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Clinical Trial Results:
A Phase III randomised, double-blind, controlled, parallel group study of intravenous volasertib in combination with subcutaneous low-dose cytarabine vs. placebo + low-dose cytarabine in patients ≥65 years with previously untreated acute myeloid leukaemia, who are ineligible for intensive remission induction therapy

Summary
EudraCT number	2012-002487-27
Trial protocol	BE DE PT GR AT FI ES IT CZ NL HU PL FR
Global end of trial date	28 May 2021

Results information
Results version number	v2(current)
This version publication date	02 Dec 2021
First version publication date	01 Oct 2021
Other versions	v1
Version creation reason

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

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Trial information

Top of page

Sponsor protocol code

1230.14

ISRCTN number

-

US NCT number

NCT01721876

WHO universal trial number (UTN)

-

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173, Ingelheim am Rhein, Germany, 55216

Public contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 +18002430127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 +18002430127, clintriage.rdg@boehringer-ingelheim.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

21 Jun 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

12 Aug 2014

Global end of trial reached?

Yes

Global end of trial date

28 May 2021

Was the trial ended prematurely?

No

Main objective of the trial

To investigate the efficacy, safety, and pharmacokinetics of intravenous volasertib + subcutaneous low-dose cytarabine (LDAC) in patients ≥65 years of age with previously untreated acute myeloid leukaemia (AML), who are ineligible for intensive remission induction therapy

Protection of trial subjects

Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

06 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

Argentina: 2

Country: Number of subjects enrolled

Austria: 14

Country: Number of subjects enrolled

Belgium: 63

Country: Number of subjects enrolled

Brazil: 8

Country: Number of subjects enrolled

Canada: 28

Country: Number of subjects enrolled

Czechia: 17

Country: Number of subjects enrolled

Finland: 17

Country: Number of subjects enrolled

France: 74

Country: Number of subjects enrolled

Germany: 168

Country: Number of subjects enrolled

Greece: 49

Country: Number of subjects enrolled

Hungary: 25

Country: Number of subjects enrolled

India: 2

Country: Number of subjects enrolled

Italy: 26

Country: Number of subjects enrolled

Japan: 52

Country: Number of subjects enrolled

Korea, Republic of: 57

Country: Number of subjects enrolled

Mexico: 4

Country: Number of subjects enrolled

Netherlands: 9

Country: Number of subjects enrolled

Norway: 4

Country: Number of subjects enrolled

Poland: 19

Country: Number of subjects enrolled

Portugal: 15

Country: Number of subjects enrolled

Russian Federation: 7

Country: Number of subjects enrolled

South Africa: 3

Country: Number of subjects enrolled

Spain: 78

Country: Number of subjects enrolled

Taiwan: 15

Country: Number of subjects enrolled

United States: 13

Worldwide total number of subjects

769

EEA total number of subjects

578

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)

0

From 65 to 84 years

769

85 years and over

0

Subject disposition

Top of page

Recruitment details

Patients aged 65 years or more with previously untreated acute myeloid leukaemia, who are ineligible for intensive remission induction therapy were recruited in the phase III randomised, double-blind, placebo-controlled, parallel group study.

Screening details

All patients were screened for eligibility to participate in the trial. Patients attended a specialist sites which ensured that they (the patients) met all strictly implemented inclusion/exclusion criteria. Patients were not to be randomized to trial treatment if any one of the specific entry criteria was violated.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Carer, Data analyst, Assessor, Subject

Blinding implementation details

It was a randomised, placebo-controlled, double-blind parallel group study.

Are arms mutually exclusive

Yes

Placebo + Low-dose Cytarabine

Arm description

Patients received placebo matching to Volasertib 350 milligram (mg) intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.

Arm type

Placebo

Investigational medicinal product name

Low-dose Cytarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Patients received placebo matching to Volasertib 350 milligram (mg) intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Patients received placebo matching to Volasertib 350 milligram (mg) intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.

Volasertib + Low-dose Cytarabine

Arm description

Patients received Volasertib 350 mg intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, wherein no dose increase was allowed after a dose reduction, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.

Arm type

Experimental

Investigational medicinal product name

Low-dose Cytarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Patients received Volasertib 350 mg intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, wherein no dose increase was allowed after a dose reduction, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle, wherein no dose reduction or increase was allowed according to protocol; however, individual administrations could be skipped at the investigator's discretion.

Investigational medicinal product name

Volasertib

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Patients received Volasertib 350 mg intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, wherein no dose increase was allowed after a dose reduction, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle, wherein no dose reduction or increase was allowed according to protocol; however, individual administrations could be skipped at the investigator's discretion.

Number of subjects in period 1 ^[1]	Placebo + Low-dose Cytarabine	Volasertib + Low-dose Cytarabine
Started	222	444
Treated	221	440
Completed	0	0
Not completed	222	444
Adverse event, serious fatal	6	13
Consent withdrawn by subject	15	38
Adverse event, non-fatal	41	165
Sponsor terminated trial	-	4
Disease progression / relapse	123	156
Not treated	1	4
Protocol deviation	2	1
Reason not listed	34	63

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Out of 769 enrolled subjects, 677 subjects were randomized.

Baseline characteristics

Top of page

Reporting group title

Placebo + Low-dose Cytarabine

Reporting group description

Patients received placebo matching to Volasertib 350 milligram (mg) intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.

Reporting group title

Volasertib + Low-dose Cytarabine

Reporting group description

Patients received Volasertib 350 mg intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, wherein no dose increase was allowed after a dose reduction, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.

Reporting group values	Placebo + Low-dose Cytarabine	Volasertib + Low-dose Cytarabine	Total
Number of subjects	222	444	666
Age categorical
The randomised set (RS) included all patients who had been randomised at the database snapshot.
Units: Subjects
Age Continuous
RS
Units: years
arithmetic mean (standard deviation)	75.5 ( 4.9 )	75.2 ( 5.4 )	-
Sex: Female, Male
RS
Units: Subjects
Female	87	203	290
Male	135	241	376
Race (NIH/OMB)
RS
Units: Subjects
American Indian or Alaska Native	0	2	2
Asian	39	74	113
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	0	2	2
White	158	328	486
More than one race	0	0	0
Unknown or Not Reported	25	38	63
Ethnicity (NIH/OMB)
RS
Units: Subjects
Hispanic or Latino	10	16	26
Not Hispanic or Latino	194	399	593
Unknown or Not Reported	18	29	47

End points

Top of page

Reporting group title

Placebo + Low-dose Cytarabine

Reporting group description

Patients received placebo matching to Volasertib 350 milligram (mg) intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.

Reporting group title

Volasertib + Low-dose Cytarabine

Reporting group description

Patients received Volasertib 350 mg intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, wherein no dose increase was allowed after a dose reduction, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.

Primary: Objective Response (OR)

Top of page

End point title

Objective Response (OR)

End point description

OR is the number of patients who achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi), where OR was based on the best response attained during the treatment period. Objective response (CR + CRi) was also analysed by the stratification factors eastern cooperative oncology group (ECOG) performance score (PS) and type of acute myeloid leukaemia (AML). The randomised set (RS) included all patients who had been randomised at the database snapshot.

End point type

Primary

End point timeframe

Response assessment was performed at the end of every 2nd cycle, (i.e. at the end of Cycle 2, 4, 6, 8, etc., and at end of treatment), i.e. up to 52 months.

End point values	Placebo + Low-dose Cytarabine	Volasertib + Low-dose Cytarabine
Number of subjects analysed	222 ^[1]	444 ^[2]
Units: Participants	38	123

Notes
[1] - RS
[2] - RS

Statistical Analysis 1

Statistical analysis description

This analysis was exploratory and descriptive.

Comparison groups

Placebo + Low-dose Cytarabine v Volasertib + Low-dose Cytarabine

Number of subjects included in analysis

666

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.0024 ^[4]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.8751

Confidence interval

level

95%

sides

2-sided

lower limit

1.2432

upper limit

2.8281

Notes
[3] - The 2-sided test of the hypothesis was performed at a 0.05 level of significance. An odds ratio (OR) = 1 would indicate that the odds of achieving CR+CRi with Volasertib + Low-dose Cytarabine is equal to the odds of achieving CR+CRi with Placebo + Low-dose Cytarabine , whereas an OR ≠ 1 would indicate the opposite. H0, CR+CRi: OR = 1 vs. Ha, CR+CRi: OR ≠ 1.
[4] - The common odds ratio is calculated by Mantel−Haenszel estimate adjusting for the two stratification factors (baseline ECOG and type of AML). If odds ratio is above 1 then it favours Volasertib+Low-dose Cytarabine.

Secondary: Overall survival (OS)

Top of page

End point title

Overall survival (OS)

End point description

OS is the key secondary endpoint and was measured from the date of randomization until death from any cause. Patients who were lost to follow-up were censored on the last date they were known to be alive. The final analysis of OS was performed after at least 574 OS events had accrued.

End point type

Secondary

End point timeframe

From randomization until death due to any cause, up to 1557 days.

End point values	Placebo + Low-dose Cytarabine	Volasertib + Low-dose Cytarabine
Number of subjects analysed	222 ^[5]	444 ^[6]
Units: Months
median (confidence interval 95%)	6.5 (4.9 to 8.0)	5.6 (4.5 to 6.8)

Notes
[5] - RS
[6] - RS

Statistical Analysis 1

Statistical analysis description

Hazard ratio is calculated from Cox proportional hazard model stratified by baseline ECOG and type of AML. If hazard ratio is below 1 then it favours volasertib. This analysis was exploratory and descriptive.

Comparison groups

Placebo + Low-dose Cytarabine v Volasertib + Low-dose Cytarabine

Number of subjects included in analysis

666

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

= 0.7571 ^[8]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.97

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

1.2

Notes
[7] - The hazard ratio (HR) between Volasertib + Low-dose Cytarabine and Placebo + Low-dose Cytarabine was tested against 1. The null hypothesis, H0,OS, was that the hazards are equal between Volasertib + Low-dose Cytarabine and Placebo + Low-dose Cytarabine, whereas the alternative hypothesis, Ha,OS, was that the hazards are not equal between the 2 treatment arms. H0, OS: HR = 1 vs. Ha, OS: HR ≠ 1.
[8] - P−value is calculated from log−rank test stratified by baseline ECOG (0−1 vs. 2) and type of AML (denovo vs. secondary).

Secondary: Event-free survival (EFS)

Top of page

End point title

Event-free survival (EFS)

End point description

EFS was measured from the date of randomisation to the date of progression or relapse, or death from any cause, whichever occurred first.

End point type

Secondary

End point timeframe

From randomization until disease progression or relapse or death from any cause, up to 1557 days.

End point values	Placebo + Low-dose Cytarabine	Volasertib + Low-dose Cytarabine
Number of subjects analysed	222 ^[9]	444 ^[10]
Units: Months
median (confidence interval 95%)	2.8 (2.1 to 4.9)	3.3 (2.6 to 4.2)

Notes
[9] - RS
[10] - RS

Statistical Analysis 1

Statistical analysis description

Hazard ratio is calculated from Cox proportional hazard model stratified by baseline ECOG and type of AML. If hazard ratio is below 1 then it favours volasertib. This analysis was exploratory and descriptive.

Comparison groups

Placebo + Low-dose Cytarabine v Volasertib + Low-dose Cytarabine

Number of subjects included in analysis

666

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.6718 ^[11]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.96

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

1.2

Notes
[11] - P−value is calculated from log−rank test stratified by baseline ECOG (0−1 vs. 2) and type of AML (denovo vs. secondary).

Secondary: Relapse-free survival (RFS)

Top of page

End point title

Relapse-free survival (RFS)

End point description

RFS was defined only for patients who achieved CR or CRi; it was measured from the date of achievement of a remission until the date of relapse or death from any cause. Patients not known to have relapsed or died at last follow-up were censored on the date they were last examined. Analysis Population Description: all patients in the RS who achieved best overall response of CR or CRi.

End point type

Secondary

End point timeframe

From randomization until disease progression or relapse or death from any cause, up to 1557 days.

End point values	Placebo + Low-dose Cytarabine	Volasertib + Low-dose Cytarabine
Number of subjects analysed	38 ^[12]	123 ^[13]
Units: Months
median (confidence interval 95%)
RFS in months	18.7 (11.3 to 99999)	13.1 (6.2 to 99999)

Notes
[12] - 99999 = cannot be estimated due to insufficient number of participants with events.
[13] - 99999 = cannot be estimated due to insufficient number of participants with events.

Statistical Analysis 1

Comparison groups

Placebo + Low-dose Cytarabine v Volasertib + Low-dose Cytarabine

Number of subjects included in analysis

161

Analysis specification

Pre-specified

Analysis type

other ^[14]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.37

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

2.7

Notes
[14] - Hazard ratio is calculated from Cox proportional hazard model stratified by baseline ECOG and type of AML. If hazard ratio is below 1 then it favours volasertib.

Adverse events

Top of page

Timeframe for reporting adverse events

From first drug administration until 21 days after last drug administration, i.e., up to 48 months.

Adverse event reporting additional description

The treated set included all patients who were dispensed study medication and were documented to have taken at least one dose of Volasertib, placebo, or Low-dose Cytarabine. One patient was randomised to the Volasertib + Low-dose Cytarabine arm but only took Low-dose Cytarabine and was therefore allocated to the Placebo + Low-dose Cytarabine arm.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

Subjects assigned to Volasertib + Low-dose Cytarabine

Reporting group description

Patients received Volasertib 350 mg intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, wherein no dose increase was allowed after a dose reduction, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.

Reporting group title

Subjects assigned to Placebo + Low-dose Cytarabine

Reporting group description

Patients received placebo matching to Volasertib 350 milligram (mg) intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.

Serious adverse events	Subjects assigned to Volasertib + Low-dose Cytarabine	Subjects assigned to Placebo + Low-dose Cytarabine
Total subjects affected by serious adverse events
subjects affected / exposed	380 / 439 (86.56%)	163 / 222 (73.42%)
number of deaths (all causes)	373	201
number of deaths resulting from adverse events	39	13
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Chronic lymphocytic leukaemia
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myeloid leukaemia
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to peritoneum
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant neoplasm of thorax
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	22 / 439 (5.01%)	17 / 222 (7.66%)
occurrences causally related to treatment / all	0 / 22	0 / 17
deaths causally related to treatment / all	0 / 13	0 / 12
Neoplasm skin
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal cancer
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour associated fever
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myeloproliferative neoplasm
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	5 / 439 (1.14%)	3 / 222 (1.35%)
occurrences causally related to treatment / all	1 / 5	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Embolism
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematoma
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive emergency
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 439 (0.23%)	2 / 222 (0.90%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypovolaemic shock
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Orthostatic hypotension
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral artery thrombosis
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Phlebitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombophlebitis
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Venous thrombosis limb
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aortitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Angioplasty
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	6 / 439 (1.37%)	2 / 222 (0.90%)
occurrences causally related to treatment / all	2 / 6	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Catheter site phlebitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Death
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	1 / 2	0 / 0
Chest pain
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Device related thrombosis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fatigue
subjects affected / exposed	2 / 439 (0.46%)	5 / 222 (2.25%)
occurrences causally related to treatment / all	2 / 2	2 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	15 / 439 (3.42%)	3 / 222 (1.35%)
occurrences causally related to treatment / all	3 / 16	0 / 3
deaths causally related to treatment / all	1 / 2	0 / 0
Induration
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malaise
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mucosal haemorrhage
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	5 / 439 (1.14%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	3 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	3 / 439 (0.68%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Performance status decreased
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pyrexia
subjects affected / exposed	33 / 439 (7.52%)	19 / 222 (8.56%)
occurrences causally related to treatment / all	11 / 38	6 / 22
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden death
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Immune system disorders
Allergy to vaccine
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anaphylactic reaction
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Vaginal haemorrhage
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute respiratory distress syndrome
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Acute respiratory failure
subjects affected / exposed	3 / 439 (0.68%)	3 / 222 (1.35%)
occurrences causally related to treatment / all	0 / 3	1 / 3
deaths causally related to treatment / all	0 / 1	1 / 2
Bronchospasm
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (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	3 / 439 (0.68%)	3 / 222 (1.35%)
occurrences causally related to treatment / all	2 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea at rest
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	6 / 439 (1.37%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	4 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemothorax
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	2 / 439 (0.46%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 2	0 / 0
Lung infiltration
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Orthopnoea
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	2 / 439 (0.46%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary haemorrhage
subjects affected / exposed	3 / 439 (0.68%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	1 / 2	0 / 0
Pulmonary hypertension
subjects affected / exposed	1 / 439 (0.23%)	2 / 222 (0.90%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	4 / 439 (0.91%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	11 / 439 (2.51%)	6 / 222 (2.70%)
occurrences causally related to treatment / all	0 / 11	2 / 6
deaths causally related to treatment / all	0 / 2	1 / 3
Respiratory tract haemorrhage
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aspiration
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	4 / 439 (0.91%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	2 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Disorientation
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mental disorder
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	2 / 439 (0.46%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	1 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Blood pressure orthostatic decreased
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	2 / 439 (0.46%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Electrocardiogram QT prolonged
subjects affected / exposed	2 / 439 (0.46%)	2 / 222 (0.90%)
occurrences causally related to treatment / all	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
C-reactive protein increased
subjects affected / exposed	2 / 439 (0.46%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Haematocrit decreased
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver function test abnormal
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	3 / 439 (0.68%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Troponin increased
subjects affected / exposed	1 / 439 (0.23%)	2 / 222 (0.90%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
White blood cell count increased
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Allergic transfusion reaction
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Concussion
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Craniocerebral injury
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Extradural haematoma
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (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 / 439 (0.00%)	3 / 222 (1.35%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	4 / 439 (0.91%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	2 / 4	1 / 1
deaths causally related to treatment / all	1 / 1	0 / 0
Tracheal obstruction
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haemorrhage
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Transfusion reaction
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transfusion-related acute lung injury
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transfusion-related circulatory overload
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wound haemorrhage
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Aplasia
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	4 / 439 (0.91%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Angina unstable
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	1 / 439 (0.23%)	2 / 222 (0.90%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Arrhythmia supraventricular
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 439 (0.23%)	2 / 222 (0.90%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bradyarrhythmia
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
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	6 / 439 (1.37%)	4 / 222 (1.80%)
occurrences causally related to treatment / all	3 / 6	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	10 / 439 (2.28%)	8 / 222 (3.60%)
occurrences causally related to treatment / all	2 / 11	2 / 8
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiac arrest
subjects affected / exposed	4 / 439 (0.91%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 1
Cardiac disorder
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiac failure congestive
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Cardiac failure acute
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	2 / 439 (0.46%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Cardiopulmonary failure
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Coronary artery disease
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 1	1 / 1
Left ventricular dysfunction
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Right ventricular failure
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tachyarrhythmia
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Subarachnoid haemorrhage
subjects affected / exposed	3 / 439 (0.68%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	1 / 2	0 / 0
Brain stem haemorrhage
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebellar haemorrhage
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cerebral haemorrhage
subjects affected / exposed	3 / 439 (0.68%)	2 / 222 (0.90%)
occurrences causally related to treatment / all	1 / 3	0 / 2
deaths causally related to treatment / all	0 / 2	0 / 1
Cerebral ischaemia
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
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	3 / 439 (0.68%)	2 / 222 (0.90%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	2 / 439 (0.46%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Embolic cerebral infarction
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 0
Haemorrhagic stroke
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Hypotonia
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	2 / 439 (0.46%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sneddon's syndrome
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stupor
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	3 / 439 (0.68%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	20 / 439 (4.56%)	10 / 222 (4.50%)
occurrences causally related to treatment / all	18 / 23	7 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Bone marrow failure
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	3 / 439 (0.68%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile bone marrow aplasia
subjects affected / exposed	5 / 439 (1.14%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	5 / 5	2 / 2
deaths causally related to treatment / all	1 / 1	0 / 0
Febrile neutropenia
subjects affected / exposed	203 / 439 (46.24%)	42 / 222 (18.92%)
occurrences causally related to treatment / all	164 / 304	35 / 66
deaths causally related to treatment / all	2 / 6	1 / 1
Haemolytic anaemia
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic disorder
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic diathesis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	0 / 439 (0.00%)	4 / 222 (1.80%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Hypofibrinogenaemia
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphadenitis
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	13 / 439 (2.96%)	2 / 222 (0.90%)
occurrences causally related to treatment / all	9 / 14	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Splenic infarction
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	23 / 439 (5.24%)	9 / 222 (4.05%)
occurrences causally related to treatment / all	21 / 28	7 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Blood loss anaemia
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Blindness transient
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Retinal haemorrhage
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anal ulcer
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anal haemorrhage
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	8 / 439 (1.82%)	2 / 222 (0.90%)
occurrences causally related to treatment / all	2 / 8	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	4 / 439 (0.91%)	3 / 222 (1.35%)
occurrences causally related to treatment / all	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Enteritis
subjects affected / exposed	3 / 439 (0.68%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	4 / 439 (0.91%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	2 / 4	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal inflammation
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gingival bleeding
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhoidal haemorrhage
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
subjects affected / exposed	2 / 439 (0.46%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Inguinal hernia strangulated
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus paralytic
subjects affected / exposed	1 / 439 (0.23%)	2 / 222 (0.90%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestinal haemorrhage
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Melaena
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mesenteric panniculitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mouth haemorrhage
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mouth ulceration
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic colitis
subjects affected / exposed	5 / 439 (1.14%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	3 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Odynophagia
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oral pain
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
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 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal ulcer
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	2 / 439 (0.46%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	6 / 439 (1.37%)	4 / 222 (1.80%)
occurrences causally related to treatment / all	5 / 6	3 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulum
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct stone
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
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	2 / 439 (0.46%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Hepatic function abnormal
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver injury
subjects affected / exposed	2 / 439 (0.46%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic cytolysis
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Drug eruption
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Erythema nodosum
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin haemorrhage
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin lesion
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Toxic skin eruption
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rash
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	19 / 439 (4.33%)	7 / 222 (3.15%)
occurrences causally related to treatment / all	3 / 22	1 / 7
deaths causally related to treatment / all	1 / 1	0 / 1
Haematuria
subjects affected / exposed	4 / 439 (0.91%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	2 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder obstruction
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	6 / 439 (1.37%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	3 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Back pain
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gouty arthritis
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bone pain
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Groin pain
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemarthrosis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neck pain
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteoporosis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Synovitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Anal abscess
subjects affected / exposed	3 / 439 (0.68%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	2 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anal infection
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Aspergillus infection
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacillus infection
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	5 / 439 (1.14%)	3 / 222 (1.35%)
occurrences causally related to treatment / all	1 / 6	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	4 / 439 (0.91%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	3 / 4	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Bronchitis
subjects affected / exposed	3 / 439 (0.68%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 3	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Bronchopulmonary aspergillosis
subjects affected / exposed	12 / 439 (2.73%)	3 / 222 (1.35%)
occurrences causally related to treatment / all	4 / 12	1 / 3
deaths causally related to treatment / all	0 / 1	0 / 0
Campylobacter sepsis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Catheter site infection
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis of male external genital organ
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	3 / 439 (0.68%)	6 / 222 (2.70%)
occurrences causally related to treatment / all	0 / 3	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium colitis
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colonic abscess
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Conjunctivitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (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	0 / 439 (0.00%)	2 / 222 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	5 / 439 (1.14%)	3 / 222 (1.35%)
occurrences causally related to treatment / all	1 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 439 (0.23%)	2 / 222 (0.90%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Enterobacter infection
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enteritis infectious
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterobacter sepsis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterococcal bacteraemia
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterococcal sepsis
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Enterocolitis infectious
subjects affected / exposed	3 / 439 (0.68%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epididymitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia infection
subjects affected / exposed	1 / 439 (0.23%)	2 / 222 (0.90%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	4 / 439 (0.91%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	4 / 5	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fungal infection
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fungal sepsis
subjects affected / exposed	3 / 439 (0.68%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Fungal skin infection
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Genital herpes
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	3 / 439 (0.68%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	1 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	2 / 439 (0.46%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Klebsiella infection
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Klebsiella sepsis
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Laryngitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Localised infection
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphadenitis bacterial
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (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	2 / 439 (0.46%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic infection
subjects affected / exposed	7 / 439 (1.59%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	6 / 8	1 / 1
deaths causally related to treatment / all	1 / 1	0 / 0
Myocarditis septic
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Neutropenic sepsis
subjects affected / exposed	2 / 439 (0.46%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oral herpes
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oral candidiasis
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oropharyngeal candidiasis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis fungal
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Parotitis
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Perichondritis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pharyngotonsillitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	113 / 439 (25.74%)	44 / 222 (19.82%)
occurrences causally related to treatment / all	51 / 127	13 / 49
deaths causally related to treatment / all	10 / 28	4 / 6
Pneumonia klebsiella
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia fungal
subjects affected / exposed	7 / 439 (1.59%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	2 / 8	0 / 1
deaths causally related to treatment / all	1 / 2	0 / 0
Pneumonia staphylococcal
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 1	1 / 1
Pseudomembranous colitis
subjects affected / exposed	2 / 439 (0.46%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prostatitis Escherichia coli
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pseudomonal sepsis
subjects affected / exposed	4 / 439 (0.91%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	2 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Pulmonary sepsis
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 1	1 / 1
Pseudomonas infection
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rash pustular
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory syncytial virus infection
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	7 / 439 (1.59%)	3 / 222 (1.35%)
occurrences causally related to treatment / all	1 / 7	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection fungal
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection viral
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	44 / 439 (10.02%)	9 / 222 (4.05%)
occurrences causally related to treatment / all	12 / 46	3 / 10
deaths causally related to treatment / all	3 / 17	1 / 3
Septic shock
subjects affected / exposed	28 / 439 (6.38%)	10 / 222 (4.50%)
occurrences causally related to treatment / all	9 / 31	7 / 10
deaths causally related to treatment / all	5 / 14	1 / 2
Sinusitis aspergillus
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	1 / 439 (0.23%)	3 / 222 (1.35%)
occurrences causally related to treatment / all	1 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Skin infection
subjects affected / exposed	4 / 439 (0.91%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	3 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sinusitis fungal
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	2 / 439 (0.46%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	1 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	3 / 439 (0.68%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Staphylococcal infection
subjects affected / exposed	2 / 439 (0.46%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Stenotrophomonas sepsis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Streptococcal sepsis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Testicular abscess
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tonsillitis bacterial
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tooth infection
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	5 / 439 (1.14%)	3 / 222 (1.35%)
occurrences causally related to treatment / all	1 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Tuberculosis
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Upper respiratory tract infection bacterial
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	12 / 439 (2.73%)	3 / 222 (1.35%)
occurrences causally related to treatment / all	3 / 12	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Vulvitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium bacteraemia
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematoma infection
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestine infection
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nasopharyngitis
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia influenzal
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia pseudomonal
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular device infection
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Acidosis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cachexia
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Decreased appetite
subjects affected / exposed	0 / 439 (0.00%)	2 / 222 (0.90%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fluid overload
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercreatininaemia
subjects affected / exposed	1 / 439 (0.23%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 439 (0.00%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypernatraemia
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 439 (0.23%)	1 / 222 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	2 / 439 (0.46%)	2 / 222 (0.90%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour lysis syndrome
subjects affected / exposed	2 / 439 (0.46%)	0 / 222 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Subjects assigned to Volasertib + Low-dose Cytarabine	Subjects assigned to Placebo + Low-dose Cytarabine
Total subjects affected by non serious adverse events
subjects affected / exposed	404 / 439 (92.03%)	203 / 222 (91.44%)
Vascular disorders
Haematoma
subjects affected / exposed	55 / 439 (12.53%)	20 / 222 (9.01%)
occurrences all number	64	25
Hypertension
subjects affected / exposed	31 / 439 (7.06%)	7 / 222 (3.15%)
occurrences all number	36	7
Hypotension
subjects affected / exposed	23 / 439 (5.24%)	9 / 222 (4.05%)
occurrences all number	28	10
General disorders and administration site conditions
Asthenia
subjects affected / exposed	64 / 439 (14.58%)	42 / 222 (18.92%)
occurrences all number	118	53
Chest pain
subjects affected / exposed	22 / 439 (5.01%)	8 / 222 (3.60%)
occurrences all number	29	8
Chills
subjects affected / exposed	26 / 439 (5.92%)	12 / 222 (5.41%)
occurrences all number	39	15
Fatigue
subjects affected / exposed	62 / 439 (14.12%)	29 / 222 (13.06%)
occurrences all number	95	43
Mucosal inflammation
subjects affected / exposed	63 / 439 (14.35%)	11 / 222 (4.95%)
occurrences all number	95	15
Oedema
subjects affected / exposed	36 / 439 (8.20%)	13 / 222 (5.86%)
occurrences all number	43	15
Oedema peripheral
subjects affected / exposed	75 / 439 (17.08%)	42 / 222 (18.92%)
occurrences all number	90	59
Pain
subjects affected / exposed	31 / 439 (7.06%)	10 / 222 (4.50%)
occurrences all number	34	10
Pyrexia
subjects affected / exposed	85 / 439 (19.36%)	58 / 222 (26.13%)
occurrences all number	132	79
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	76 / 439 (17.31%)	30 / 222 (13.51%)
occurrences all number	90	35
Cough
subjects affected / exposed	95 / 439 (21.64%)	21 / 222 (9.46%)
occurrences all number	121	25
Epistaxis
subjects affected / exposed	71 / 439 (16.17%)	28 / 222 (12.61%)
occurrences all number	99	33
Oropharyngeal pain
subjects affected / exposed	28 / 439 (6.38%)	4 / 222 (1.80%)
occurrences all number	33	4
Pleural effusion
subjects affected / exposed	17 / 439 (3.87%)	17 / 222 (7.66%)
occurrences all number	18	20
Psychiatric disorders
Insomnia
subjects affected / exposed	38 / 439 (8.66%)	21 / 222 (9.46%)
occurrences all number	51	21
Confusional state
subjects affected / exposed	22 / 439 (5.01%)	7 / 222 (3.15%)
occurrences all number	24	7
Investigations
Alanine aminotransferase increased
subjects affected / exposed	26 / 439 (5.92%)	16 / 222 (7.21%)
occurrences all number	31	29
Aspartate aminotransferase increased
subjects affected / exposed	19 / 439 (4.33%)	14 / 222 (6.31%)
occurrences all number	21	20
Electrocardiogram QT prolonged
subjects affected / exposed	32 / 439 (7.29%)	8 / 222 (3.60%)
occurrences all number	53	9
Weight decreased
subjects affected / exposed	39 / 439 (8.88%)	20 / 222 (9.01%)
occurrences all number	44	21
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	26 / 439 (5.92%)	9 / 222 (4.05%)
occurrences all number	27	9
Nervous system disorders
Headache
subjects affected / exposed	48 / 439 (10.93%)	23 / 222 (10.36%)
occurrences all number	74	32
Dizziness
subjects affected / exposed	43 / 439 (9.79%)	18 / 222 (8.11%)
occurrences all number	58	22
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	101 / 439 (23.01%)	28 / 222 (12.61%)
occurrences all number	142	50
Anaemia
subjects affected / exposed	137 / 439 (31.21%)	53 / 222 (23.87%)
occurrences all number	361	120
Thrombocytopenia
subjects affected / exposed	163 / 439 (37.13%)	59 / 222 (26.58%)
occurrences all number	605	195
Neutropenia
subjects affected / exposed	124 / 439 (28.25%)	34 / 222 (15.32%)
occurrences all number	449	93
Leukopenia
subjects affected / exposed	45 / 439 (10.25%)	23 / 222 (10.36%)
occurrences all number	114	38
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	47 / 439 (10.71%)	26 / 222 (11.71%)
occurrences all number	57	36
Abdominal pain upper
subjects affected / exposed	30 / 439 (6.83%)	14 / 222 (6.31%)
occurrences all number	34	18
Constipation
subjects affected / exposed	122 / 439 (27.79%)	55 / 222 (24.77%)
occurrences all number	156	71
Diarrhoea
subjects affected / exposed	116 / 439 (26.42%)	49 / 222 (22.07%)
occurrences all number	176	73
Nausea
subjects affected / exposed	123 / 439 (28.02%)	79 / 222 (35.59%)
occurrences all number	183	116
Stomatitis
subjects affected / exposed	75 / 439 (17.08%)	13 / 222 (5.86%)
occurrences all number	94	15
Vomiting
subjects affected / exposed	71 / 439 (16.17%)	27 / 222 (12.16%)
occurrences all number	97	36
Dyspepsia
subjects affected / exposed	22 / 439 (5.01%)	9 / 222 (4.05%)
occurrences all number	26	13
Skin and subcutaneous tissue disorders
Petechiae
subjects affected / exposed	73 / 439 (16.63%)	24 / 222 (10.81%)
occurrences all number	93	29
Alopecia
subjects affected / exposed	30 / 439 (6.83%)	4 / 222 (1.80%)
occurrences all number	32	4
Pruritus
subjects affected / exposed	27 / 439 (6.15%)	17 / 222 (7.66%)
occurrences all number	45	22
Rash
subjects affected / exposed	72 / 439 (16.40%)	30 / 222 (13.51%)
occurrences all number	96	33
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	45 / 439 (10.25%)	30 / 222 (13.51%)
occurrences all number	58	32
Back pain
subjects affected / exposed	50 / 439 (11.39%)	18 / 222 (8.11%)
occurrences all number	59	24
Pain in extremity
subjects affected / exposed	30 / 439 (6.83%)	12 / 222 (5.41%)
occurrences all number	37	17
Infections and infestations
Oral herpes
subjects affected / exposed	31 / 439 (7.06%)	10 / 222 (4.50%)
occurrences all number	45	10
Oral candidiasis
subjects affected / exposed	25 / 439 (5.69%)	5 / 222 (2.25%)
occurrences all number	28	5
Pneumonia
subjects affected / exposed	38 / 439 (8.66%)	9 / 222 (4.05%)
occurrences all number	43	9
Urinary tract infection
subjects affected / exposed	24 / 439 (5.47%)	4 / 222 (1.80%)
occurrences all number	30	4
Nasopharyngitis
subjects affected / exposed	18 / 439 (4.10%)	13 / 222 (5.86%)
occurrences all number	24	17
Metabolism and nutrition disorders
Hyperuricaemia
subjects affected / exposed	13 / 439 (2.96%)	13 / 222 (5.86%)
occurrences all number	14	24
Decreased appetite
subjects affected / exposed	82 / 439 (18.68%)	43 / 222 (19.37%)
occurrences all number	115	62
Hypoalbuminaemia
subjects affected / exposed	24 / 439 (5.47%)	14 / 222 (6.31%)
occurrences all number	30	29
Hypokalaemia
subjects affected / exposed	120 / 439 (27.33%)	37 / 222 (16.67%)
occurrences all number	166	48
Hypomagnesaemia
subjects affected / exposed	23 / 439 (5.24%)	13 / 222 (5.86%)
occurrences all number	27	14
Hypophosphataemia
subjects affected / exposed	22 / 439 (5.01%)	6 / 222 (2.70%)
occurrences all number	30	10

More information

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Were there any global substantial amendments to the protocol? Yes

18 Feb 2013

Amendment 1 was submitted because the volasertib vial size was to change with the next resupply to the sites. The amendment also included minor corrections and clarifications.

25 Jun 2013

Amendment 2 was issued to incorporate several minor corrections and clarifications in the clinical trial protocol (CTP).

26 Sep 2014

Amendment 3 was issued to specify that the database snapshot for the interim analysis was targeted as close as possible to the projected date of recruitment completion and was not to interfere with the completion of recruitment.

28 Nov 2014

Amendment 4 was issued and implemented without IRB/IEC/Competent Authority approval, as the changes involved administrative or logistical aspects only. The definition of CR and CRi were further refined. For CR, independence of red blood cell transfusions was defined as no transfusion for at least 7 days prior to response assessment, and it was specified that there is no minimum duration of response required. For CRi, it was clarified that incomplete blood count recovery includes red blood cells (with potential need for red blood cell transfusions).

29 Jan 2015

Amendment 5 which was issued and implemented immediately and communicated to all relevant investigators, competent authorities and ethics committees in a timely manner to eliminate hazard: 1. Inform investigators of the key results of the primary analysis 2. Unblind all patients currently on treatment 3. Allow patients to continue study treatment at the discretion of the investigators

24 May 2017

Amendment 6 was issued on 24 May 2017 after approval of the Institutional Review Board/Independent Ethics Committee/Competent Authority. After the final analysis (based on at least 574 Overal Survival) was conducted as planned, patients still on treatment and with clinical benefit from Volasertib and/or Low-dose Cytarabine were kept on treatment in this trial. The mandatory protocol procedures as well as data collection were reduced after the planned final analysis was conducted.

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.

The final analysis presented in this report was conducted after 574 OS events had occurred. The final analysis was exploratory and descriptive.

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