Flag of the European Union

EU Clinical Trials Register

Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:

interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC

clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
Clinical Trials Information System (CTIS).

The EU Clinical Trials Register currently displays 43871 clinical trials with a EudraCT protocol, of which 7290 are clinical trials conducted with subjects less than 18 years old. The register also displays information on 18700 older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).

Examples: Cancer AND drug name. Pneumonia AND sponsor name.
How to search [pdf]

Advanced Search:

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

< Back to search results

Clinical Trial Results:
A randomized, controlled, double-blind Phase III trial to compare the efficacy, safety and pharmacokinetics of GP2013 plus cyclophosphamide, vincristine, prednisone vs. MabThera® plus cyclophosphamide, vincristine, prednisone, followed by GP2013 or MabThera® maintenance therapy in patients with previously untreated, advanced stage follicular lymphoma

Summary
EudraCT number	2010-019522-13
Trial protocol	NL PT FR HU DE AT BG ES PL GR IT GB IE
Global end of trial date	22 Jan 2018

Results information
Results version number	v1(current)
This version publication date	06 Feb 2019
First version publication date	06 Feb 2019
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

CIGG013A2301J

ISRCTN number

-

US NCT number

NCT01419665

WHO universal trial number (UTN)

-

Sponsor organisation name

Hexal AG/ Novartis Pharmaceuticals

Sponsor organisation address

Industriestr. 25, Holzkirchen, Germany, D-83607

Public contact

Study Director, Hexal AG / Novartis, 41 613241111, novartis.email@novartis.com

Scientific contact

Study Director, Hexal AG / Novartis Pharmaceuticals, +41 613241111, novartis.email@novartis.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

22 Jan 2018

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

22 Jan 2018

Was the trial ended prematurely?

No

Main objective of the trial

The primary objective of this study was to demonstrate comparability of the overall response rate (ORR) in patients with previously untreated, advanced stage follicular lymphoma who received GP2013-CVP combination treatment to patients who received MabThera-CVP combination treatment.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

cyclophosphamide, vincristine, prednisone

Evidence for comparator

MabThera

Actual start date of recruitment

01 Dec 2011

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 27

Country: Number of subjects enrolled

Argentina: 5

Country: Number of subjects enrolled

Austria: 6

Country: Number of subjects enrolled

Bulgaria: 15

Country: Number of subjects enrolled

Brazil: 102

Country: Number of subjects enrolled

Colombia: 2

Country: Number of subjects enrolled

France: 9

Country: Number of subjects enrolled

Germany: 2

Country: Number of subjects enrolled

United Kingdom: 1

Country: Number of subjects enrolled

Greece: 9

Country: Number of subjects enrolled

Hungary: 14

Country: Number of subjects enrolled

India: 94

Country: Number of subjects enrolled

Ireland: 2

Country: Number of subjects enrolled

Israel: 12

Country: Number of subjects enrolled

Italy: 23

Country: Number of subjects enrolled

Japan: 29

Country: Number of subjects enrolled

Malaysia: 30

Country: Number of subjects enrolled

Netherlands: 17

Country: Number of subjects enrolled

Peru: 9

Country: Number of subjects enrolled

Poland: 41

Country: Number of subjects enrolled

Portugal: 33

Country: Number of subjects enrolled

Romania: 13

Country: Number of subjects enrolled

Russian Federation: 46

Country: Number of subjects enrolled

South Africa: 28

Country: Number of subjects enrolled

Spain: 37

Country: Number of subjects enrolled

Ukraine: 21

Worldwide total number of subjects

627

EEA total number of subjects

222

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)

461

From 65 to 84 years

166

85 years and over

0

Subject disposition

Top of page

Recruitment details

A total of 629 patients were randomized at 159 centers in 26 countries, 314 patients to GP2013 (312 patients treated) and 315 to MabThera. Of those 314 patients in the GP2013 group, 2 patients were randomized by error and discontinued before any treatment with GP2013. The number of patients in both treatment groups remained similar.

Screening details

full analysis set participants : GP2013 312 MabThera 315 safety set participants : GP2013 312 MabThera 315 per protocol set participants: GP2013 310 MabThera 312 pharmacokinetic analysis set 1 : GP2013 119 MabThera 120 immunogenicity analysis set: GP2013 275 MabThera 287 pharmacodynamic analysis set : GP2013 24 MabThera 24

Period 1 title

combination treatment

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

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

Are arms mutually exclusive

Yes

GP2013

Arm description

Experimental Type: Biological/Vaccine

Arm type

Experimental

Investigational medicinal product name

GP2013

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

GP2013 was provided as sterile, colorless, preservative-free liquid concentrate for solution for i.v. infusion. It was supplied at a concentration of 10 mg/mL in 500 mg (50 mL) single use vials.

MabThera

Arm description

Comparator Type: Biological/Vaccine

Arm type

Active comparator

Investigational medicinal product name

MabThera

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

MabThera (Roche Registration Ltd.) was provided as sterile, colorless, preservative-free liquid concentrate for solution for i.v. infusion. It was supplied at a concentration of 10 mg/mL in 500 mg (50 mL) single use vials.

Number of subjects in period 1	GP2013	MabThera
Started	312	315
Completed	274	274
Not completed	38	41
Adverse event, serious fatal	5	7
Physician decision	5	8
Consent withdrawn by subject	5	4
Adverse event, non-fatal	7	10
administrative problems	-	1
disease progression	10	9
Protocol deviation	6	2

Period 2 title

Maintenance treatment and/or follow up

Is this the baseline period?

No

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

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

Are arms mutually exclusive

Yes

GP2013

Arm description

Experimental Type: Biological/Vaccine

Arm type

Experimental

Investigational medicinal product name

GP2013

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

GP2013 was provided as sterile, colorless, preservative-free liquid concentrate for solution for i.v. infusion. It was supplied at a concentration of 10 mg/mL in 500 mg (50 mL) single use vials.

MabThera

Arm description

Comparator Type: Biological/Vaccine

Arm type

Active comparator

Investigational medicinal product name

MabThera

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

MabThera (Roche Registration Ltd.) was provided as sterile, colorless, preservative-free liquid concentrate for solution for i.v. infusion. It was supplied at a concentration of 10 mg/mL in 500 mg (50 mL) single use vials.

Number of subjects in period 2 ^[1]	GP2013	MabThera
Started	254	252
Completed	132	150
Not completed	122	102
Adverse event, serious fatal	1	2
Consent withdrawn by subject	6	6
Physician decision	5	2
Adverse event, non-fatal	11	7
switch to open label	44	39
administrative problems	-	6
Lost to follow-up	1	2
disease progression	53	37
Protocol deviation	1	1

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: numbers are correct

Period 3 title

open label phase

Is this the baseline period?

No

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

MabThera

Arm description

Experimental Type: Biological/Vaccine, all patients switched to MabThera

Arm type

all patients in this phase received MabThera

Investigational medicinal product name

No investigational medicinal product assigned in this arm

MabThera

Arm description

Comparator Type: Biological/Vaccine

Arm type

Active comparator

Investigational medicinal product name

MabThera

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

MabThera (Roche Registration Ltd.) was provided as sterile, colorless, preservative-free liquid concentrate for solution for i.v. infusion. It was supplied at a concentration of 10 mg/mL in 500 mg (50 mL) single use vials.

Number of subjects in period 3 ^[2]	MabThera	MabThera
Started	44	39
Completed	43	38
Not completed	1	1
Adverse event, serious fatal	1	-
disease progression	-	1

Notes
[2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: numbers are correct

Baseline characteristics

Top of page

Reporting group title

GP2013

Reporting group description

Experimental Type: Biological/Vaccine

Reporting group title

MabThera

Reporting group description

Comparator Type: Biological/Vaccine

Reporting group values	GP2013	MabThera	Total
Number of subjects	312	315	627
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	226	235	461
From 65-84 years	86	80	166
85 years and over	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	57.5 ± 11.86	56.4 ± 11.72	-
Sex: Female, Male
Units: Subjects
Female	181	169	350
Male	131	146	277
Race, Customized
Race
Units: Subjects
Asian	71	85	156
Black	6	3	9
Caucasian	214	207	421
Native American	2	5	7
Other	19	15	34
Ethnicity, Customized
Ethnicity
Units: Subjects
Chinese	5	6	11
Hispanic / Latino	59	68	127
Indian (Indian Subcontinent)	40	54	94
Mixed Ethnicity	8	3	11
Other	183	170	353
Unknown / missing	1	0	1
Japanese	16	14	30

End points

Top of page

Reporting group title

GP2013

Reporting group description

Experimental Type: Biological/Vaccine

Reporting group title

MabThera

Reporting group description

Comparator Type: Biological/Vaccine

Reporting group title

GP2013

Reporting group description

Experimental Type: Biological/Vaccine

Reporting group title

MabThera

Reporting group description

Comparator Type: Biological/Vaccine

Reporting group title

MabThera

Reporting group description

Experimental Type: Biological/Vaccine, all patients switched to MabThera

Reporting group title

MabThera

Reporting group description

Comparator Type: Biological/Vaccine

Primary: Overall response rate (ORR)

Top of page

End point title

Overall response rate (ORR)

End point description

ORR is defined as the proportion of patients whose best overall disease response was either CR or PR during the combination treatment period based on blinded independent central radiology review. Per protocol set.

End point type

Primary

End point timeframe

24 weeks

End point values	GP2013	MabThera
Number of subjects analysed	311	313
Units: percentage
number (confidence interval 90%)	87.1 (83.59 to 90.15)	87.5 (84.04 to 90.49)

comparison of ORR between the 2 arms

Statistical analysis description

Equivalence to be concluded if the entire 95% CI of the difference in ORR between both groups is within the pre-specified margin of (-12%, 12%).

Comparison groups

GP2013 v MabThera

Number of subjects included in analysis

624

Analysis specification

Pre-specified

Analysis type

equivalence ^[1]

Method

Binomial approximation

Parameter type

difference in ORR ( GP2013 –MabThera)

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-5.94

upper limit

5.14

Notes
[1] - The equivalence margin of + or - 12% was determined considering the variability of the point estimate of the add-on effect by taking a value lower than the lower boundary of the 95% CI for Rituximab+chemotherapy versus chemotherapy obtained from historical data.

Secondary: To evaluate the Complete Response (CR) rate during the combination treatment period

Top of page

End point title

To evaluate the Complete Response (CR) rate during the combination treatment period

End point description

Per protocol set

End point type

Secondary

End point timeframe

24 weeks

End point values	GP2013	MabThera
Number of subjects analysed	311	313
Units: participants	46	42

No statistical analyses for this end point

Secondary: To evaluate the Partial Response (PR) rate during the combination treatment period

Top of page

End point title

To evaluate the Partial Response (PR) rate during the combination treatment period

End point description

Per protocol set

End point type

Secondary

End point timeframe

24 weeks

End point values	GP2013	MabThera
Number of subjects analysed	311	313
Units: participants	225	232

No statistical analyses for this end point

Secondary: To evaluate the progression free survival (PFS) with up to 3 years of follow-up post randomization

Top of page

End point title

To evaluate the progression free survival (PFS) with up to 3 years of follow-up post randomization

End point description

Number of participants with progression free survival events. PFS was defined as the time from the date of randomization to the date of event defined as the first observation of documented disease progression or death due to any cause. full analysis set

End point type

Secondary

End point timeframe

3 years

End point values	GP2013	MabThera
Number of subjects analysed	312	315
Units: participants	97	78

PFS

Statistical analysis description

PFS evaluation was based on the investigators’ assessment of documented disease Progression. If a patient did not have an event, PFS was censored at the date of last adequate Tumor assessment. The PFS analysis contained data from the Combination Phase, the Maintenance Phase, the Open-label Phase, and the Follow-up Phase of the study.

Comparison groups

GP2013 v MabThera

Number of subjects included in analysis

627

Analysis specification

Pre-specified

Analysis type

^[2]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.97

upper limit

1.76

Notes
[2] - descriptive purposes, not powered for hypothesis testing

Secondary: Overall survival (OS) with up to 3 years of follow- up post randomization, as assessed by the number of deaths

Top of page

End point title

Overall survival (OS) with up to 3 years of follow- up post randomization, as assessed by the number of deaths

End point description

OS was defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died, OS was censored at the date of last contact. full analysis set

End point type

Secondary

End point timeframe

3 years

End point values	GP2013	MabThera
Number of subjects analysed	312	315
Units: participants	29	31

Overall Survival

Comparison groups

GP2013 v MabThera

Number of subjects included in analysis

627

Analysis specification

Pre-specified

Analysis type

^[3]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.55

upper limit

1.52

Notes
[3] - descriptive analysis, not powered for hypothesis testing

Secondary: To evaluate the incidence of immunogenicity (ADA formation) against GP2013 and MabThera (rituximab)

Top of page

End point title

To evaluate the incidence of immunogenicity (ADA formation) against GP2013 and MabThera (rituximab)

End point description

number of participants with confirmed positive ADA immunogenicity analysis set

End point type

Secondary

End point timeframe

24 weeks, 3 years

End point values	GP2013	MabThera
Number of subjects analysed	275	287
Units: participants
end of treatment combination phase (24 weeks)	1	2
end of treatment manintenance phase (3 years)	1	0

No statistical analyses for this end point

Secondary: To evaluate a PK marker following the treatment with GP2013-Chemotherapy and MabThera-Chemotherapy (Cmax)

Top of page

End point title

To evaluate a PK marker following the treatment with GP2013-Chemotherapy and MabThera-Chemotherapy (Cmax)

End point description

Cmax PK analysis set 1 Day 63 is the C4D1 (cycle 4 day 1) of the combination phase For descriptive purposes only, no hypothesis testing

End point type

Secondary

End point timeframe

day 63

End point values	GP2013	MabThera
Number of subjects analysed	119 ^[4]	120 ^[5]
Units: microg/mL
geometric mean (geometric coefficient of variation)	333.59 ± 41.09	331.93 ± 35.32

Notes
[4] - number of participants with data : 108
[5] - number of participants with data : 111

No statistical analyses for this end point

Secondary: To evaluate a PK marker following the treatment with GP2013-Chemotherapy and MabThera-Chemotherapy (Ctrough)

Top of page

End point title

To evaluate a PK marker following the treatment with GP2013-Chemotherapy and MabThera-Chemotherapy (Ctrough)

End point description

Cthrough PK analysis set 1 For descriptive purposes only, no hypothesis testing

End point type

Secondary

End point timeframe

day 63

End point values	GP2013	MabThera
Number of subjects analysed	119 ^[6]	120 ^[7]
Units: microg/mL
arithmetic mean (standard deviation)	66.42 ± 47.593	82.13 ± 61.526

Notes
[6] - number of participants with data : 104
[7] - number of participants with data : 110

No statistical analyses for this end point

Secondary: To evaluate a PD marker (peripheral CD19+ B-cell counts) following the treatment with GP2013 + Chemotherapy and MabThera- Chemotherapy

Top of page

End point title

To evaluate a PD marker (peripheral CD19+ B-cell counts) following the treatment with GP2013 + Chemotherapy and MabThera- Chemotherapy

End point description

AUEC (0-21d) PD analysis set For descriptive purposes only, no hypothesis testing

End point type

Secondary

End point timeframe

21 days

End point values	GP2013	MabThera
Number of subjects analysed	24 ^[8]	24 ^[9]
Units: %*day
geometric mean (geometric coefficient of variation)	1790 ± 23.5	1910 ± 13.3

Notes
[8] - number of participants with data : 19
[9] - number of participants with data : 18

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Timeframe for AE

Adverse event reporting additional description

AE additional description : Note that maintenance treatment phase data include the open label phase

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Combination GP2013+CVP

Reporting group description

Combination GP2013+CVP

Reporting group title

Combination MabThera+CVP

Reporting group description

Combination MabThera+CVP

Reporting group title

Maintenance GP2013

Reporting group description

Maintenance GP2013

Reporting group title

Maintenance MabThera

Reporting group description

Maintenance MabThera

Serious adverse events	Combination GP2013+CVP	Combination MabThera+CVP	Maintenance GP2013	Maintenance MabThera
Total subjects affected by serious adverse events
subjects affected / exposed	71 / 312 (22.76%)	63 / 315 (20.00%)	24 / 254 (9.45%)	21 / 252 (8.33%)
number of deaths (all causes)	4	5	2	2
number of deaths resulting from adverse events	3	2	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Invasive ductal breast carcinoma
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Circulatory collapse
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 312 (0.32%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral artery stenosis
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	1 / 254 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	1 / 254 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chills
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypothermia
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 312 (0.00%)	2 / 315 (0.63%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 312 (0.32%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 312 (0.32%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	4 / 312 (1.28%)	7 / 315 (2.22%)	1 / 254 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 4	2 / 8	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cytokine release syndrome
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug hypersensitivity
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Endometrial hyperplasia
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prostatism
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Scrotal swelling
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine haemorrhage
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal haemorrhage
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory distress syndrome
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	1 / 312 (0.32%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Asthmatic crisis
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis chronic
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 312 (0.00%)	6 / 315 (1.90%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 7	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	1 / 312 (0.32%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Laryngeal pain
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiogenic pulmonary oedema
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 312 (0.00%)	3 / 315 (0.95%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	1 / 254 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary arterial hypertension
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 312 (0.32%)	3 / 315 (0.95%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Pulmonary mass
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	1 / 254 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 312 (0.32%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Delirium
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mental disorder
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coagulation test abnormal
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lipase increased
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Head injury
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	3 / 312 (0.96%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	3 / 3	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multiple fractures
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Patella fracture
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pubis fracture
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	1 / 254 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	1 / 254 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Congenital cystic kidney disease
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hydrocele
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Polycystic liver disease
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 312 (0.32%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Cardiac failure
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Extrasystoles
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Palpitations
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prinzmetal angina
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	1 / 254 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervical cord compression
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dementia
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	1 / 254 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	1 / 254 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	2 / 254 (0.79%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Meningeal disorder
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Occipital neuralgia
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	2 / 312 (0.64%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular dementia
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 312 (0.00%)	2 / 315 (0.63%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	15 / 312 (4.81%)	9 / 315 (2.86%)	0 / 254 (0.00%)	2 / 252 (0.79%)
occurrences causally related to treatment / all	14 / 17	12 / 13	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	2 / 312 (0.64%)	2 / 315 (0.63%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	2 / 2	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Microcytic anaemia
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	4 / 312 (1.28%)	5 / 315 (1.59%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	2 / 4	5 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	2 / 312 (0.64%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	1 / 254 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	4 / 312 (1.28%)	6 / 315 (1.90%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 4	2 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute abdomen
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 312 (0.32%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis microscopic
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	3 / 312 (0.96%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 312 (0.32%)	3 / 315 (0.95%)	1 / 254 (0.39%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	1 / 1	1 / 3	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erosive duodenitis
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal hypomotility
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	1 / 254 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus paralytic
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 312 (0.00%)	3 / 315 (0.95%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mouth ulceration
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 312 (0.00%)	2 / 315 (0.63%)	1 / 254 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	1 / 312 (0.32%)	2 / 315 (0.63%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic cirrhosis
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Skin and subcutaneous tissue disorders
Drug eruption
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Toxic skin eruption
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anuria
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	1 / 254 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	2 / 254 (0.79%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oliguria
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pollakiuria
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal colic
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	2 / 312 (0.64%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	3 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Inappropriate antidiuretic hormone secretion
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 312 (0.00%)	2 / 315 (0.63%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Flank pain
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	1 / 254 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc disorder
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess limb
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	2 / 252 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	2 / 312 (0.64%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis infective
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	1 / 254 (0.39%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endometritis
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia infection
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Genital herpes
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Helicobacter infection
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis B
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	1 / 254 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 312 (0.32%)	1 / 315 (0.32%)	1 / 254 (0.39%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infectious pleural effusion
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malaria
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oral candidiasis
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peritonsillar abscess
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	3 / 312 (0.96%)	4 / 315 (1.27%)	3 / 254 (1.18%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	3 / 4	3 / 5	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Pneumonia pseudomonal
subjects affected / exposed	0 / 312 (0.00%)	0 / 315 (0.00%)	1 / 254 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	2 / 254 (0.79%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 312 (0.64%)	5 / 315 (1.59%)	1 / 254 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 2	2 / 5	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	3 / 312 (0.96%)	1 / 315 (0.32%)	1 / 254 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	2 / 3	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	2 / 2	1 / 1	0 / 0	0 / 0
Tooth infection
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	3 / 312 (0.96%)	1 / 315 (0.32%)	0 / 254 (0.00%)	2 / 252 (0.79%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 312 (0.32%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperuricaemia
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypervolaemia
subjects affected / exposed	0 / 312 (0.00%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	2 / 312 (0.64%)	1 / 315 (0.32%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	1 / 312 (0.32%)	0 / 315 (0.00%)	0 / 254 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Combination GP2013+CVP	Combination MabThera+CVP	Maintenance GP2013	Maintenance MabThera
Total subjects affected by non serious adverse events
subjects affected / exposed	262 / 312 (83.97%)	255 / 315 (80.95%)	141 / 254 (55.51%)	144 / 252 (57.14%)
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	41 / 312 (13.14%)	37 / 315 (11.75%)	5 / 254 (1.97%)	4 / 252 (1.59%)
occurrences all number	73	61	9	11
Vascular disorders
Hypertension
subjects affected / exposed	22 / 312 (7.05%)	15 / 315 (4.76%)	12 / 254 (4.72%)	12 / 252 (4.76%)
occurrences all number	28	17	15	13
Nervous system disorders
Dizziness
subjects affected / exposed	18 / 312 (5.77%)	12 / 315 (3.81%)	5 / 254 (1.97%)	2 / 252 (0.79%)
occurrences all number	19	12	6	2
Headache
subjects affected / exposed	29 / 312 (9.29%)	34 / 315 (10.79%)	12 / 254 (4.72%)	14 / 252 (5.56%)
occurrences all number	45	51	19	18
Neuropathy peripheral
subjects affected / exposed	49 / 312 (15.71%)	30 / 315 (9.52%)	8 / 254 (3.15%)	2 / 252 (0.79%)
occurrences all number	78	43	8	3
Paraesthesia
subjects affected / exposed	24 / 312 (7.69%)	44 / 315 (13.97%)	7 / 254 (2.76%)	4 / 252 (1.59%)
occurrences all number	33	61	7	5
Peripheral sensory neuropathy
subjects affected / exposed	26 / 312 (8.33%)	23 / 315 (7.30%)	6 / 254 (2.36%)	5 / 252 (1.98%)
occurrences all number	39	33	7	7
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	25 / 312 (8.01%)	28 / 315 (8.89%)	2 / 254 (0.79%)	5 / 252 (1.98%)
occurrences all number	55	58	2	5
Leukopenia
subjects affected / exposed	23 / 312 (7.37%)	25 / 315 (7.94%)	11 / 254 (4.33%)	5 / 252 (1.98%)
occurrences all number	56	57	15	9
Neutropenia
subjects affected / exposed	78 / 312 (25.00%)	91 / 315 (28.89%)	32 / 254 (12.60%)	16 / 252 (6.35%)
occurrences all number	177	220	41	21
General disorders and administration site conditions
Asthenia
subjects affected / exposed	30 / 312 (9.62%)	31 / 315 (9.84%)	12 / 254 (4.72%)	11 / 252 (4.37%)
occurrences all number	40	46	14	11
Fatigue
subjects affected / exposed	35 / 312 (11.22%)	31 / 315 (9.84%)	6 / 254 (2.36%)	10 / 252 (3.97%)
occurrences all number	59	41	6	12
Oedema peripheral
subjects affected / exposed	13 / 312 (4.17%)	24 / 315 (7.62%)	4 / 254 (1.57%)	11 / 252 (4.37%)
occurrences all number	13	37	4	13
Pyrexia
subjects affected / exposed	27 / 312 (8.65%)	32 / 315 (10.16%)	12 / 254 (4.72%)	13 / 252 (5.16%)
occurrences all number	38	44	15	15
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	28 / 312 (8.97%)	35 / 315 (11.11%)	6 / 254 (2.36%)	7 / 252 (2.78%)
occurrences all number	35	46	6	9
Abdominal pain upper
subjects affected / exposed	20 / 312 (6.41%)	16 / 315 (5.08%)	4 / 254 (1.57%)	7 / 252 (2.78%)
occurrences all number	24	17	4	9
Constipation
subjects affected / exposed	69 / 312 (22.12%)	64 / 315 (20.32%)	8 / 254 (3.15%)	10 / 252 (3.97%)
occurrences all number	95	98	8	13
Diarrhoea
subjects affected / exposed	39 / 312 (12.50%)	33 / 315 (10.48%)	11 / 254 (4.33%)	18 / 252 (7.14%)
occurrences all number	55	48	14	19
Nausea
subjects affected / exposed	51 / 312 (16.35%)	42 / 315 (13.33%)	11 / 254 (4.33%)	8 / 252 (3.17%)
occurrences all number	77	66	11	8
Vomiting
subjects affected / exposed	22 / 312 (7.05%)	26 / 315 (8.25%)	6 / 254 (2.36%)	12 / 252 (4.76%)
occurrences all number	34	38	9	12
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	32 / 312 (10.26%)	37 / 315 (11.75%)	33 / 254 (12.99%)	23 / 252 (9.13%)
occurrences all number	40	44	38	28
Dyspnoea
subjects affected / exposed	16 / 312 (5.13%)	17 / 315 (5.40%)	5 / 254 (1.97%)	4 / 252 (1.59%)
occurrences all number	18	24	5	4
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	31 / 312 (9.94%)	26 / 315 (8.25%)	1 / 254 (0.39%)	1 / 252 (0.40%)
occurrences all number	34	27	1	1
Psychiatric disorders
Insomnia
subjects affected / exposed	15 / 312 (4.81%)	19 / 315 (6.03%)	3 / 254 (1.18%)	4 / 252 (1.59%)
occurrences all number	17	22	5	4
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	19 / 312 (6.09%)	21 / 315 (6.67%)	9 / 254 (3.54%)	21 / 252 (8.33%)
occurrences all number	20	27	11	26
Back pain
subjects affected / exposed	26 / 312 (8.33%)	30 / 315 (9.52%)	14 / 254 (5.51%)	14 / 252 (5.56%)
occurrences all number	30	45	17	20
Myalgia
subjects affected / exposed	17 / 312 (5.45%)	20 / 315 (6.35%)	4 / 254 (1.57%)	3 / 252 (1.19%)
occurrences all number	22	27	4	4
Pain in extremity
subjects affected / exposed	19 / 312 (6.09%)	24 / 315 (7.62%)	7 / 254 (2.76%)	14 / 252 (5.56%)
occurrences all number	22	31	10	19
Infections and infestations
Influenza
subjects affected / exposed	16 / 312 (5.13%)	7 / 315 (2.22%)	7 / 254 (2.76%)	8 / 252 (3.17%)
occurrences all number	17	8	9	11
Upper respiratory tract infection
subjects affected / exposed	22 / 312 (7.05%)	22 / 315 (6.98%)	12 / 254 (4.72%)	17 / 252 (6.75%)
occurrences all number	25	35	15	29
Urinary tract infection
subjects affected / exposed	27 / 312 (8.65%)	22 / 315 (6.98%)	14 / 254 (5.51%)	25 / 252 (9.92%)
occurrences all number	34	33	19	35
Viral upper respiratory tract infection
subjects affected / exposed	8 / 312 (2.56%)	10 / 315 (3.17%)	5 / 254 (1.97%)	15 / 252 (5.95%)
occurrences all number	9	10	7	28
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	17 / 312 (5.45%)	21 / 315 (6.67%)	3 / 254 (1.18%)	4 / 252 (1.59%)
occurrences all number	20	25	3	4
Hyperglycaemia
subjects affected / exposed	17 / 312 (5.45%)	22 / 315 (6.98%)	4 / 254 (1.57%)	9 / 252 (3.57%)
occurrences all number	28	48	4	11
Hyperuricaemia
subjects affected / exposed	8 / 312 (2.56%)	18 / 315 (5.71%)	5 / 254 (1.97%)	10 / 252 (3.97%)
occurrences all number	9	22	5	14

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

27 Feb 2012

The key purpose of this protocol amendment was to update and clearly define the attributes of the study inclusion and exclusion criteria, revise the recommended dose modification per current clinical practice, and change the primary ORR analysis from local to central blinded review of radiological response.

21 Jan 2013

The primary purpose of this amendment was to allow lymph node biopsy samples collected within 5 months of screening to establish and confirm the diagnosis of follicular lymphoma. As follicular lymphoma is a slowly progressing disease and lymph node biopsy is considered an invasive procedure, lymph node biopsy samples collected within 5 months of screening were allowed to confirm patient eligibility. To simplify the assessment and interpretation of tuberculosis testing at Screening, the status of active tuberculosis infection was assessed as per the local standard of care for patient eligibility. Furthermore, the population PK of GP2013 and MabThera was removed in the amendment as this analysis was not deemed necessary to compare the PK of GP2013 and MabThera.

26 Sep 2013

The primary reason for this protocol amendment was to add a planned interim analysis (based on specific health authority feedback) to support the regulatory filing of GP2013 with EMA and potentially other health authorities.

10 Nov 2014

this amendment was based on health authority feedback received in Feb-2014, which led to the removal of the planned interim analysis added in protocol amendment version 4.0.

09 Jun 2016

The amendment text clarified that blinded monitors, medical monitors, data management, investigator site staff, and patients would be kept blinded (with the exception of the coordinating investigator who has to sign the CSR for the Combination Phase) until the final DBL.

23 Feb 2017

This amendment described a Urgent Safety Measure that was issued on 22-Dec-2016. The clinical batch of GP2013 was quarantined due to out-of-specification findings in routine stability testing.

Were there any global interruptions to the trial? No

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

None reported

For support, Contact us.

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

European Medicines Agency © 1995-Sun May 05 09:58:15 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands