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Clinical Trial Results:
A prospective, phase III, controlled, multicentre, randomised clinical trial comparing combination gemcitabine and capecitabine therapy with concurrent and sequential chemoimmunotherapy using a telomerase vaccine in locally advanced and metastatic pancreatic cancer.

Summary
EudraCT number	2006-000461-10
Trial protocol	GB
Global end of trial date	27 May 2012

Results information
Results version number	v1(current)
This version publication date	28 Feb 2019
First version publication date	28 Feb 2019
Other versions

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

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Trial information

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Sponsor protocol code

ISRCTN43482138

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

The Royal Liverpool and Broadgreen University Hospitals NHS Trust

Sponsor organisation address

Prescot Street, Liverpool, United Kingdom, L7 8XP

Public contact

Ms Charlotte Rawcliffe, Liverpool Cancer Trials Unit, University of Liverpool, 0151 794 8167, C.Rawcliffe@liverpool.ac.uk

Scientific contact

Dr Victoria Shaw, GCLP Labs, University of Liverpool, 0151 706 4180, Victoria.Shaw@liverpool.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

25 Apr 2014

Is this the analysis of the primary completion data?

Yes

Primary completion date

27 May 2011

Global end of trial reached?

Yes

Global end of trial date

27 May 2012

Was the trial ended prematurely?

Yes

Main objective of the trial

To investigate the efficacy of GV1001 on length of survival when added concurrently or sequentially to the combination gemcitabine and capecitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma.

Protection of trial subjects

Patients were asked to consent that data are recorded, collected, stored and processed and might be transferred to other countries, in accordance with any national legislation implementing the EU Data Protection Directive (95/46/EC). Data was processed in accordance with the general terms and conditions of the authorisation from the ‘Information Commissioner's Office’ to the LCTU, as required, according to national legislation implementing the Data Protection Directive; 95/46/EC.

Background therapy

Evidence for comparator

For patients with locally advanced or metastatic pancreatic cancer, who wish to have, and are fit enough to benefit from, active treatment, chemotherapy with single agent gemcitabine has for several years been the standard of care. The recently reported results of the NCRI GEMCAP trial, a randomised comparison of gemcitabine versus the combination of gemcitabine and capecitabine, and associated meta-analysis demonstrated a statistically significant survival benefit for patients receiving the combined treatment with acceptable levels of toxicity. Therefore all subjects enrolled in this programme will receive the GEM-CAP combination chemotherapy. The benefits of the combination, though real, are modest and continual efforts to improve our management of this disease are essential. Vaccination of pancreatic cancer patients with the Telomerase vaccine GV1001 has yielded promising results. It has been administered to over 100 subjects and has been well tolerated with no serious adverse events. The most commonly reported adverse events are injection site reactions, chills, nausea and dizziness of which the majority were of mild intensity. It is thus an attractive candidate therapy to add to gemcitabine and capecitabine in order to try and improve outcomes in this disease. This trial will not be placebo controlled as it is not felt to be acceptable to submit patients in the control arm to unnecessary injections.

Actual start date of recruitment

29 Mar 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: 1062

Worldwide total number of subjects

1062

EEA total number of subjects

1062

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)

601

From 65 to 84 years

461

85 years and over

Subject disposition

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Recruitment details

UK only. First patient, first visit (FPFV; date of randomisation): 29 Mar 2007 and date of close of recruitment of the study: 27 May 2011 (closed early based on the final interim analysis by the Independent Safety and Data Monitoring Committee (ISDMC) as the sequential immunotherapy arm appeared to be inferior), Quality of life, Pain assessment

Screening details

Histology/cytology, Informed consent, Inclusion criteria, Randomisation, Demography & medical history, Physical examination, Vital signs, ECOG Performance status, ECG, Haematology, Serum Chemistry, Genomic/Proteomic Sampling, Blood, Proteomic Sampling - Urine, CT scan (RECIST), CA19-9 1573 patients screened, 108 patients declined, 402 ineligible

Period 1 title

Treatment Phase (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Gemcitabine and Capecitabine Therapy

Arm description

Gemcitabine will be administered on day 1, 8 and 15 followed by 7 days' rest. Per oral capecitabine will be administered morning and evening for 21 days followed by 7 days' rest. Gemcitabine and capecitabine therapy cycle will be repeated every 4 weeks until withdrawal from trial treatment due to patient choice, intolerable toxicity or disease progression. Patients will have a CT scan at baseline, week 8 and every 12 weeks until the patient is withdrawn from the study. Upon withdrawal patients will be treated according to local practice and be subject to follow-up every 3 months until death.

Arm type

Active comparator

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Gemzar

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1000mg/m2 gemcitabine must be given as an intravenous infusion over 30 minutes unless haematological toxicity occurs requiring dose adjustment

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Xeloda

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

830 mg/m2 capecitabine must be administered orally morning and evening daily (total daily dose of 1660 mg/m2) unless toxicity occurs requiring dose adjustment

Investigational medicinal product name

GV1001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intradermal use

Dosage and administration details

3.5 ml sterile single dosage

Gemcitabine and Capecitabine then Sequential GV1001 Therapy

Arm description

Patients will receive two cycles of combination gemcitabine and capecitabine before Each of the two cycles of combination gemcitabine and capecitabine consists of: Gemcitabine administered on day 1, 8 and 15 followed by 7 days‟ rest. Per oral capecitabine administered morning and evening for 21 days followed by 7 days' rest. Following completion of two cycles of gemcitabine and capecitabine therapy, GV1001 will be administered intradermally on Monday, Wednesday and Friday during week 9 and once weekly during weeks 10, 11, 12 and 14. After that, vaccinations will follow a once monthly schedule until patient choice, intolerable toxicity or disease progression. Granulocytemacrophage colony-stimulating factor (GM-CSF) will be used as an adjuvant, given 10-15 minutes prior to each administration of GV1001.

Arm type

Experimental

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

830 mg/m2 capecitabine must be administered orally morning and evening daily (total daily dose of 1660 mg/m2) unless toxicity occurs requiring dose adjustment as described below.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Gemzar

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1000mg/m2 gemcitabine must be given as an intravenous infusion over 30 minutes unless haematological toxicity occurs requiring dose adjustment

Concurrent Gemcitabine, Capecitabine and GV1001 Therapy

Arm description

Arm type

Experimental

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Gemzar

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1000mg/m2 gemcitabine must be given as an intravenous infusion over 30 minutes unless haematological toxicity occurs requiring dose adjustment

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

830 mg/m2 capecitabine must be administered orally morning and evening daily (total daily dose of 1660 mg/m2) unless toxicity occurs requiring dose adjustment as described below.

Investigational medicinal product name

GV1001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intradermal use

Dosage and administration details

3.5 ml sterile single dosage

Investigational medicinal product name

GM-CSF

Investigational medicinal product code

Other name

Leukine

Pharmaceutical forms

Powder for solution for injection/infusion

Routes of administration

Subcutaneous use, Intravenous use

Dosage and administration details

Sterile vials containing 250 g lyophilised Leukine

Number of subjects in period 1	Gemcitabine and Capecitabine Therapy	Gemcitabine and Capecitabine then Sequential GV1001 Therapy	Concurrent Gemcitabine, Capecitabine and GV1001 Therapy
Started	358	350	354
Completed	358	350	354

Baseline characteristics

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Reporting group title

Gemcitabine and Capecitabine Therapy

Reporting group description

Reporting group title

Gemcitabine and Capecitabine then Sequential GV1001 Therapy

Reporting group description

Reporting group title

Concurrent Gemcitabine, Capecitabine and GV1001 Therapy

Reporting group description

Reporting group values	Gemcitabine and Capecitabine Therapy	Gemcitabine and Capecitabine then Sequential GV1001 Therapy	Concurrent Gemcitabine, Capecitabine and GV1001 Therapy	Total
Number of subjects	358	350	354	1062
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
arithmetic mean (standard deviation)	61.9 ( 9.6 )	62.7 ( 9.5 )	62.3 ( 9.5 )	-
Gender categorical
Units: Subjects
Female	209	203	196	608
Male	149	147	158	454

Subject analysis set title

Full Analysis Set

Subject analysis set type

Intention-to-treat

Subject analysis set description

In order to follow the Intention to Treat (ITT) principle this will consist of all randomised patients excepting for a) patients withdrawing consent between randomisation and starting therapy b) patients withdrawn from the study after randomisation because of irregularities with the consent process.

Subject analysis set title

Safety Set

Subject analysis set type

Safety analysis

Subject analysis set description

All patients who received any trial treatment

Subject analysis sets values	Full Analysis Set	Safety Set
Number of subjects	1062	1062
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
arithmetic mean (standard deviation)	62.3 ( 9.5 )	62.3 ( 9.5 )
Gender categorical
Units: Subjects
Female	454	454
Male	608	608

End points

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Reporting group title

Gemcitabine and Capecitabine Therapy

Reporting group description

Reporting group title

Gemcitabine and Capecitabine then Sequential GV1001 Therapy

Reporting group description

Reporting group title

Concurrent Gemcitabine, Capecitabine and GV1001 Therapy

Reporting group description

Subject analysis set title

Full Analysis Set

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Safety Set

Subject analysis set type

Safety analysis

Subject analysis set description

All patients who received any trial treatment

Primary: Overall Survival

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End point title

Overall Survival

End point description

End point type

Primary

End point timeframe

From randomisation until death by any cause

End point values	Gemcitabine and Capecitabine Therapy	Gemcitabine and Capecitabine then Sequential GV1001 Therapy	Concurrent Gemcitabine, Capecitabine and GV1001 Therapy
Number of subjects analysed	358	350	354
Units: Subjects
median (confidence interval 95%)	7.89 (7.07 to 8.85)	6.94 (6.35 to 7.60)	8.36 (7.30 to 9.74)

Primary Efficacy Analysis Arm 1 Vs Arm 2

Statistical analysis description

Primary efficacy analysis of overall survival between the three treatment arms carried out using Cox Proportional Hazards modelling

Comparison groups

Gemcitabine and Capecitabine then Sequential GV1001 Therapy v Gemcitabine and Capecitabine Therapy

Number of subjects included in analysis

708

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05 ^[1]

Method

Regression, Cox

Parameter type

Cox proportional hazard

Point estimate

1.19

Confidence interval

level

98.25%

sides

2-sided

lower limit

0.97

upper limit

1.48

Variability estimate

Standard error of the mean

Notes
[1] - Please note this is a family wise type I error for the full trial which includes multiple comparisons and formal interim analysis. The final P-value to determine significance of an experimental treatment over the control used a P-value of 0.02078.

Primary Efficacy Analysis Arm 1 Vs Arm 3

Statistical analysis description

Primary efficacy analysis of overall survival between the three treatment arms carried out using Cox Proportional Hazards modelling

Comparison groups

Gemcitabine and Capecitabine Therapy v Concurrent Gemcitabine, Capecitabine and GV1001 Therapy

Number of subjects included in analysis

712

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05 ^[2]

Method

Regression, Cox

Parameter type

Cox proportional hazard

Point estimate

1.05

Confidence interval

level

98.25%

sides

2-sided

lower limit

0.85

upper limit

1.29

Variability estimate

Standard error of the mean

Notes
[2] - Please note this is a family wise type I error for the full trial which includes multiple comparisons and formal interim analysis. The final P-value to determine significance of an experimental treatment over the control used a P-value of 0.02078.

Secondary: Progression Free Survival

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End point title

Progression Free Survival

End point description

End point type

Secondary

End point timeframe

Measured as the time from randomisation until progression or death by any cause

End point values	Gemcitabine and Capecitabine Therapy	Gemcitabine and Capecitabine then Sequential GV1001 Therapy	Concurrent Gemcitabine, Capecitabine and GV1001 Therapy
Number of subjects analysed	358	350	354
Units: Subjects
median (confidence interval 95%)	6.35 (4.77 to 7.07)	4.54 (4.34 to 4.61)	6.58 (5.03 to 7.27)

Progression Free Survival Arm 1 Vs Arm 2

Comparison groups

Gemcitabine and Capecitabine Therapy v Gemcitabine and Capecitabine then Sequential GV1001 Therapy

Number of subjects included in analysis

708

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.5

Confidence interval

level

95%

sides

2-sided

lower limit

1.26

upper limit

1.78

Variability estimate

Standard error of the mean

Progression Free Survival Arm 1 Vs Arm 3

Comparison groups

Gemcitabine and Capecitabine Therapy v Concurrent Gemcitabine, Capecitabine and GV1001 Therapy

Number of subjects included in analysis

712

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

1.19

Variability estimate

Standard error of the mean

Secondary: Best Overall Clinical Response

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End point title

Best Overall Clinical Response

End point description

End point type

Secondary

End point timeframe

From randomisation until death or competition of follow-up

End point values	Gemcitabine and Capecitabine Therapy	Gemcitabine and Capecitabine then Sequential GV1001 Therapy	Concurrent Gemcitabine, Capecitabine and GV1001 Therapy	Full Analysis Set
Number of subjects analysed	358	350	354
Units: Subjects
number (not applicable)
Missing	28	19	26	73
Dead by 8 weeks	3	6	4	13
Dead other	4	2	2	8
Progressive Disease	106	95	94	295
Stable Disease	154	197	173	524
Partial Response	60	30	52	142
Complete Response	3	1	3	7

Analysis of Best Overall Response Arm 1 Vs Arm 2

Comparison groups

Gemcitabine and Capecitabine Therapy v Gemcitabine and Capecitabine then Sequential GV1001 Therapy

Number of subjects included in analysis

708

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.01

Method

Chi-squared

Parameter type

Risk ratio (RR)

Point estimate

1.99

Confidence interval

level

95%

sides

2-sided

lower limit

1.33

upper limit

2.98

Variability estimate

Standard error of the mean

Analysis of Best Overall Response Arm 1 Vs Arm 3

Comparison groups

Gemcitabine and Capecitabine Therapy v Concurrent Gemcitabine, Capecitabine and GV1001 Therapy

Number of subjects included in analysis

712

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.46

Method

Chi-squared

Parameter type

Risk ratio (RR)

Point estimate

1.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.81

upper limit

1.58

Variability estimate

Standard error of the mean

Adverse events

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Timeframe for reporting adverse events

AEs: Consent to last day of IMP administration/final study visit SAEs (except deaths due to progressive disease): Consent until 28 days after last administration of trial treatment After reporting period if AE/SAE possibly related to IMP

Adverse event reporting additional description

ALL AEs recorded on CRF ALL SAEs reported to ORION PVG via the documented reporting system

Assessment type

Systematic

Dictionary name

CTCAE

Dictionary version

Reporting group title

Gemcitabine and Capecitabine Therapy

Reporting group description

Reporting group title

Gemcitabine and Capecitabine then Sequential GV1001 Therapy

Reporting group description

Reporting group title

Concurrent Gemcitabine, Capecitabine and GV1001 Therapy

Reporting group description

Serious adverse events	Gemcitabine and Capecitabine Therapy	Gemcitabine and Capecitabine then Sequential GV1001 Therapy	Concurrent Gemcitabine, Capecitabine and GV1001 Therapy
Total subjects affected by serious adverse events
subjects affected / exposed	134 / 358 (37.43%)	147 / 350 (42.00%)	167 / 354 (47.18%)
number of deaths (all causes)	245	268	259
number of deaths resulting from adverse events	10	13	10
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Malignant ascites
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant ovarian cyst
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tumour invasion
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tumour pain
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (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
Vascular disorders
Circulatory collapse
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	2 / 4
Deep vein thrombosis
subjects affected / exposed	11 / 358 (3.07%)	8 / 350 (2.29%)	7 / 354 (1.98%)
occurrences causally related to treatment / all	10 / 22	14 / 20	14 / 36
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Hypotension
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	5 / 354 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 19
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Phlebitis
subjects affected / exposed	1 / 358 (0.28%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	1 / 2	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombophlebitis
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vena cava thrombosis
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 4
Surgical and medical procedures
Pain management
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stent placement
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 358 (0.56%)	0 / 350 (0.00%)	0 / 354 (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
Chest discomfort
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	4 / 358 (1.12%)	1 / 350 (0.29%)	4 / 354 (1.13%)
occurrences causally related to treatment / all	1 / 8	0 / 4	1 / 16
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chills
subjects affected / exposed	1 / 358 (0.28%)	3 / 350 (0.86%)	3 / 354 (0.85%)
occurrences causally related to treatment / all	2 / 2	6 / 12	1 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	1 / 358 (0.28%)	2 / 350 (0.57%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 6	0 / 0
deaths causally related to treatment / all	2 / 2	0 / 6	0 / 0
Device occlusion
subjects affected / exposed	9 / 358 (2.51%)	22 / 350 (6.29%)	17 / 354 (4.80%)
occurrences causally related to treatment / all	2 / 20	0 / 72	1 / 70
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	25 / 358 (6.98%)	31 / 350 (8.86%)	22 / 354 (6.21%)
occurrences causally related to treatment / all	2 / 51	1 / 112	0 / 86
deaths causally related to treatment / all	0 / 24	0 / 52	0 / 32
Fatigue
subjects affected / exposed	3 / 358 (0.84%)	2 / 350 (0.57%)	2 / 354 (0.56%)
occurrences causally related to treatment / all	6 / 10	0 / 6	6 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	3 / 358 (0.84%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 4	0 / 0
Influenza like illness
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	1 / 358 (0.28%)	1 / 350 (0.29%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	2 / 2	0 / 2	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oedema
subjects affected / exposed	0 / 358 (0.00%)	2 / 350 (0.57%)	2 / 354 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 6	2 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	7 / 358 (1.96%)	2 / 350 (0.57%)	5 / 354 (1.41%)
occurrences causally related to treatment / all	2 / 14	2 / 4	3 / 24
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	4 / 358 (1.12%)	6 / 350 (1.71%)	4 / 354 (1.13%)
occurrences causally related to treatment / all	0 / 8	0 / 22	0 / 16
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	22 / 358 (6.15%)	29 / 350 (8.29%)	37 / 354 (10.45%)
occurrences causally related to treatment / all	25 / 55	41 / 99	71 / 176
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stent malfunction
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Sudden death
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	2 / 354 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 8
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	0 / 358 (0.00%)	2 / 350 (0.57%)	3 / 354 (0.85%)
occurrences causally related to treatment / all	0 / 0	5 / 8	7 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Scrotal oedema
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Acute respiratory distress syndrome
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aspiration
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	9 / 358 (2.51%)	5 / 350 (1.43%)	4 / 354 (1.13%)
occurrences causally related to treatment / all	5 / 17	0 / 14	5 / 16
deaths causally related to treatment / all	0 / 0	0 / 8	0 / 0
Epistaxis
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hiccups
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (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
Hydropneumothorax
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	6 / 358 (1.68%)	3 / 350 (0.86%)	3 / 354 (0.85%)
occurrences causally related to treatment / all	2 / 14	0 / 16	0 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	1 / 358 (0.28%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	1 / 2	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	19 / 358 (5.31%)	26 / 350 (7.43%)	16 / 354 (4.52%)
occurrences causally related to treatment / all	11 / 40	19 / 82	14 / 64
deaths causally related to treatment / all	0 / 0	1 / 8	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (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
Pulmonary thrombosis
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	3 / 358 (0.84%)	3 / 350 (0.86%)	4 / 354 (1.13%)
occurrences causally related to treatment / all	0 / 6	2 / 6	0 / 16
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mood altered
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (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
Blood albumin decreased
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	4 / 354 (1.13%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 16
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (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
Blood glucose increased
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Body temperature increased
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	3 / 354 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
International normalised ratio
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
International normalised ratio increased
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Liver function test abnormal
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urine output decreased
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (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
Weight decreased
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
White blood cell count increased
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (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
Injury, poisoning and procedural complications
Afferent loop syndrome
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (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
Fall
subjects affected / exposed	0 / 358 (0.00%)	2 / 350 (0.57%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Laceration
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Narcotic intoxication
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (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
Overdose
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural bile leak
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural haematoma
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pubis fracture
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stent occlusion
subjects affected / exposed	0 / 358 (0.00%)	2 / 350 (0.57%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transfusion reaction
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Wound complication
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	2 / 354 (0.56%)
occurrences causally related to treatment / all	0 / 0	1 / 2	2 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 4
Arteriospasm coronary
subjects affected / exposed	2 / 358 (0.56%)	0 / 350 (0.00%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	2 / 354 (0.56%)
occurrences causally related to treatment / all	0 / 2	0 / 0	2 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Cardiac arrest
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 4
Coronary artery occlusion
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	5 / 358 (1.40%)	1 / 350 (0.29%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	5 / 10	1 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 358 (0.28%)	1 / 350 (0.29%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	2 / 2	0 / 2	1 / 4
deaths causally related to treatment / all	2 / 2	0 / 0	0 / 0
Palpitations
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (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
Sinus bradycardia
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Amnesia
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ataxia
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	3 / 358 (0.84%)	0 / 350 (0.00%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	2 / 358 (0.56%)	1 / 350 (0.29%)	2 / 354 (0.56%)
occurrences causally related to treatment / all	0 / 4	0 / 4	2 / 8
deaths causally related to treatment / all	0 / 2	0 / 4	2 / 4
Depressed level of consciousness
subjects affected / exposed	1 / 358 (0.28%)	1 / 350 (0.29%)	0 / 354 (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
Epilepsy
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Facial palsy
subjects affected / exposed	0 / 358 (0.00%)	2 / 350 (0.57%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	4 / 8	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Facial spasm
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Headache
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lethargy
subjects affected / exposed	2 / 358 (0.56%)	1 / 350 (0.29%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 4	0 / 4	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Migraine
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Parkinsonism
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral motor neuropathy
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Presyncope
subjects affected / exposed	1 / 358 (0.28%)	1 / 350 (0.29%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	1 / 358 (0.28%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 2	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 358 (0.28%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Unresponsive to stimuli
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	13 / 358 (3.63%)	10 / 350 (2.86%)	14 / 354 (3.95%)
occurrences causally related to treatment / all	21 / 28	9 / 28	21 / 64
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Febrile neutropenia
subjects affected / exposed	2 / 358 (0.56%)	3 / 350 (0.86%)	3 / 354 (0.85%)
occurrences causally related to treatment / all	4 / 4	6 / 6	6 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	4 / 358 (1.12%)	5 / 350 (1.43%)	8 / 354 (2.26%)
occurrences causally related to treatment / all	8 / 8	9 / 14	20 / 32
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	5 / 358 (1.40%)	2 / 350 (0.57%)	6 / 354 (1.69%)
occurrences causally related to treatment / all	11 / 12	4 / 4	13 / 24
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	1 / 358 (0.28%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	27 / 358 (7.54%)	25 / 350 (7.14%)	26 / 354 (7.34%)
occurrences causally related to treatment / all	5 / 56	4 / 98	7 / 116
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	5 / 358 (1.40%)	1 / 350 (0.29%)	4 / 354 (1.13%)
occurrences causally related to treatment / all	2 / 10	0 / 4	1 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	20 / 358 (5.59%)	20 / 350 (5.71%)	17 / 354 (4.80%)
occurrences causally related to treatment / all	0 / 43	2 / 88	0 / 92
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colonic pseudo-obstruction
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	13 / 358 (3.63%)	10 / 350 (2.86%)	12 / 354 (3.39%)
occurrences causally related to treatment / all	8 / 30	6 / 28	2 / 52
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	12 / 358 (3.35%)	16 / 350 (4.57%)	16 / 354 (4.52%)
occurrences causally related to treatment / all	13 / 26	27 / 42	25 / 67
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Duodenal obstruction
subjects affected / exposed	0 / 358 (0.00%)	4 / 350 (1.14%)	6 / 354 (1.69%)
occurrences causally related to treatment / all	0 / 0	0 / 14	0 / 24
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Duodenal stenosis
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	2 / 354 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	2 / 2	0 / 0
Eructation
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (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
Gastritis erosive
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal fistula
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	3 / 358 (0.84%)	7 / 350 (2.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 6	1 / 20	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal obstruction
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal perforation
subjects affected / exposed	0 / 358 (0.00%)	2 / 350 (0.57%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 8	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 4
Impaired gastric emptying
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal infarction
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	3 / 358 (0.84%)	1 / 350 (0.29%)	3 / 354 (0.85%)
occurrences causally related to treatment / all	0 / 6	0 / 2	0 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 4
Large intestinal obstruction
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (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
Melaena
subjects affected / exposed	0 / 358 (0.00%)	2 / 350 (0.57%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 8	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mesenteric vein thrombosis
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Nausea
subjects affected / exposed	8 / 358 (2.23%)	18 / 350 (5.14%)	17 / 354 (4.80%)
occurrences causally related to treatment / all	11 / 16	29 / 61	22 / 71
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Obstruction gastric
subjects affected / exposed	5 / 358 (1.40%)	10 / 350 (2.86%)	5 / 354 (1.41%)
occurrences causally related to treatment / all	0 / 10	0 / 40	0 / 20
deaths causally related to treatment / all	0 / 0	0 / 8	0 / 0
Oesophageal varices haemorrhage
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 358 (0.28%)	2 / 350 (0.57%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 4	0 / 0
Peptic ulcer perforation
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 4	0 / 0
Peritoneal perforation
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 358 (0.28%)	3 / 350 (0.86%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 10	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestinal haemorrhage
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	4 / 358 (1.12%)	1 / 350 (0.29%)	4 / 354 (1.13%)
occurrences causally related to treatment / all	0 / 8	0 / 4	0 / 16
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	3 / 358 (0.84%)	1 / 350 (0.29%)	2 / 354 (0.56%)
occurrences causally related to treatment / all	6 / 6	2 / 4	2 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	3 / 358 (0.84%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0
Vomiting
subjects affected / exposed	28 / 358 (7.82%)	25 / 350 (7.14%)	33 / 354 (9.32%)
occurrences causally related to treatment / all	26 / 59	27 / 95	43 / 144
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct obstruction
subjects affected / exposed	8 / 358 (2.23%)	7 / 350 (2.00%)	7 / 354 (1.98%)
occurrences causally related to treatment / all	0 / 16	0 / 30	0 / 32
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bile duct stenosis
subjects affected / exposed	1 / 358 (0.28%)	4 / 350 (1.14%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 2	0 / 14	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Biliary dilatation
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	4 / 354 (1.13%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 16
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	12 / 358 (3.35%)	9 / 350 (2.57%)	11 / 354 (3.11%)
occurrences causally related to treatment / all	8 / 26	0 / 38	0 / 50
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	1 / 358 (0.28%)	3 / 350 (0.86%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 2	0 / 8	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (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
Gallbladder obstruction
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 8	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 4	0 / 0
Hepatic failure
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	1 / 358 (0.28%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic pain
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Hyperbilirubinaemia
subjects affected / exposed	6 / 358 (1.68%)	4 / 350 (1.14%)	2 / 354 (0.56%)
occurrences causally related to treatment / all	0 / 16	0 / 14	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	3 / 358 (0.84%)	0 / 350 (0.00%)	3 / 354 (0.85%)
occurrences causally related to treatment / all	0 / 6	0 / 0	1 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Jaundice cholestatic
subjects affected / exposed	3 / 358 (0.84%)	6 / 350 (1.71%)	8 / 354 (2.26%)
occurrences causally related to treatment / all	0 / 6	0 / 20	0 / 36
deaths causally related to treatment / all	0 / 0	0 / 4	0 / 0
Liver disorder
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Perforation bile duct
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Portal vein thrombosis
subjects affected / exposed	2 / 358 (0.56%)	2 / 350 (0.57%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	2 / 4	2 / 10	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Blister
subjects affected / exposed	1 / 358 (0.28%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	2 / 2	3 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	1 / 2	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Panniculitis
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Plantar erythema
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	1 / 358 (0.28%)	3 / 350 (0.86%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	2 / 2	5 / 8	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rash generalised
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Rash pruritic
subjects affected / exposed	0 / 358 (0.00%)	2 / 350 (0.57%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	3 / 4	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Swelling face
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	3 / 358 (0.84%)	0 / 350 (0.00%)	2 / 354 (0.56%)
occurrences causally related to treatment / all	1 / 6	0 / 0	1 / 8
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 4
Renal failure acute
subjects affected / exposed	1 / 358 (0.28%)	2 / 350 (0.57%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	2 / 358 (0.56%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	2 / 358 (0.56%)	2 / 350 (0.57%)	4 / 354 (1.13%)
occurrences causally related to treatment / all	0 / 4	0 / 6	0 / 16
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Abdominal sepsis
subjects affected / exposed	1 / 358 (0.28%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 4	0 / 0
Anal abscess
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Biliary sepsis
subjects affected / exposed	16 / 358 (4.47%)	16 / 350 (4.57%)	16 / 354 (4.52%)
occurrences causally related to treatment / all	2 / 40	12 / 72	4 / 98
deaths causally related to treatment / all	0 / 0	0 / 4	0 / 4
Biliary tract infection
subjects affected / exposed	3 / 358 (0.84%)	1 / 350 (0.29%)	2 / 354 (0.56%)
occurrences causally related to treatment / all	4 / 6	0 / 2	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	2 / 2	0 / 0
Cellulitis
subjects affected / exposed	12 / 358 (3.35%)	4 / 350 (1.14%)	6 / 354 (1.69%)
occurrences causally related to treatment / all	5 / 26	6 / 10	5 / 23
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholangitis suppurative
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Clostridial infection
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 358 (0.00%)	2 / 350 (0.57%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 8	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 358 (0.00%)	3 / 350 (0.86%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 12	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gallbladder abscess
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	16 / 358 (4.47%)	4 / 350 (1.14%)	12 / 354 (3.39%)
occurrences causally related to treatment / all	20 / 36	1 / 18	9 / 56
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infectious peritonitis
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Klebsiella infection
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Klebsiella sepsis
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	1 / 358 (0.28%)	2 / 350 (0.57%)	3 / 354 (0.85%)
occurrences causally related to treatment / all	0 / 2	0 / 8	0 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 4
Lower respiratory tract infection
subjects affected / exposed	6 / 358 (1.68%)	11 / 350 (3.14%)	9 / 354 (2.54%)
occurrences causally related to treatment / all	10 / 12	8 / 34	10 / 44
deaths causally related to treatment / all	0 / 0	0 / 4	0 / 0
Mastoiditis
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenic infection
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	8 / 358 (2.23%)	3 / 350 (0.86%)	2 / 354 (0.56%)
occurrences causally related to treatment / all	16 / 16	6 / 8	4 / 8
deaths causally related to treatment / all	2 / 2	0 / 0	0 / 0
Opportunistic infection
subjects affected / exposed	1 / 358 (0.28%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 4	0 / 0
Oral candidiasis
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Paronychia
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Peritonitis bacterial
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Pharyngitis
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	3 / 358 (0.84%)	5 / 350 (1.43%)	4 / 354 (1.13%)
occurrences causally related to treatment / all	2 / 6	3 / 16	4 / 20
deaths causally related to treatment / all	0 / 0	0 / 6	0 / 0
Pneumonia klebsiella
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural infection
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (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
Pseudomonas infection
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Respiratory tract infection
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	2 / 354 (0.56%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	6 / 358 (1.68%)	8 / 350 (2.29%)	13 / 354 (3.67%)
occurrences causally related to treatment / all	0 / 12	10 / 20	9 / 56
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 8
Septic shock
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 4
Skin infection
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Stent related infection
subjects affected / exposed	2 / 358 (0.56%)	4 / 350 (1.14%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 4	0 / 10	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 4
Streptococcal sepsis
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	1 / 2	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	3 / 358 (0.84%)	3 / 350 (0.86%)	3 / 354 (0.85%)
occurrences causally related to treatment / all	3 / 6	2 / 10	0 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 2	0 / 0	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound abscess
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Anorexia
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	4 / 358 (1.12%)	3 / 350 (0.86%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	4 / 8	0 / 10	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	5 / 358 (1.40%)	10 / 350 (2.86%)	4 / 354 (1.13%)
occurrences causally related to treatment / all	4 / 10	6 / 32	0 / 16
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 358 (0.00%)	1 / 350 (0.29%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	2 / 358 (0.56%)	1 / 350 (0.29%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	1 / 4	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Gout
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	3 / 358 (0.84%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 6	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 4
Hyperglycaemia
subjects affected / exposed	1 / 358 (0.28%)	7 / 350 (2.00%)	0 / 354 (0.00%)
occurrences causally related to treatment / all	0 / 2	4 / 20	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	2 / 358 (0.56%)	3 / 350 (0.86%)	2 / 354 (0.56%)
occurrences causally related to treatment / all	0 / 4	0 / 10	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	2 / 354 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	2 / 358 (0.56%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyponatraemic syndrome
subjects affected / exposed	1 / 358 (0.28%)	0 / 350 (0.00%)	0 / 354 (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
Oral intake reduced
subjects affected / exposed	0 / 358 (0.00%)	0 / 350 (0.00%)	1 / 354 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Gemcitabine and Capecitabine Therapy	Gemcitabine and Capecitabine then Sequential GV1001 Therapy	Concurrent Gemcitabine, Capecitabine and GV1001 Therapy
Total subjects affected by non serious adverse events
subjects affected / exposed	320 / 358 (89.39%)	306 / 350 (87.43%)	325 / 354 (91.81%)
General disorders and administration site conditions
Fatigue
subjects affected / exposed	69 / 358 (19.27%)	63 / 350 (18.00%)	61 / 354 (17.23%)
occurrences all number	105	103	105
Gastrointestinal disorders
Nausea
subjects affected / exposed	60 / 358 (16.76%)	52 / 350 (14.86%)	57 / 354 (16.10%)
occurrences all number	101	87	99

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Were there any global substantial amendments to the protocol? Yes

08 Jan 2007

SUBSTANTIAL AMENDMENT (MREC 01) - Change in the content of clinical Kit 1 (include one more vial of Leukine (GM-CSF) and one less vial of Bacteriostatic Water) - Change in label text to clarify the storage conditions and in-use shelf-life for GV1001 and Leukine after reconstitution Both reflected in minor changes in the protocol

05 Mar 2007

SUBSTANTIAL AMENDMENT (MREC 02) - Changes to the protocol - Submission of Investigators Brochure (IB) to replace SmPC

05 Mar 2007

SUBSTANTIAL AMENDMENT (MREC 03) - Changes to Protocol (Submitted to both MHRA and MREC in order to seek approval of amendment 2 to Protocol version 5) - Change in Clinical Trial Agreement (Chief Investigator changed from Professor J Neoptolemos to Dr G Middleton, Principal Investigator has changed from Dr G Middleton to Professor J Neoptolemos)

08 Mar 2007

SUBSTANTIAL AMENDMENT (MREC 04) Protocol Changes - Deletion of University as a co-sponsor - Deletion of University as a co-sponsor on Patient Information Sheet Clinical Trial Agreement Changes - Deletion of University as a co-sponsor

06 Jul 2007

SUBSTANTIAL AMENDMENT (MREC 06) - Changes to the Protocol - Change in the Clinical Trial Application - Change in the MREC Parts A&B - Change of Investigators - Addition of new sites - Update of IMPD of GV1001 to extend the shelf-life and change of the specifications

20 Dec 2007

SUBSTANTIAL AMENDMENT (MREC 07) - Changes to the Protocol: Change in GV1001 Kit 1 design Change of sample schedule for immunomonitoring Change of type of documents to be reviewed by LCTU before randomisation of a patient - Change in the Clinical Trial Application – Addition of new sites - Change in the MREC Parts A&B – Addition of new sites

01 May 2008

SUBSTANTIAL AMENDMENT (MREC 08) - Change of PI due to maternity leave – Dr Pippa Corrie from Addenbrooke's hospital will be on maternity leave from the 06/05/2008 to the 04/01/2008. The new PI for the site will be Dr Hugo Ford. - Addition of new site – Weston General Hospital in Weston-Super-Mare has joined the list of sites on the TeloVac trial. The PI for this site is Dr Serena Hilman.

20 May 2008

SUBSTANTIAL AMENDMENT (MREC 09) - Change of PI due to maternity leave - Dr Archer from Portsmouth Hospital will be on maternity leave until October. The new PI will be Ann O'Callaghan - Change of PI due to Dr Ostrowski retiring 0 Dr Ostrowski will be replaced by Dr Stubbings at Norfolk and Norwich

10 Jul 2008

SUBSTANTIAL AMENDMENT (MREC 10) - Change of PI at James Paget Hospital - Addition of site namely Alexandra Hospital - Notification of update to the GV1001 IB (for information only)

17 Nov 2008

SUBSTANTIAL AMENDMENT (MREC 11) - Notification of update to the Xeloda (capecitabine) IB - Notification of change of Principal Investigator

27 Feb 2009

MINOR AMENDMENT (MREC) 12 - Information only - Submission of additional label text provided for capecitabine by Roche

05 Aug 2009

SUBSTANTIAL AMENDMENT (MREC 13) - Change in PI at 3 sites: Norfolk and Norwich, Churchill and Yeovil District Hospital

18 Jan 2010

MINOR AMENDMENT (MREC 14) - Updated IBs (information only): Xeloda v10 and v11

02 Feb 2010

SUBSTANTIAL AMENDMENT (MREC 15&16) - Change to Patient Diary and Skin Test Ruler - Change in PI at Torbay Hospital

24 Jun 2010

MINOR AMENDMENT (MREC 17) - Information Only - Capecitabine diary footer altered to state version 3 - GV1001 IB v6 submitted for information

04 Aug 2010

SUBSTANTIAL AMENDMENT (MREC 18) - Protocol amended to allow for treatment breaks for patients - Administrative changes for protocol (re-ordering sections). - Notification of change of name from Cookridge Hospital to St James (named as Cookridge on original CTA). - Information sheet and informed consent form re-numbered as version 8 to avoid confusion.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
26 May 2011	There was evidence that patients receiving vaccine treatment alone (Arm 2) had a poorer outcome than patients receiving standard chemotherapy treatment and there was no evidence of a a survival benefit from the addition of vaccine to chemotherapy compared to chemotherapy alone. The MHRA and Ethics were first informed of Urgent Safety Measures taken on 24/05/2011 that resulted in suspension of recruitment to Arm 2 of the trial. Given the advanced stage of the trial and the relatively small number of patients needed to completed target recruitment, the recommendation of the DMC and TSC (26/05/2011) was to close the TeloVac trial to further recruitment on 27/05/2011.	-

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

None reported

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A prospective, phase III, controlled, multicentre, randomised clinical trial comparing combination gemcitabine and capecitabine therapy with concurrent and sequential chemoimmunotherapy using a telomerase vaccine in locally advanced and metastatic pancreatic cancer.

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Clinical Trial Results: A prospective, phase III, controlled, multicentre, randomised clinical trial comparing combination gemcitabine and capecitabine therapy with concurrent and sequential chemoimmunotherapy using a telomerase vaccine in locally advanced and metastatic pancreatic cancer.

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Primary: Overall Survival

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Clinical Trial Results:
A prospective, phase III, controlled, multicentre, randomised clinical trial comparing combination gemcitabine and capecitabine therapy with concurrent and sequential chemoimmunotherapy using a telomerase vaccine in locally advanced and metastatic pancreatic cancer.