0 / 24 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	7 / 533 (1.31%)	8 / 530 (1.51%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	6 / 7	8 / 8	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 533 (0.19%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	0 / 533 (0.00%)	1 / 530 (0.19%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 533 (0.00%)	2 / 530 (0.38%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	1 / 533 (0.19%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	ECX (Arm A)	ECX + Bev (arm B)	ECX (Arm C)	ECX + Lap (Arm D)
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 533 (0.00%)	0 / 530 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)

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Were there any global substantial amendments to the protocol? Yes

14 Mar 2008

Version 2 of protocol. The main changes concerned the additional of the Translation sub study, additional funding available as well as further clarification to the protocol Patient Inclusion Criteria has been updated Patient Exclusion Criteria: patients with clinically apparent hearing impairment has been removed from the exclusion criteria. Warfarin has been removed as an excluded concomitant medication, but is advised that it should be used with caution. Guidance is given for patients with raised BP and hearing impairment. Tissue and Blood Collection for Translational Research has been added Capecitabine Diary Card has been added Cisplatin and Capecitabine dose modifications for ECX has been updated to be more reader friendly. If cisplatin is substituted for carboplatin, patients should continue to receive epirubicin. Instructions on all patients receiving lansoprazole 30mg od po, or an alternative proton pump inhibitor (PPI), is given. New guidance has been added for patients that remain unfit to commence post-operative chemotherapy, 10 weeks post surgery The intervals for the initial follow-up assessments have been corrected, this is also reflected in the ST03 Trial schema diagram and trial summary Specific toxicities requiring discontinuation of bevacizumab. Patients with any grade of fistulae should have bevacizumab discontinued Recommendations for managing patients that develop fistula are given. All grades of fistulae has been added as an ST03 notable event Sites will receive additional funding via per patient payments for the first 100 patients randomised The central pathology review has been updated and new information has been added to describe the collection of blood and tumour samples for future translational research Patient Information Sheet has been updated ST03 Trial Consent Form has been updated  Trans ST03 Consent Form has been added

17 Jun 2009

Version 3 of protocol. The main changes concern the additional of the Type II junctional tumours to the inclusion criteria as well as further clarification to the protocol. Full details of the protocol changes are given in the summary of amendments to Version 3, however, the key changes include: Type II tumours now eligible for the trial 24 hour urine collection is no longer mandatory at baseline Patients with high frequency hearing loss are eligible for ST03, they should be treated with cisplatin but changed to carboplatin if there is any evidence of deterioration Patients with severe tinnitus should not be randomised Positive serology for HIV, Hepatitis C of active Hepatitis B have been added as exclusion criteria Some flexibility with screening assessments and investigations have been added Updated information on proteinuria to include use of urine protein-creatinine ratio New guidelines provided to include surgical techniques for Type II junctional tumours and information on performing totally minimally invasive surgery New table added to show CRF completion schedule for patients who do not complete protocol treatment Further guidance and clarification on various elements of the central pathology review and storage of translational ST03 samples SPC updated where necessary

01 Feb 2010

Protocol version 3 - Addendum 1 urgent safety amendment. A nadir blood count is now required during cycle 1 at approximately day 10 of treatment. Any patients who experience Grade 4 neutropenia should receive GCSF for 3-5 days starting on day 10. Any patients who have Grade 3 neutropenia should be treated with GCSF at the discretion of the Investigator. These patients should also receive GSCF during all further cycles of ECX+/-B.

27 May 2010

Version 4 of protocol The main changes concern the addition of a nadir blood count during cycle one and guidance for commencing GCSF, changes to the cardiac monitoring recommendations and TNM7 staging clarification. Section 6.1 Patient Inclusion Criteria Guidance for any patients staged according to the TNM7 staging criteria Cardiac function measured by MUGA can be above centre’s LLN if this is lower than 50% Patients who have received chemotherapy or radiotherapy for a previous malignancy are ineligible Section 8.1 Treatment of Patients A nadir blood count is now required during cycle 1 at approximately day 10 of treatment and any patients who experience Grade 4 should receive GCSF for 3-5 days starting on day 10. Any patients who have Grade 3 neutropenia should be treated with GCSF at the discretion of the Investigator. These patients should also receive GSCF during all further cycles of ECX+/-B. Section 8.1.2 Cardiac Monitoring Patients in whom a drop in LVEF of >15% or to less than 50% is seen should have a further measurement taken 3 months later Section 8.4.2 Guidance on omitting doses of Bevacizumab Bevacizumab may be reintroduced if it was ceased following a reduction in LVEF if recovery to the normal range is observed at the next cardiac monitoring scan. Section 9.2.6 Hypertension An ACE inhibitor should be used as first line to treat hypertension. Section 11.2 Management of LVEF Where a range is reported, management should be based on the lower bound of the range. Any patients with a reduction in LVEF of >15% or to <50% should have an additional scan 3 months after the abnormal measurement. Epirubicin and/or Bevacizumab may be restarted if the LVEF recovers to >50%.

15 Feb 2011

Version 5 of protocol The main changes concern the inclusion of lower oesophageal and Type I tumours and associated updated staging, screening, surgery and pathology guidance, changes to the hypertension recommendations and ECG requirements, guidance on treatment recommendations for patients with symptomatic Pulmonary Embolisms and addition of the MRI Sub-study.

04 Jul 2011

Protocol version 5 - Addendum 1, urgent safety amendment The additional cardiac monitoring assessments (pre-op and post chemo ECHO/MUGAs) have been discontinued from the sECX+/- bevacizumab arms (Arms A and B) of the study following a safety analysis. Study visit schedules and CRF return schedules have also been updated to reflect this.

28 Sep 2012

Version 6 of protocol The main changes concern the addition of a lapatinib feasibility study within the ST03 trial. Selected centres will participate in this feasibility trial which will involve testing the HER-2 status of the patient’s tumour biopsy centrally at the Royal Marsden Hospital (or locally if permitted) prior to randomisation into the trial. Patients with HER-2 positive tumours will be randomised to sECX Vs mECX+Lapatinib and patients with HER-2 negative or unknown/undefined tumours will be randomised to sECX+/-Bevacizumab. This is in response to newly published data in the advanced setting (73). Section B has been added to the protocol to include instructions for the selected centres involved in the feasibility study. Section A provides information for centres not involved in the feasibility study and the patients with HER-2 negative or unknown/undefined tumours randomised into the sECX+/-Bevacizumab arms. Section B provides information for the centres involved in the feasibility study on the registration of patients and the HER-2 sample testing process and then goes on to provide details for the management of patients with HER-2 positive tumours randomised to the sECX Vs mECX+Lapatinib arms.

01 Oct 2013

Protocol version 6 - addendum 1, urgent safety amendment Inclusion criteria for the ST03 main trial (sECX+/-bevacizumab comparison) amended to exclude patients with lower oesophageal, Siewert Type I, II or III oesophagogastric junctional (OGJ) adenocarcinomas from entering this comparison. The trial remains open and unchanged for patients with gastric adenocarcinomas who do not require oesophagogastrectomy. Patients with lower oesophageal, Siewert Type I, II or III OGJ adenocarcinomas who have already entered the sECX+B arm (Arm B) must not receive any further pre-operative bevacizumab. Following surgery patients may resume treatment with bevacizumab provided that there are no other contraindications.

17 Feb 2014

Version 7 of protocol The main changes to the protocol are organisational and have been made to reflect the closure of the bevacizumab comparison and to allow patients with a negative or unknown/undefined HER-2 status to be registered into the observation only, imaging sub-studies (MRI and PET/CT) at participating centres.

25 Jun 2015

Protocol version 9 The changes mainly concern including patients scheduled to receive chemotherapy regimes other than ECX to register into the PET/CT and/or MRI Sub studies only. Patients entering one or both studies that are also randomised into the feasibility study should be scheduled to receive sECX or mECX+L as per allocated treatment.

19 Oct 2017

Protocol version 10. The changes made were mainly to reflect the current status of each of the 4 studies within the ST03 protocol.

Were there any global interruptions to the trial? No

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

Only around half of patients start post-operative chemotherapy, and only one fifth completed all maintenance treatment. Small sample size for lapatinib study (feasibility only). Regimens (chemo and HER2-targeted) used have since been superceded.

http://www.ncbi.nlm.nih.gov/pubmed/28163000
http://www.ncbi.nlm.nih.gov/pubmed/31219517

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Primary: Overall survival at 3 years (Bev comparison)

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