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Clinical Trial Results:
A Randomized, Double-Blind, Phase III Study of the Efficacy and Safety of Gemcitabine in Combination With TH-302 Compared With Gemcitabine in Combination With Placebo in Previously Untreated Subjects With Metastatic or Locally Advanced Unresectable Pancreatic Adenocarcinoma

Summary
EudraCT number	2012-002957-42
Trial protocol	BE GB CZ DE HU ES SK IT PL FI NL AT
Global end of trial date	04 May 2016

Results information
Results version number	v1(current)
This version publication date	11 Jul 2018
First version publication date	11 Jul 2018
Other versions

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

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Trial information

Top of page

Sponsor protocol code

EMR200592-001

ISRCTN number

-

US NCT number

NCT01746979

WHO universal trial number (UTN)

-

Sponsor organisation name

Molecular Templates (formerly Threshold Pharmaceuticals)

Sponsor organisation address

9301 Amberglen Blvd, Suite 100, Austin, United States, TX 78729

Public contact

Kristina Dabovic, PharmD, Molecular Templates, +1 (862) 204-7184, kristina.dabovic@mtem.com

Scientific contact

Nenad Sarapa, MD, Molecular Templates, +1 (973) 796-6104, nenad.sarapa@mtem.com

Is trial part of an agreed paediatric investigation plan (PIP)

No

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Analysis stage

Final

Date of interim/final analysis

04 May 2016

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

04 May 2016

Was the trial ended prematurely?

No

Main objective of the trial

The primary objective of the trial was to evaluate efficacy, as measured by overall survival (OS), of gemcitabine in combination with TH-302 compared to gemcitabine in combination with placebo in subjects with previously untreated locally advanced unresectable or metastatic pancreatic adenocarcinoma.

Protection of trial subjects

Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

24 Jan 2013

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Slovakia: 6

Country: Number of subjects enrolled

Spain: 45

Country: Number of subjects enrolled

United Kingdom: 39

Country: Number of subjects enrolled

United States: 81

Country: Number of subjects enrolled

Argentina: 4

Country: Number of subjects enrolled

Australia: 19

Country: Number of subjects enrolled

Austria: 6

Country: Number of subjects enrolled

Belgium: 49

Country: Number of subjects enrolled

Brazil: 5

Country: Number of subjects enrolled

Canada: 15

Country: Number of subjects enrolled

Czech Republic: 35

Country: Number of subjects enrolled

Finland: 13

Country: Number of subjects enrolled

France: 58

Country: Number of subjects enrolled

Germany: 24

Country: Number of subjects enrolled

Hungary: 40

Country: Number of subjects enrolled

Israel: 21

Country: Number of subjects enrolled

Italy: 17

Country: Number of subjects enrolled

Japan: 116

Country: Number of subjects enrolled

Korea, Republic of: 7

Country: Number of subjects enrolled

Netherlands: 4

Country: Number of subjects enrolled

Poland: 23

Country: Number of subjects enrolled

Romania: 12

Country: Number of subjects enrolled

Russian Federation: 54

Worldwide total number of subjects

693

EEA total number of subjects

371

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

325

From 65 to 84 years

367

85 years and over

1

Subject disposition

Top of page

Recruitment details

-

Screening details

A total of 969 subjects were screened, out of which 693 subjects were randomized in the study.

Period 1 title

Overall Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Gemcitabine Plus TH-302

Arm description

TH-302: TH-302 was administered at a dose of 340 milligrams per square meter (mg/m^2) as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle until evidence of progressive disease, intolerable toxicity or subject withdrawal. Gemcitabine: Gemcitabine was administered at a dose of 1000 mg/m^2 as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle until evidence of progressive disease, intolerable toxicity or subject withdrawal.

Arm type

Active comparator

Investigational medicinal product name

TH-302

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

TH-302 was administered at a dose of 340 mg/m^2 as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle until evidence of progressive disease, intolerable toxicity or subject withdrawal.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Gemcitabine was administered at a dose of 1000 mg/m^2 as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle until evidence of progressive disease, intolerable toxicity or subject withdrawal.

Gemcitabine Plus Placebo

Arm description

Gemcitabine: Gemcitabine was administered at a dose of 1000 mg/m^2 as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle until evidence of progressive disease, intolerable toxicity or subject withdrawal. Placebo (5 percent dextrose - D5W): TH-302 placebo (5 percent dextrose - D5W) was administered as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle until evidence of progressive disease, intolerable toxicity or subject withdrawal.

Arm type

Placebo

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Gemcitabine was administered at a dose of 1000 mg/m^2 as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle until evidence of progressive disease, intolerable toxicity or subject withdrawal.

Investigational medicinal product name

Placebo (5 percent dextrose - D5W)

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

TH-302 placebo (5 percent dextrose - D5W) was administered as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle until evidence of progressive disease, intolerable toxicity or subject withdrawal.

Number of subjects in period 1	Gemcitabine Plus TH-302	Gemcitabine Plus Placebo
Started	346	347
Completed	0	0
Not completed	346	347
Discontinued	346	347

Baseline characteristics

Top of page

Reporting group title

Gemcitabine Plus TH-302

Reporting group description

TH-302: TH-302 was administered at a dose of 340 milligrams per square meter (mg/m^2) as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle until evidence of progressive disease, intolerable toxicity or subject withdrawal. Gemcitabine: Gemcitabine was administered at a dose of 1000 mg/m^2 as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle until evidence of progressive disease, intolerable toxicity or subject withdrawal.

Reporting group title

Gemcitabine Plus Placebo

Reporting group description

Gemcitabine: Gemcitabine was administered at a dose of 1000 mg/m^2 as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle until evidence of progressive disease, intolerable toxicity or subject withdrawal. Placebo (5 percent dextrose - D5W): TH-302 placebo (5 percent dextrose - D5W) was administered as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle until evidence of progressive disease, intolerable toxicity or subject withdrawal.

Reporting group values	Gemcitabine Plus TH-302	Gemcitabine Plus Placebo	Total
Number of subjects	346	347	693
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	65 ( 9.70 )	63.8 ( 9.82 )	-
Gender categorical
Units: Subjects
Female	155	168	323
Male	191	179	370

End points

Top of page

Reporting group title

Gemcitabine Plus TH-302

Reporting group description

TH-302: TH-302 was administered at a dose of 340 milligrams per square meter (mg/m^2) as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle until evidence of progressive disease, intolerable toxicity or subject withdrawal. Gemcitabine: Gemcitabine was administered at a dose of 1000 mg/m^2 as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle until evidence of progressive disease, intolerable toxicity or subject withdrawal.

Reporting group title

Gemcitabine Plus Placebo

Reporting group description

Gemcitabine: Gemcitabine was administered at a dose of 1000 mg/m^2 as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle until evidence of progressive disease, intolerable toxicity or subject withdrawal. Placebo (5 percent dextrose - D5W): TH-302 placebo (5 percent dextrose - D5W) was administered as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle until evidence of progressive disease, intolerable toxicity or subject withdrawal.

Primary: Overall Survival

Top of page

End point title

Overall Survival

End point description

Overall survival is defined as time from randomization to death or last day known to be alive.

End point type

Primary

End point timeframe

From date of randomization until date of death from any cause or last day known to be alive, assessed up to 2 years

End point values	Gemcitabine Plus TH-302	Gemcitabine Plus Placebo
Number of subjects analysed	346	347
Units: Months
median (confidence interval 95%)	8.9 (7.6 to 9.9)	7.6 (6.7 to 8.3)

Statistical analysis of Overall Survival

Comparison groups

Gemcitabine Plus TH-302 v Gemcitabine Plus Placebo

Number of subjects included in analysis

693

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.0588

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.844

Confidence interval

level

95%

sides

2-sided

lower limit

0.708

upper limit

1.006

Secondary: Progression Free Survival

Top of page

End point title

Progression Free Survival

End point description

Progression Free Survival is defined as the time from randomization to either first observation of progressive disease or occurrence of death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

End point type

Secondary

End point timeframe

From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years

End point values	Gemcitabine Plus TH-302	Gemcitabine Plus Placebo
Number of subjects analysed	346	347
Units: Months
median (confidence interval 95%)	5.5 (4.8 to 5.6)	3.7 (3.6 to 3.8)

Statistical Analysis of Progression-free Survival

Comparison groups

Gemcitabine Plus TH-302 v Gemcitabine Plus Placebo

Number of subjects included in analysis

693

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.0015

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.747

Confidence interval

level

95%

sides

2-sided

lower limit

0.623

upper limit

0.895

Secondary: Objective Response Rate

Top of page

End point title

Objective Response Rate

End point description

Objective response rate defined as the percentage of subjects having achieved complete response (CR: Disappearance of all target lesions) or partial response (PR: At least a 30 percent decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) as the best overall response according to local unconfirmed radiological assessments from randomization until the end of study treatment.

End point type

Secondary

End point timeframe

From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years

End point values	Gemcitabine Plus TH-302	Gemcitabine Plus Placebo
Number of subjects analysed	346	347
Units: Percentage of Subjects
number (confidence interval 95%)	20.5 (16.4 to 25.2)	17.3 (13.5 to 21.7)

Statistical analysis of Objective Response Rate

Comparison groups

Gemcitabine Plus TH-302 v Gemcitabine Plus Placebo

Number of subjects included in analysis

693

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.2757

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.26

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

1.89

Secondary: Disease Control Rate

Top of page

End point title

Disease Control Rate

End point description

Disease control rate defined as the percentage of subjects having achieved CR, PR or stable disease (SD) as the best overall response according to local radiological assessments from randomization until the end of study treatment.

End point type

Secondary

End point timeframe

From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years

End point values	Gemcitabine Plus TH-302	Gemcitabine Plus Placebo
Number of subjects analysed	346	347
Units: Percentage of Subjects
number (confidence interval 95%)	69.1 (63.9 to 73.9)	63.1 (57.8 to 68.2)

Statistical analysis of Disease Control Rate

Comparison groups

Gemcitabine Plus TH-302 v Gemcitabine Plus Placebo

Number of subjects included in analysis

693

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.085

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.32

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

1.83

Adverse events

Top of page

Timeframe for reporting adverse events

Baseline up to 2 years

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Gemcitabine Plus TH-302

Reporting group description

TH-302: TH-302 was administered at a dose of 340 milligrams per square meter (mg/m^2) as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle until evidence of progressive disease, intolerable toxicity or subject withdrawal. Gemcitabine: Gemcitabine was administered at a dose of 1000 mg/m^2 as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle until evidence of progressive disease, intolerable toxicity or subject withdrawal.

Reporting group title

Gemcitabine Plus Placebo

Reporting group description

Gemcitabine: Gemcitabine was administered at a dose of 1000 mg/m^2 as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle until evidence of progressive disease, intolerable toxicity or subject withdrawal. Placebo (5 percent dextrose - D5W): TH-302 placebo (5 percent dextrose - D5W) was administered as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle until evidence of progressive disease, intolerable toxicity or subject withdrawal.

Serious adverse events	Gemcitabine Plus TH-302	Gemcitabine Plus Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	183 / 338 (54.14%)	177 / 341 (51.91%)
number of deaths (all causes)	241	260
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	2 / 338 (0.59%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant ascites
subjects affected / exposed	1 / 338 (0.30%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Paraneoplastic syndrome
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Vascular disorders
Aortic dissection
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arterial occlusive disease
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Arterial thrombosis
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Axillary vein thrombosis
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Circulatory collapse
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	7 / 338 (2.07%)	4 / 341 (1.17%)
occurrences causally related to treatment / all	1 / 7	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Embolism
subjects affected / exposed	0 / 338 (0.00%)	3 / 341 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Hypertension
subjects affected / exposed	1 / 338 (0.30%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	1 / 338 (0.30%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Phlebitis
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Shock haemorrhagic
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Thrombophlebitis
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Venous thrombosis limb
subjects affected / exposed	2 / 338 (0.59%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	4 / 338 (1.18%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	1 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Chills
subjects affected / exposed	0 / 338 (0.00%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Device malfunction
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device occlusion
subjects affected / exposed	3 / 338 (0.89%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Disease progression
subjects affected / exposed	4 / 338 (1.18%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 3	0 / 2
Fatigue
subjects affected / exposed	2 / 338 (0.59%)	3 / 341 (0.88%)
occurrences causally related to treatment / all	0 / 2	1 / 3
deaths causally related to treatment / all	0 / 1	0 / 0
General physical health deterioration
subjects affected / exposed	11 / 338 (3.25%)	14 / 341 (4.11%)
occurrences causally related to treatment / all	1 / 12	1 / 15
deaths causally related to treatment / all	1 / 7	1 / 9
Generalised oedema
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infusion site extravasation
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injection site extravasation
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Local swelling
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malaise
subjects affected / exposed	2 / 338 (0.59%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Multi-organ failure
subjects affected / exposed	1 / 338 (0.30%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1
Non-cardiac chest pain
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	2 / 338 (0.59%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 338 (0.00%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	14 / 338 (4.14%)	11 / 341 (3.23%)
occurrences causally related to treatment / all	3 / 15	5 / 12
deaths causally related to treatment / all	0 / 0	0 / 0
Stent malfunction
subjects affected / exposed	1 / 338 (0.30%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Drug hypersensitivity
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute interstitial pneumonitis
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute pulmonary oedema
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	2 / 338 (0.59%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hiccups
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	2 / 338 (0.59%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pneumonitis
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	11 / 338 (3.25%)	10 / 341 (2.93%)
occurrences causally related to treatment / all	1 / 11	2 / 10
deaths causally related to treatment / all	1 / 1	1 / 1
Respiratory failure
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Confusional state
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Depression
subjects affected / exposed	1 / 338 (0.30%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	2 / 338 (0.59%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	2 / 338 (0.59%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	2 / 338 (0.59%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	3 / 338 (0.89%)	3 / 341 (0.88%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	1 / 338 (0.30%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood glucose fluctuation
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
C-reactive protein increased
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gamma-glutamyltransferase increased
subjects affected / exposed	4 / 338 (1.18%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
General physical condition abnormal
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver function test abnormal
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	2 / 338 (0.59%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	8 / 338 (2.37%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	6 / 8	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	2 / 338 (0.59%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	3 / 5	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cervical vertebral fracture
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Chemical peritonitis
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural bile leak
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prescribed overdose
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Traumatic haemothorax
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Pyloric stenosis
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	2 / 338 (0.59%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 338 (0.30%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Aortic valve disease
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 338 (0.00%)	3 / 341 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial tachycardia
subjects affected / exposed	1 / 338 (0.30%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiac failure
subjects affected / exposed	0 / 338 (0.00%)	3 / 341 (0.88%)
occurrences causally related to treatment / all	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Myocardial infarction
subjects affected / exposed	2 / 338 (0.59%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Nervous system disorders
Amnesia
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Balance disorder
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral artery stenosis
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	1 / 338 (0.30%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	3 / 338 (0.89%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Coma
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Convulsion
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hemianopia
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	1 / 338 (0.30%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Spinal cord compression
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	16 / 338 (4.73%)	15 / 341 (4.40%)
occurrences causally related to treatment / all	8 / 18	4 / 18
deaths causally related to treatment / all	0 / 0	0 / 0
Bone marrow failure
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	6 / 338 (1.78%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	6 / 7	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	9 / 338 (2.66%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	12 / 13	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	2 / 338 (0.59%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Splenic infarction
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Splenic vein thrombosis
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	19 / 338 (5.62%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	17 / 25	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Macular hole
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	10 / 338 (2.96%)	7 / 341 (2.05%)
occurrences causally related to treatment / all	0 / 10	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 338 (0.30%)	3 / 341 (0.88%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	2 / 338 (0.59%)	5 / 341 (1.47%)
occurrences causally related to treatment / all	0 / 2	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis ischaemic
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Constipation
subjects affected / exposed	1 / 338 (0.30%)	3 / 341 (0.88%)
occurrences causally related to treatment / all	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	8 / 338 (2.37%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	9 / 11	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal obstruction
subjects affected / exposed	1 / 338 (0.30%)	4 / 341 (1.17%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal perforation
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal stenosis
subjects affected / exposed	3 / 338 (0.89%)	4 / 341 (1.17%)
occurrences causally related to treatment / all	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	1 / 338 (0.30%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal ulcer haemorrhage
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric perforation
subjects affected / exposed	0 / 338 (0.00%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	1 / 1
Gastric ulcer haemorrhage
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer perforation
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 338 (0.30%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal inflammation
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal obstruction
subjects affected / exposed	0 / 338 (0.00%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal perforation
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	1 / 338 (0.30%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
subjects affected / exposed	2 / 338 (0.59%)	3 / 341 (0.88%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Impaired gastric emptying
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Intestinal ischaemia
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Intestinal obstruction
subjects affected / exposed	2 / 338 (0.59%)	3 / 341 (0.88%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Intra-abdominal haemorrhage
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestinal obstruction
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Nausea
subjects affected / exposed	3 / 338 (0.89%)	4 / 341 (1.17%)
occurrences causally related to treatment / all	0 / 4	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Obstruction gastric
subjects affected / exposed	0 / 338 (0.00%)	3 / 341 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Oedematous pancreatitis
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Oesophageal ulcer
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal varices haemorrhage
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 338 (0.30%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Proctalgia
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 338 (0.30%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subileus
subjects affected / exposed	0 / 338 (0.00%)	3 / 341 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 2
Upper gastrointestinal haemorrhage
subjects affected / exposed	2 / 338 (0.59%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	7 / 338 (2.07%)	13 / 341 (3.81%)
occurrences causally related to treatment / all	1 / 8	4 / 13
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct obstruction
subjects affected / exposed	3 / 338 (0.89%)	6 / 341 (1.76%)
occurrences causally related to treatment / all	0 / 3	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Bile duct stenosis
subjects affected / exposed	5 / 338 (1.48%)	5 / 341 (1.47%)
occurrences causally related to treatment / all	0 / 5	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary dilatation
subjects affected / exposed	2 / 338 (0.59%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholangiectasis acquired
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholangiolitis
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	12 / 338 (3.55%)	15 / 341 (4.40%)
occurrences causally related to treatment / all	1 / 12	3 / 21
deaths causally related to treatment / all	0 / 0	0 / 0
Cholangitis acute
subjects affected / exposed	1 / 338 (0.30%)	6 / 341 (1.76%)
occurrences causally related to treatment / all	0 / 1	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	2 / 338 (0.59%)	3 / 341 (0.88%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	1 / 338 (0.30%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholestasis
subjects affected / exposed	3 / 338 (0.89%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gallbladder obstruction
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	3 / 338 (0.89%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	1 / 3	0 / 2
deaths causally related to treatment / all	1 / 2	0 / 1
Hepatic function abnormal
subjects affected / exposed	4 / 338 (1.18%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatorenal failure
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Hyperbilirubinaemia
subjects affected / exposed	0 / 338 (0.00%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice
subjects affected / exposed	1 / 338 (0.30%)	4 / 341 (1.17%)
occurrences causally related to treatment / all	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 1
Jaundice cholestatic
subjects affected / exposed	3 / 338 (0.89%)	6 / 341 (1.76%)
occurrences causally related to treatment / all	0 / 3	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Portal hypertension
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic foot
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rash
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin maceration
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Yellow skin
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Dysuria
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Proteinuria
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	2 / 338 (0.59%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	1 / 2	0 / 2
deaths causally related to treatment / all	1 / 1	0 / 0
Renal failure acute
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Renal impairment
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	3 / 338 (0.89%)	3 / 341 (0.88%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Flank pain
subjects affected / exposed	2 / 338 (0.59%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gouty arthritis
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	2 / 338 (0.59%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Bacterial infection
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial prostatitis
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary sepsis
subjects affected / exposed	2 / 338 (0.59%)	3 / 341 (0.88%)
occurrences causally related to treatment / all	1 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 2
Biliary tract infection
subjects affected / exposed	0 / 338 (0.00%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	0 / 338 (0.00%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	2 / 338 (0.59%)	3 / 341 (0.88%)
occurrences causally related to treatment / all	2 / 2	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	2 / 338 (0.59%)	4 / 341 (1.17%)
occurrences causally related to treatment / all	1 / 2	3 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Device related sepsis
subjects affected / exposed	0 / 338 (0.00%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic gangrene
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterococcal infection
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia infection
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	1 / 338 (0.30%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile infection
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fungal oesophagitis
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 338 (0.30%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Infusion site infection
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Klebsiella bacteraemia
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Klebsiella sepsis
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Meningoencephalitis herpetic
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal candidiasis
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oropharyngeal candidiasis
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic abscess
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Penile infection
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Pharyngitis
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	8 / 338 (2.37%)	9 / 341 (2.64%)
occurrences causally related to treatment / all	2 / 8	1 / 11
deaths causally related to treatment / all	1 / 1	1 / 3
Respiratory tract infection
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	5 / 338 (1.48%)	5 / 341 (1.47%)
occurrences causally related to treatment / all	1 / 5	1 / 5
deaths causally related to treatment / all	0 / 0	1 / 1
Septic shock
subjects affected / exposed	2 / 338 (0.59%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Splenic abscess
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 338 (0.00%)	4 / 341 (1.17%)
occurrences causally related to treatment / all	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vaginal infection
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Cachexia
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	2 / 338 (0.59%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	1 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	2 / 338 (0.59%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	2 / 338 (0.59%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	0 / 338 (0.00%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 338 (0.30%)	2 / 341 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypovolaemia
subjects affected / exposed	1 / 338 (0.30%)	0 / 341 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolic disorder
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	0 / 338 (0.00%)	1 / 341 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Gemcitabine Plus TH-302	Gemcitabine Plus Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	331 / 338 (97.93%)	328 / 341 (96.19%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	34 / 338 (10.06%)	30 / 341 (8.80%)
occurrences all number	86	52
Aspartate aminotransferase increased
subjects affected / exposed	29 / 338 (8.58%)	27 / 341 (7.92%)
occurrences all number	71	44
Blood alkaline phosphatase increased
subjects affected / exposed	20 / 338 (5.92%)	29 / 341 (8.50%)
occurrences all number	34	41
Blood bilirubin increased
subjects affected / exposed	21 / 338 (6.21%)	22 / 341 (6.45%)
occurrences all number	39	36
Neutrophil count decreased
subjects affected / exposed	52 / 338 (15.38%)	29 / 341 (8.50%)
occurrences all number	301	94
Platelet count decreased
subjects affected / exposed	100 / 338 (29.59%)	44 / 341 (12.90%)
occurrences all number	476	122
Weight decreased
subjects affected / exposed	31 / 338 (9.17%)	34 / 341 (9.97%)
occurrences all number	38	38
White blood cell count decreased
subjects affected / exposed	55 / 338 (16.27%)	28 / 341 (8.21%)
occurrences all number	263	84
Vascular disorders
Hypertension
subjects affected / exposed	16 / 338 (4.73%)	21 / 341 (6.16%)
occurrences all number	30	28
Nervous system disorders
Dizziness
subjects affected / exposed	28 / 338 (8.28%)	24 / 341 (7.04%)
occurrences all number	38	32
Dysgeusia
subjects affected / exposed	46 / 338 (13.61%)	33 / 341 (9.68%)
occurrences all number	57	39
Headache
subjects affected / exposed	23 / 338 (6.80%)	26 / 341 (7.62%)
occurrences all number	29	33
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	164 / 338 (48.52%)	108 / 341 (31.67%)
occurrences all number	582	254
Leukopenia
subjects affected / exposed	47 / 338 (13.91%)	29 / 341 (8.50%)
occurrences all number	198	47
Neutropenia
subjects affected / exposed	140 / 338 (41.42%)	94 / 341 (27.57%)
occurrences all number	546	248
Thrombocytopenia
subjects affected / exposed	158 / 338 (46.75%)	61 / 341 (17.89%)
occurrences all number	772	151
General disorders and administration site conditions
Asthenia
subjects affected / exposed	81 / 338 (23.96%)	71 / 341 (20.82%)
occurrences all number	229	165
Fatigue
subjects affected / exposed	98 / 338 (28.99%)	106 / 341 (31.09%)
occurrences all number	234	219
Oedema peripheral
subjects affected / exposed	64 / 338 (18.93%)	72 / 341 (21.11%)
occurrences all number	87	104
Pyrexia
subjects affected / exposed	64 / 338 (18.93%)	76 / 341 (22.29%)
occurrences all number	104	147
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	65 / 338 (19.23%)	70 / 341 (20.53%)
occurrences all number	110	149
Abdominal pain upper
subjects affected / exposed	44 / 338 (13.02%)	38 / 341 (11.14%)
occurrences all number	66	58
Ascites
subjects affected / exposed	18 / 338 (5.33%)	29 / 341 (8.50%)
occurrences all number	18	42
Constipation
subjects affected / exposed	104 / 338 (30.77%)	104 / 341 (30.50%)
occurrences all number	171	146
Diarrhoea
subjects affected / exposed	112 / 338 (33.14%)	89 / 341 (26.10%)
occurrences all number	245	181
Haemorrhoids
subjects affected / exposed	39 / 338 (11.54%)	13 / 341 (3.81%)
occurrences all number	59	15
Nausea
subjects affected / exposed	168 / 338 (49.70%)	150 / 341 (43.99%)
occurrences all number	354	320
Stomatitis
subjects affected / exposed	86 / 338 (25.44%)	53 / 341 (15.54%)
occurrences all number	172	78
Vomiting
subjects affected / exposed	109 / 338 (32.25%)	109 / 341 (31.96%)
occurrences all number	243	233
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	28 / 338 (8.28%)	27 / 341 (7.92%)
occurrences all number	34	30
Dyspnoea
subjects affected / exposed	44 / 338 (13.02%)	27 / 341 (7.92%)
occurrences all number	55	44
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	68 / 338 (20.12%)	23 / 341 (6.74%)
occurrences all number	81	30
Dry skin
subjects affected / exposed	22 / 338 (6.51%)	13 / 341 (3.81%)
occurrences all number	30	13
Erythema
subjects affected / exposed	25 / 338 (7.40%)	10 / 341 (2.93%)
occurrences all number	32	12
Pruritus
subjects affected / exposed	23 / 338 (6.80%)	25 / 341 (7.33%)
occurrences all number	27	32
Rash
subjects affected / exposed	63 / 338 (18.64%)	46 / 341 (13.49%)
occurrences all number	104	65
Skin hyperpigmentation
subjects affected / exposed	44 / 338 (13.02%)	3 / 341 (0.88%)
occurrences all number	59	4
Psychiatric disorders
Insomnia
subjects affected / exposed	25 / 338 (7.40%)	33 / 341 (9.68%)
occurrences all number	26	36
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	30 / 338 (8.88%)	45 / 341 (13.20%)
occurrences all number	35	58
Pain in extremity
subjects affected / exposed	16 / 338 (4.73%)	18 / 341 (5.28%)
occurrences all number	27	23
Infections and infestations
Urinary tract infection
subjects affected / exposed	30 / 338 (8.88%)	19 / 341 (5.57%)
occurrences all number	44	36
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	117 / 338 (34.62%)	116 / 341 (34.02%)
occurrences all number	205	184
Hyperglycaemia
subjects affected / exposed	27 / 338 (7.99%)	23 / 341 (6.74%)
occurrences all number	44	55
Hypokalaemia
subjects affected / exposed	22 / 338 (6.51%)	27 / 341 (7.92%)
occurrences all number	30	36

More information

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Were there any global substantial amendments to the protocol? Yes

27 Jun 2013

The changes made to Version 3.0 of the clinical trial protocol are as follows: 1. Clarification of the exclusion criteria with respect to alternative treatments (changes previously incorporated in Local Amendment 1 [9 April 2013], which was implemented in Belgium, Czech Republic, France, Germany, Hungary, Romania, Spain, and the United Kingdom). 2. Clarification of the investigator’s obligations for emergency unblinding (changes previously incorporated in Local Amendment 1 [9 April 2013], which was implemented in Belgium, Czech Republic, France, Germany, Hungary, Romania, Spain, and the United Kingdom). 3. Minor modification to the “Numerical Rating Scale for Pain”. 4. Addition of the trial acronym (MAESTRO: TH-302 in the treatment of Metastatic or locally Advanced unrESectable pancreaTic adenocaRcinOma). 5. Correction of minor typographical errors in the document.

Were there any global interruptions to the trial? No

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

None reported

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The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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