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Clinical Trial Results:
A Multicenter, Phase III, Open-Label, Randomized Study in Previously Untreated Patients With Advanced Indolent Non-Hodgkin's Lymphoma Evaluating the Benefit of GA101 (RO5072759) Plus Chemotherapy Compared with Rituximab Plus Chemotherapy Followed by GA101 or Rituximab Maintenance Therapy in Responders

Summary
EudraCT number	2010-024132-41
Trial protocol	BE GB CZ SE DE HU FR ES IT FI
Global end of trial date	30 Jul 2021

Results information
Results version number	v3(current)
This version publication date	25 Aug 2022
First version publication date	16 Mar 2017
Other versions	v1 , v2
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

BO21223

ISRCTN number

US NCT number

NCT01332968

WHO universal trial number (UTN)

Other trial identifiers

Study name: GALLIUM

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

30 Jul 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

31 Jan 2016

Global end of trial reached?

Yes

Global end of trial date

30 Jul 2021

Was the trial ended prematurely?

Main objective of the trial

To assess the efficacy of obinutuzumab (RO5072759) in combination with chemotherapy compared to rituximab (MabThera/Rituxan) with chemotherapy followed by obinutuzumab or rituximab maintenance in subjects with previously untreated advanced follicular non-Hodgkin's lymphoma.

Protection of trial subjects

All study subjects were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

06 Jul 2011

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

China: 58

Country: Number of subjects enrolled

Japan: 129

Country: Number of subjects enrolled

Taiwan: 4

Country: Number of subjects enrolled

Czechia: 100

Country: Number of subjects enrolled

Hungary: 71

Country: Number of subjects enrolled

Russian Federation: 12

Country: Number of subjects enrolled

Canada: 138

Country: Number of subjects enrolled

United States: 31

Country: Number of subjects enrolled

Australia: 135

Country: Number of subjects enrolled

Israel: 6

Country: Number of subjects enrolled

Belgium: 35

Country: Number of subjects enrolled

Germany: 237

Country: Number of subjects enrolled

Spain: 48

Country: Number of subjects enrolled

Finland: 4

Country: Number of subjects enrolled

France: 30

Country: Number of subjects enrolled

United Kingdom: 294

Country: Number of subjects enrolled

Italy: 59

Country: Number of subjects enrolled

Sweden: 10

Worldwide total number of subjects

1401

EEA total number of subjects

594

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

937

From 65 to 84 years

454

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 177 centers in 18 countries.

Screening details

Eleven patients withdrew from the study after randomization but prior to receiving study treatment.

Period 1 title

Overall Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Rituximab+Chemotherapy – Induction

Arm description

Arm type

Active comparator

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 750 milligrams per square metre (mg/m^2) will be administered intravenously (IV) on Day 1 of each cycle during induction period.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Doxorubicin 50 mg/m^2 IV will be administered on Day 1 of each cycle during induction period.

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Vincristine 1.4 mg/m^2 (maximum 2 mg) IV will be administered on Day 1 of each cycle during induction period.

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone 100 mg (or equivalent prednisolone or methylprednisolone) will be administered orally on Days 1-5 of each cycle during induction period

Investigational medicinal product name

Bendamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Bendamustine 90 mg/m^2 IV infusion will be administered on Days 1 and 2 of each cycle during induction period.

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

MabThera/Rituxan

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab 375 mg/m^2 IV infusion will be administered on Day 1 of each cycle during induction period and rituximab 375 mg/m^2 every 2 months during maintenance period.

Obinutuzumab+Chemotherapy – Induction

Arm description

Arm type

Experimental

Investigational medicinal product name

Obinutuzumab

Investigational medicinal product code

Other name

GA101; RO5072759

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Obinutuzumab 1000 mg IV infusion will be administered on Day 1, 8, and 15 of Cycle 1 and then on Day 1 of each subsequent cycle during induction period and obinutuzumab 1000 mg IV infusion every 2 months during maintenance period.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 750 mg/m^2 IV will be administered on Day 1 of each cycle during induction period.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Doxorubicin 50 mg/m^2 IV will be administered on Day 1 of each cycle during induction period.

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Vincristine 1.4 mg/m^2 (maximum 2 mg) IV will be administered on Day 1 of each cycle during induction period.

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone 100 mg (or equivalent prednisolone or methylprednisolone) will be administered orally on Days 1-5 of each cycle during induction period

Investigational medicinal product name

Bendamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Bendamustine 90 mg/m^2 IV infusion will be administered on Days 1 and 2 of each cycle during induction period.

Rituximab+Chemotherapy – Maintenance

Arm description

The induction period was followed by either a maintenance or observation period for responders or non-responders, respectively. Responders received rituximab monotherapy every 2 months for 2 years during the maintenance period.

Arm type

Active comparator

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

MabThera/Rituxan

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab 375 mg/m^2 IV infusion will be administered on Day 1 of each cycle during induction period and rituximab 375 mg/m^2 every 2 months during maintenance period.

Obinutuzumab+Chemotherapy – Maintenance

Arm description

The induction period was followed by either a maintenance or observation period for responders or non-responders, respectively. Responders received obinutuzumab monotherapy every 2 months for 2 years during the maintenance period.

Arm type

Experimental

Investigational medicinal product name

Obinutuzumab

Investigational medicinal product code

Other name

GA101; RO5072759

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab+Chemotherapy – Observation

Arm description

The induction period was followed by either a maintenance or observation period for responders or non-responders, respectively. Non-responders received no protocol specified treatment during the 2-year observation period.

Arm type

Active comparator

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

MabThera/Rituxan

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab 375 mg/m^2 IV infusion will be administered on Day 1 of each cycle during induction period and rituximab 375 mg/m^2 every 2 months during maintenance period.

Obinutuzumab+Chemotherapy – Observation

Arm description

Arm type

Experimental

Investigational medicinal product name

Obinutuzumab

Investigational medicinal product code

Other name

GA101; RO5072759

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab+Chemotherapy – Follow-up

Arm description

Finally, subjects were followed during a 5-year follow-up period.

Arm type

Active comparator

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

MabThera/Rituxan

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab 375 mg/m^2 IV infusion will be administered on Day 1 of each cycle during induction period and rituximab 375 mg/m^2 every 2 months during maintenance period.

Obinutuzumab+Chemotherapy – Follow-up

Arm description

Finally, subjects were followed during a 5-year follow-up period.

Arm type

Experimental

Investigational medicinal product name

Obinutuzumab

Investigational medicinal product code

Other name

GA101; RO5072759

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Number of subjects in period 1	Rituximab+Chemotherapy – Induction	Obinutuzumab+Chemotherapy – Induction	Rituximab+Chemotherapy – Maintenance	Obinutuzumab+Chemotherapy – Maintenance	Rituximab+Chemotherapy – Observation	Obinutuzumab+Chemotherapy – Observation	Rituximab+Chemotherapy – Follow-up	Obinutuzumab+Chemotherapy – Follow-up
Started	699	702	612	624	12	11	554	602
Completed	641	646	451	475	12	10	324	367
Not completed	58	56	161	149	0	1	230	235
Physician decision	6	1	14	19	-	1	12	15
Adverse Event	23	26	53	66	-	-	-	4
Death	1	4	5	6	-	-	27	30
Progressive Disease	15	7	72	40	-	-	126	106
Not Specified	2	2	4	7	-	-	18	21
Non-compliance	1	-	4	3	-	-	4	9
Randomised but not treated	4	7	-	-	-	-	-	-
Withdrawal by Subject	3	5	7	5	-	-	29	32
Lost to follow-up	-	-	1	2	-	-	11	15
Protocol deviation	3	4	1	1	-	-	1	-
No reason provided	-	-	-	-	-	-	2	3

Baseline characteristics

Top of page

Reporting group title

Overall Period

Reporting group description

Reporting group values	Overall Period	Total
Number of subjects	1401	1401
Age Categorical
Units: Subjects
Adults (18-64 years)	937	937
From 65-84 years	454	454
85 years and over	10	10
Age Continuous
Units: years
arithmetic mean (standard deviation)	58.5 ± 11.9	-
Gender Categorical
Units: Subjects
Female	739	739
Male	662	662
Age Continuous in Follicular Lymphoma Sub-Population
Age continuous for subjects with follicular lymphoma, who encompassed the population for the primary endpoint (n=601 for each arm in the follicular lymphoma intent-to-treat population).
Units: years
arithmetic mean (standard deviation)	57.9 ± 11.9	-

Subject analysis set title

Rituximab+Chemotherapy

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects received either 8 cycles of rituximab along with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (21-day cycle) or 8 cycles of rituximab along with 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) (21-day cycles) or 6 cycles of rituximab along with 6 cycles of bendamustine (28-day cycle) during the induction period. The induction period was followed by either a maintenance or observation period for responders or non-responders, respectively. Responders received rituximab monotherapy every 2 months for 2 years during the maintenance period. Non-responders received no protocol specified treatment during the 2-year observation period. Finally, subjects were followed during a 5-year follow-up period. The chemotherapy regimen (CHOP or CVP or bendamustine) for individual subject was chosen by the site prior to initiation of the study.

Subject analysis set title

Obinutuzumab+Chemotherapy

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects received either 8 cycles of obinutuzumab along with 6 cycles of CHOP (21-day cycle) or 8 cycles of obinutuzumab along with 8 cycles of CVP (21-day cycles) or 6 cycles of obinutuzumab along with 6 cycles of bendamustine (28-day cycle) during induction period. The induction period was followed by either a maintenance or observation period for responders or non-responders, respectively. Responders received obinutuzumab monotherapy every 2 months for 2 years during the maintenance period. Non-responders received no protocol specified treatment during the 2-year observation period. Finally, subjects were followed during a 5-year follow-up period. The chemotherapy regimen (CHOP or CVP or bendamustine) for individual subject was chosen by the site prior to initiation of the study.

Subject analysis sets values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects	699	702
Age Categorical
Units: Subjects
Adults (18-64 years)	473	464
From 65-84 years	221	233
85 years and over	5	5
Age Continuous
Units: years
arithmetic mean (standard deviation)	58.1 ± 12.3	58.9 ± 11.6
Gender Categorical
Units: Subjects
Female	374	365
Male	325	337
Age Continuous in Follicular Lymphoma Sub-Population
Age continuous for subjects with follicular lymphoma, who encompassed the population for the primary endpoint (n=601 for each arm in the follicular lymphoma intent-to-treat population).
Units: years
arithmetic mean (standard deviation)	57.7 ± 12.2	58.2 ± 11.5

End points

Top of page

Reporting group title

Rituximab+Chemotherapy – Induction

Reporting group description

Reporting group title

Obinutuzumab+Chemotherapy – Induction

Reporting group description

Reporting group title

Rituximab+Chemotherapy – Maintenance

Reporting group description

Reporting group title

Obinutuzumab+Chemotherapy – Maintenance

Reporting group description

Reporting group title

Rituximab+Chemotherapy – Observation

Reporting group description

Reporting group title

Obinutuzumab+Chemotherapy – Observation

Reporting group description

Reporting group title

Rituximab+Chemotherapy – Follow-up

Reporting group description

Finally, subjects were followed during a 5-year follow-up period.

Reporting group title

Obinutuzumab+Chemotherapy – Follow-up

Reporting group description

Finally, subjects were followed during a 5-year follow-up period.

Subject analysis set title

Rituximab+Chemotherapy

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Obinutuzumab+Chemotherapy

Subject analysis set type

Intention-to-treat

Subject analysis set description

Primary: Progression-Free Survival (PFS) in the Follicular Lymphoma Population, Investigator-Assessed

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End point title

Progression-Free Survival (PFS) in the Follicular Lymphoma Population, Investigator-Assessed

End point description

PFS in subjects with follicular lymphoma was defined as the time from randomisation until the first documented day of disease progression or death from any cause, whichever occurred first, on the basis of investigator assessments according to the Revised Response Criteria for Malignant Lymphoma. Progression was defined as at least 50% increase in nodal lesions or >/=50% increase in any node > 1 centimetre (cm) or >/= 50% increase in other target measurable lesions and/or appearance of any new bone marrow involvement and/or appearance of any new lesion > 1.5 cm or >/= 50% increase in any previously involved node with a diameter </= 1 cm such that it is now >1.5 cm. Tumour measurements were obtained by computed tomography (CT) or magnetic resonance imaging (MRI). FL ITT population was defined as all randomized participants with follicular histology, where participants were grouped according to their randomized treatment arm regardless of what treatments were actually received.

End point type

Primary

End point timeframe

Baseline up to data cut-off (up to approximately 4 years and 7 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	601	601
Units: percentage of subjects with event
number (not applicable)	24.0	16.8

Rituximab versus Obinutuzumab

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0012 ^[1]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.66

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

0.85

Notes
[1] - Stratified by chemotherapy regimen and Follicular Lymphoma International Prognostic Index (FLIPI) risk group.

Secondary: Progression-Free Survival in the Follicular Lymphoma Population, Investigator-Assessed

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End point title

Progression-Free Survival in the Follicular Lymphoma Population, Investigator-Assessed

End point description

End point type

Secondary

End point timeframe

Baseline up to final analysis (up to 10 years)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	601	601
Units: percentage of subjects with event
number (not applicable)	40.6	34.3

Rituximab versus Obinutuzumab

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0055

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.64

upper limit

0.93

Secondary: Progression-Free Survival in the Overall Study Population, Investigator-Assessed

Top of page

End point title

Progression-Free Survival in the Overall Study Population, Investigator-Assessed

End point description

PFS in the overall study population was defined as the time from randomisation until the first documented day of disease progression or death from any cause, whichever occurred first, on the basis of investigator assessments according to the Revised Response Criteria for Malignant Lymphoma. Progression was defined as at least 50% increase in nodal lesions or >/=50% increase in any node > 1 centimeter (cm) or >/= 50% increase in other target measurable lesions (e.g., splenic or hepatic nodules) and/or appearance of any new bone marrow involvement and/or appearance of any new lesion > 1.5 cm or >/= 50% increase in any previously involved node with a diameter </= 1 cm such that it is now >1.5 cm. Tumour measurements were obtained by CT/MRI. The ITT population was defined as all randomised subjects grouped according to their randomised treatment arm regardless of what treatments were actually received.

End point type

Secondary

End point timeframe

Baseline up to data cut-off (up to approximately 5 years and 2 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	699	702
Units: percentage of subjects with event
number (not applicable)	41.5	34.8

Rituximab versus Obinutuzumab

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0028

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.65

upper limit

0.91

Secondary: Progression-Free Survival (PFS) (Follicular Lymphoma Population), IRC-Assessed

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End point title

Progression-Free Survival (PFS) (Follicular Lymphoma Population), IRC-Assessed

End point description

PFS in the subjects with follicular lymphoma was defined as the time from randomisation until the first documented day of disease progression or death from any cause, whichever occurred first, on the basis of IRC assessments according to the Revised Response Criteria for Malignant Lymphoma. Progression was defined as at least 50% increase in nodal lesions or >/=50% increase in any node > 1 centimeter (cm) or >/= 50% increase in other target measurable lesions (e.g., splenic or hepatic nodules) and/or appearance of any new bone marrow involvement and/or appearance of any new lesion > 1.5 cm or >/= 50% increase in any previously involved node with a diameter </= 1 cm such that it is now >1.5 cm. Tumour measurements were obtained by CT/MRI. The FL ITT population was defined as all randomised subjects with follicular histology grouped according to their randomised treatment arm regardless of what treatments were actually received.

End point type

Secondary

End point timeframe

Baseline up to data cut-off (up to approximately 5 years and 2 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	601	601
Units: percentage of subjects with event
number (not applicable)	23.5	18.0

Rituximab versus Obinutuzumab

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0118

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.72

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

0.93

Secondary: Progression-Free Survival (PFS) (Overall Study Population), Assessed by Independent Review Committee (IRC)

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End point title

Progression-Free Survival (PFS) (Overall Study Population), Assessed by Independent Review Committee (IRC)

End point description

PFS in the overall study population was defined as the time from randomisation until the first documented day of disease progression or death from any cause, whichever occurred first, on the basis of IRC assessments according to the Revised Response Criteria for Malignant Lymphoma. Progression was defined as at least 50% increase in nodal lesions or >/=50% increase in any node > 1 centimeter (cm) or >/= 50% increase in other target measurable lesions (e.g., splenic or hepatic nodules) and/or appearance of any new bone marrow involvement and/or appearance of any new lesion > 1.5 cm or >/= 50% increase in any previously involved node with a diameter </= 1 cm such that it is now >1.5 cm. Tumour measurements were obtained by CT/MRI. The ITT population was defined as all randomised subjects grouped according to their randomised treatment arm regardless of what treatments were actually received.

End point type

Secondary

End point timeframe

Baseline up to data cut-off (up to approximately 5 years and 2 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	699	702
Units: percentage of subjects with event
number (not applicable)	24.6	18.4

Rituximab versus Obinutuzumab

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0038

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.71

Confidence interval

level

95%

sides

2-sided

lower limit

0.57

upper limit

0.9

Secondary: Overall Response (Follicular Lymphoma Population), Investigator-Assessed

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End point title

Overall Response (Follicular Lymphoma Population), Investigator-Assessed

End point description

Percentage of subjects with overall response in the follicular lymphoma population was defined as percentage of subjects with PR or complete response CR determined on the basis of investigator assessments with the use of Revised Response Criteria for Malignant Lymphoma. Tumour assessments were performed with CT/MRI with or without PET. CR was defined as disappearance of all target lesions; PR was defined as >=50% decrease target lesions in up to six dominant lesions identified at baseline, no new lesions and no increase in the size of the liver, spleen, or other nodes. Splenic and hepatic nodules must have regressed by >/= 50%. Overall Response (OR) = CR + PR. The FL ITT population was defined as all randomised subjects with follicular histology grouped according to their randomised treatment arm regardless of what treatments were actually received.

End point type

Secondary

End point timeframe

Baseline up to end of induction period (up to approximately 7 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	601	601
Units: percentage of subjects with event
number (not applicable)
Without PET (n=519, 530)	86.4	88.2
With PET (n=242, 254)	81.2	85.5

Without PET

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3

Method

Logrank

Parameter type

Absolute difference in %

Point estimate

1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-2.02

upper limit

5.68

With PET

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.17

Method

Logrank

Parameter type

Absolute difference in %

Point estimate

4.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1.8

upper limit

10.5

Secondary: Overall Response (Overall Study Population), Investigator-Assessed

Top of page

End point title

Overall Response (Overall Study Population), Investigator-Assessed

End point description

Percentage of subjects with overall response in the overall study population was defined as percentage of subjects with partial response (PR) or complete response (CR) determined on the basis of investigator assessments with the use of Revised Response Criteria for Malignant Lymphoma. Tumour assessments were performed with CT/MRI with or without positron emission tomography (PET). CR was defined as disappearance of all target lesions; PR was defined as >=50% decrease target lesions in up to six dominant lesions identified at baseline, no new lesions and no increase in the size of the liver, spleen, or other nodes. Splenic and hepatic nodules must have regressed by >/= 50%; Overall Response (OR) = CR + PR. The ITT population was defined as all randomised subjects grouped according to their randomised treatment arm regardless of what treatments were actually received.

End point type

Secondary

End point timeframe

Baseline up to end of induction period (up to approximately 7 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	699	702
Units: percentage of subjects with event
number (not applicable)
Without PET (n=599, 613)	85.7	87.3
With PET (n=270, 274)	81.8	85.4

With PET

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.17

Method

Logrank

Parameter type

Absolute difference in %

Point estimate

3.5

Confidence interval

level

95%

sides

2-sided

lower limit

-2.3

upper limit

9.4

Without PET

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.33

Method

Logrank

Parameter type

Absolute difference in %

Point estimate

1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

5.3

Secondary: Complete Response (Follicular Lymphoma Population), Investigator-Assessed

Top of page

End point title

Complete Response (Follicular Lymphoma Population), Investigator-Assessed

End point description

Complete response in the follicular lymphoma population was determined on the basis of investigator assessments with the use of Revised Response Criteria for Malignant Lymphoma. Tumour assessments were performed with CT/MRI with or without PET. CR was defined as disappearance of all target lesions. The FL ITT population was defined as all randomised subjects with follicular histology grouped according to their randomised treatment arm regardless of what treatments were actually received.

End point type

Secondary

End point timeframe

Baseline up to end of induction period (up to approximately 7 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	601	601
Units: percentage of subjects with event
number (not applicable)
Without PET (n=145, 112)	24.1	18.6
With PET (n=169, 184)	56.7	62.0

Without PET

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.02

Method

Logrank

Parameter type

Absolute difference in %

Point estimate

-5.5

Confidence interval

level

95%

sides

2-sided

lower limit

-10.2

upper limit

-0.78

With PET

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.32

Method

Logrank

Parameter type

Absolute difference in %

Point estimate

5.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.8

upper limit

13.3

Secondary: Complete Response (Overall Study Population), Investigator-Assessed

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End point title

Complete Response (Overall Study Population), Investigator-Assessed

End point description

Complete response in the overall study population was determined on the basis of investigator assessments with the use of Revised Response Criteria for Malignant Lymphoma. Tumor assessments were performed with CT/MRI with or without PET. CR was defined as disappearance of all target lesions. The ITT population was defined as all randomised subjects grouped according to their randomised treatment arm regardless of what treatments were actually received. Reported is the percentage of subjects with event.

End point type

Secondary

End point timeframe

Baseline up to end of induction period (up to approximately 7 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	699	702
Units: percentage of subjects with event
number (not applicable)
Without PET (n=163, 129)	23.3	18.4
With PET (n=188, 196)	57.0	61.1

With PET

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.33

Method

Logrank

Parameter type

Absolute difference in %

Point estimate

4.1

Confidence interval

level

95%

sides

2-sided

lower limit

-3.6

upper limit

11.8

Without PET

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.02

Method

Logrank

Parameter type

Absolute difference in %

Point estimate

-4.9

Confidence interval

level

95%

sides

2-sided

lower limit

-9.3

upper limit

0.6

Secondary: Overall Response (Follicular Lymphoma Population), IRC-Assessed

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End point title

Overall Response (Follicular Lymphoma Population), IRC-Assessed

End point description

Percentage of subjects with overall response in the follicular lymphoma population was defined as percentage of subjects with PR or complete response CR determined on the basis of IRC assessments with the use of Revised Response Criteria for Malignant Lymphoma. Tumour assessments were performed with CT/MRI with or without PET. CR was defined as disappearance of all target lesions; PR was defined as >=50% decrease target lesions in up to six dominant lesions identified at baseline, no new lesions and no increase in the size of the liver, spleen, or other nodes. Splenic and hepatic nodules must have regressed by >/= 50%. Overall Response (OR) = CR + PR. The FL ITT population was defined as all randomised subjects with follicular histology grouped according to their randomised treatment arm regardless of what treatments were actually received.

End point type

Secondary

End point timeframe

Baseline up to end of induction period (up to approximately 7 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	601	601
Units: percentage of subjects with event
number (not applicable)
Without PET (n=529, 549)	88.0	91.3
With PET (n=254, 263)	85.2	88.6

Without PET

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.052

Method

Logrank

Parameter type

Absolute difference in %

Point estimate

3.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.19

upper limit

6.85

With PET

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3

Method

Logrank

Parameter type

Absolute difference in %

Point estimate

3.3

Confidence interval

level

95%

sides

2-sided

lower limit

-2.3

upper limit

8.9

Secondary: Overall Response (Overall Study Population), IRC-Assessed

Top of page

End point title

Overall Response (Overall Study Population), IRC-Assessed

End point description

Percentage of subjects with overall response in the overall study population was defined as percentage of subjects with PR or CR determined on the basis of IRC assessments with the use of Revised Response Criteria for Malignant Lymphoma. Tumour assessments were performed with CT/MRI with or without PET. CR was defined as disappearance of all target lesions; PR was defined as >=50% decrease target lesions in up to six dominant lesions identified at baseline, no new lesions and no increase in the size of the liver, spleen, or other nodes. Splenic and hepatic nodules must have regressed by >/= 50%; Overall Response (OR) = CR + PR. The ITT population was defined as all randomised subjects grouped according to their randomised treatment arm regardless of what treatments were actually received.

End point type

Secondary

End point timeframe

Baseline up to end of induction period (up to approximately 7 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	699	702
Units: percentage of subjects with event
number (not applicable)
Without PET (n=606, 631)	86.7	89.9
With PET (n=330, 321)	83.3	87.2

Without PET

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.049

Method

Logrank

Parameter type

Absolute difference in %

Point estimate

3.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

6.6

With PET

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.22

Method

Logrank

Parameter type

Absolute difference in %

Point estimate

3.9

Confidence interval

level

95%

sides

2-sided

lower limit

-1.7

upper limit

9.5

Secondary: Complete Response (Follicular Lymphoma Population), IRC-Assessed

Top of page

End point title

Complete Response (Follicular Lymphoma Population), IRC-Assessed

End point description

Complete response in the follicular lymphoma population was determined on the basis of IRC assessments with the use of Revised Response Criteria for Malignant Lymphoma. Tumour assessments were performed with CT/MRI with or without PET. CR was defined as disappearance of all target lesions. The FL ITT population was defined as all randomised subjects with follicular histology grouped according to their randomised treatment arm regardless of what treatments were actually received.

End point type

Secondary

End point timeframe

Baseline up to end of induction period (up to approximately 7 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	601	601
Units: percentage of subjects with event
number (not applicable)
Without PET (n=161, 171)	26.8	28.5
With PET (n=178, 212)	59.7	71.4

Wirh PET

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.006

Method

Logrank

Parameter type

Absolute difference in %

Point estimate

11.7

Confidence interval

level

95%

sides

2-sided

lower limit

3.9

upper limit

19.4

Without PET

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.58

Method

Logrank

Parameter type

Absolute difference in %

Point estimate

1.7

Confidence interval

level

95%

sides

2-sided

lower limit

-3.5

upper limit

6.8

Secondary: Complete Response (Overall Study Population), IRC-Assessed

Top of page

End point title

Complete Response (Overall Study Population), IRC-Assessed

End point description

Complete response in the overall study population was determined on the basis of IRC assessments with the use of Revised Response Criteria for Malignant Lymphoma. Tumour assessments were performed with CT/MRI with or without PET. CR was defined as disappearance of all target lesions. The ITT population was defined as all randomised subjects grouped according to their randomised treatment arm regardless of what treatments were actually received.

End point type

Secondary

End point timeframe

Baseline up to end of induction period (up to approximately 7 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	699	702
Units: percentage of subjects with event
number (not applicable)
Without PET (n=184, 190)	26.3	27.1
With PET (n=196, 223)	59.4	69.5

Without PET

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8

Method

Logrank

Parameter type

Absolute difference in %

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-4

upper limit

5.5

With PET

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.009

Method

Logrank

Parameter type

Absolute difference in %

Point estimate

10.1

Confidence interval

level

95%

sides

2-sided

lower limit

2.6

upper limit

17.6

Secondary: Overall Survival (Follicular Lymphoma Population)

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End point title

Overall Survival (Follicular Lymphoma Population)

End point description

Overall survival in the follicular lymphoma population was defined as the time from the date of randomisation to the date of death from any cause. The FL ITT population was defined as all randomised subjects with follicular histology grouped according to their randomised treatment arm regardless of what treatments were actually received. Reported is the percentage of subjects with event.

End point type

Secondary

End point timeframe

Baseline up to 10 years

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	601	601
Units: percentage of subjects with event
number (not applicable)	14.3	12.6

Rituximab versus Obinutuzumab

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3577

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.86

Confidence interval

level

95%

sides

2-sided

lower limit

0.63

upper limit

1.18

Secondary: Overall Survival (Overall Study Population)

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End point title

Overall Survival (Overall Study Population)

End point description

Overall survival in the overall study population was defined as the time from the date of randomisation to the date of death from any cause. The ITT population was defined as all randomised subjects grouped according to their randomised treatment arm regardless of what treatments were actually received. Reported is the percentage of subjects with event.

End point type

Secondary

End point timeframe

Baseline up to data cut-off (up to approximately 5 years and 2 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	699	702
Units: percentage of subjects with event
number (not applicable)	10.2	8.4

Rituximab versus Obinutuzumab

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.25

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.82

Confidence interval

level

95%

sides

2-sided

lower limit

0.58

upper limit

1.16

Secondary: Event-Free Survival (Follicular Lymphoma Population)

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End point title

Event-Free Survival (Follicular Lymphoma Population)

End point description

Event-free survival: time from the date of randomisation to the date to disease progression/relapse, death from any cause, or initiation of a new anti-lymphoma treatment (NALT) on the basis of investigator assessment assessments with the use of Revised Response Criteria for Malignant Lymphoma. Disease progression/relapse was defined as at least 50% increase in nodal lesions or >/=50% increase in any node > 1 centimeter (cm) or >/= 50% increase in other target measurable lesions (e.g., splenic or hepatic nodules) and/or appearance of any new bone marrow involvement and/or appearance of any new lesion > 1.5 cm or >/= 50% increase in any previously involved node with a diameter </= 1 cm such that it is now >1.5 cm. Tumour measurements were obtained by CT/MRI. FL ITT population: all randomised subjects with follicular histology grouped according to their randomised treatment arm regardless of what treatments were actually received. Reported: percentage of subjects with event

End point type

Secondary

End point timeframe

Baseline up to 10 years

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	601	601
Units: percentage of subjects with event
number (not applicable)	42.9	35.8

Rituximab versus Obinutuzumab

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0015

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.74

Confidence interval

level

95%

sides

2-sided

lower limit

0.62

upper limit

0.89

Secondary: Event-Free Survival (Overall Study Population)

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End point title

Event-Free Survival (Overall Study Population)

End point description

Event-free survival was defined as the time from the date of randomisation to the date to disease progression/relapse, death from any cause, or initiation of a new anti-lymphoma treatment (NALT) on the basis of investigator assessment assessments with the use of Revised Response Criteria for Malignant Lymphoma. Disease progression/relapse was defined as at least 50% increase in nodal lesions or >/=50% increase in any node > 1 centimeter (cm) or >/= 50% increase in other target measurable lesions (e.g., splenic or hepatic nodules) and/or appearance of any new bone marrow involvement and/or appearance of any new lesion > 1.5 cm or >/= 50% increase in any previously involved node with a diameter </= 1 cm such that it is now >1.5 cm. Tumour measurements were obtained by CT/MRI. The ITT population was defined as all randomised subjects grouped according to their randomised treatment arm regardless of what treatments were actually received. Reported: percentage of subjects with event.

End point type

Secondary

End point timeframe

Baseline up to data cut-off (up to approximately 4 years and 7 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	699	702
Units: percentage of subjects with event
number (not applicable)	30.6	22.6

Rituximab versus Obinutuzumab

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0004

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.69

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

0.85

Secondary: Disease-Free Survival (DFS), (Follicular Lymphoma Population)

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End point title

Disease-Free Survival (DFS), (Follicular Lymphoma Population)

End point description

DFS: time from the date of the first occurrence of a documented CR to the date of disease progression/ relapse, or death from any cause on the basis of investigator assessments with the use of Revised Response Criteria for Malignant Lymphoma. Tumour assessments were performed with CT/MRI. CR was defined as disappearance of all target lesions. Progression/relapse was defined as at least 50% increase in nodal lesions or >/=50% increase in any node > 1 centimeter (cm) or >/= 50% increase in other target measurable lesions (e.g., splenic or hepatic nodules) and/or appearance of any new bone marrow involvement and/or appearance of any new lesion > 1.5 cm or >/= 50% increase in any previously involved node with a diameter </= 1 cm such that it is now >1.5 cm. Subjects with CR within the FL ITT population were included in the analysis. Reported: percentage of subjects with event.

End point type

Secondary

End point timeframe

From first occurrence of documented CR to data cut-off (up to approximately 5 years and 2 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	330	355
Units: percentage of subjects with event
number (not applicable)	27.9	26.3

Rituximab versus Obinutuzumab

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

685

Analysis specification

Pre-specified

Analysis type

superiority

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

1.27

Secondary: Disease-Free Survival (DFS) (Overall Study Population)

Top of page

End point title

Disease-Free Survival (DFS) (Overall Study Population)

End point description

DFS: time from the date of the first occurrence of a documented CR to the date of disease progression/ relapse, or death from any cause on the basis of investigator assessments with the use of Revised Response Criteria for Malignant Lymphoma. Tumour assessments were performed with CT/MRI. CR was defined as disappearance of all target lesions. Progression/relapse was defined as at least 50% increase in nodal lesions or >/=50% increase in any node > 1 centimeter (cm) or >/= 50% increase in other target measurable lesions (e.g., splenic or hepatic nodules) and/or appearance of any new bone marrow involvement and/or appearance of any new lesion > 1.5 cm or >/= 50% increase in any previously involved node with a diameter </= 1 cm such that it is now >1.5 cm. Subjects with CR within the ITT population were included in the analysis. Reported: percentage of subjects with event.

End point type

Secondary

End point timeframe

From first occurrence of documented CR to data cut-off (up to approximately 5 years and 2 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	320	343
Units: percentage of subjects with event
number (not applicable)	14.9	11.2

Rituximab versus Obinutuzumab

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.78

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

1.19

Secondary: Duration of Response (DOR) (Follicular Lymphoma Population), Investigator-Assessed

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End point title

Duration of Response (DOR) (Follicular Lymphoma Population), Investigator-Assessed

End point description

DOR was defined as the time from first occurrence of a documented CR or PR to disease progression/relapse, or death from any cause. Tumour assessments by CT/MRI. CR: disappearance of all target lesions. PR: >/=50% decrease target lesions in up to six dominant lesions identified at baseline, no new lesions, no increase in the size of the liver, spleen, or other nodes. Splenic and hepatic nodules must have regressed by >/= 50%. Progression/relapse was defined as at least 50% increase in nodal lesions or >/=50% increase in any node > 1 centimeter (cm) or >/= 50% increase in other target measurable lesions (e.g., splenic or hepatic nodules) and/or appearance of any new bone marrow involvement and/or appearance of any new lesion > 1.5 cm or >/= 50% increase in any previously involved node with a diameter </= 1 cm such that it is now >1.5 cm.Subjects with CR or PR within the FL ITT population were included in the analysis. Reported is the percentage of subjects with event.

End point type

Secondary

End point timeframe

From first occurrence of documented CR or PR to data cut-off (up to approximately 5 years and 2 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	568	571
Units: percentage of subjects with event
number (not applicable)	39.3	33.3

Rituximab versus Obinutuzumab

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1139

Analysis specification

Pre-specified

Analysis type

superiority

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.76

Confidence interval

level

95%

sides

2-sided

lower limit

0.63

upper limit

0.93

Secondary: Duration of Response (DOR) (Overall Study Population), Investigator-Assessed

Top of page

End point title

Duration of Response (DOR) (Overall Study Population), Investigator-Assessed

End point description

DOR was defined as the time from first occurrence of a documented CR or PR to disease progression/relapse, or death from any cause. Tumour assessments by CT/MRI. CR: disappearance of all target lesions. PR: >/=50% decrease target lesions in up to six dominant lesions identified at baseline, no new lesions and no increase in the size of the liver, spleen, or other nodes. Splenic and hepatic nodules must have regressed by >/= 50%. Progression/relapse was defined as at least 50% increase in nodal lesions or >/=50% increase in any node > 1 centimeter (cm) or >/= 50% increase in other target measurable lesions (e.g., splenic or hepatic nodules) and/or appearance of any new bone marrow involvement and/or appearance of any new lesion > 1.5 cm or >/= 50% increase in any previously involved node with a diameter </= 1 cm such that it is now >1.5 cm. Subjects with CR or PR within the ITT population were included in the analysis. Reported is the percentage of subjects with event.

End point type

Secondary

End point timeframe

From first occurrence of documented CR or PR to data cut-off (up to approximately 5 years and 2 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	656	659
Units: percentage of subjects with event
number (not applicable)	25.5	18.7

Rituximab versus Obinutuzumab

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1315

Analysis specification

Pre-specified

Analysis type

superiority

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.69

Confidence interval

level

95%

sides

2-sided

lower limit

0.55

upper limit

0.88

Secondary: Time to Next Anti-Lymphoma Treatment (Follicular Lymphoma Population)

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End point title

Time to Next Anti-Lymphoma Treatment (Follicular Lymphoma Population)

End point description

Time to next anti-lymphoma treatment was defined as the time from the date of randomisation to the start date of the next anti-lymphoma treatment or death from any cause. Reported is the percentage of subjects who started next anti-lymphoma treatment. The FL ITT population was defined as all randomised subjects with follicular histology grouped according to their randomised treatment arm regardless of what treatments were actually received. Reported is the percentage of subjects with event.

End point type

Secondary

End point timeframe

Baseline up to 10 years

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	601	601
Units: percentage of subjects with event
number (not applicable)	34.8	26.6

Rituximab versus Obinutuzumab

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1202

Analysis specification

Pre-specified

Analysis type

superiority

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.71

Confidence interval

level

95%

sides

2-sided

lower limit

0.58

upper limit

0.87

Secondary: Time to Next Anti-Lymphoma Treatment (Overall Study Population)

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End point title

Time to Next Anti-Lymphoma Treatment (Overall Study Population)

End point description

Time to next anti-lymphoma treatment was defined as the time from the date of randomisation to the start date of the next anti-lymphoma treatment or death from any cause. Reported is the percentage of subjects who started next anti-lymphoma treatment. The ITT population was defined as all randomised subjects grouped according to their randomised treatment arm regardless of what treatments were actually received. Reported is the percentage of subjects with event.

End point type

Secondary

End point timeframe

Baseline up to data cut-off (up to approximately 5 years and 2 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	699	702
Units: percentage of subjects with event
number (not applicable)	21.6	15.7

Rituximab versus Obinutuzumab

Comparison groups

Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

superiority

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

0.89

Secondary: Percentage of Subjects With Adverse Events

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End point title

Percentage of Subjects With Adverse Events

End point description

An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. The safety analysis population included all subjects who received any amount of any study drug and subjects were analysed according to the treatment received.

End point type

Secondary

End point timeframe

Baseline up to 10 years

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	692	698
Units: percentage of subjects
number (not applicable)	99.6	99.9

No statistical analyses for this end point

Secondary: Change from Baseline in All Domains of FACT-G (Follicular Lymphoma Population)

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End point title

Change from Baseline in All Domains of FACT-G (Follicular Lymphoma Population)

End point description

FACT-G consists of the following 4 FACT-Lym sub-questionnaires: Physical Well-being (range: 0-28), Social/Family Well-being (range: 0-28), Emotional Well-being (range: 0-24) and Functional Well-being (range: 0-28). Higher scores indicate better outcomes. A positive change from baseline indicates improvement. The FL ITT population was defined as all randomised subjects with follicular histology grouped according to their randomised treatment arm regardless of what treatments were actually received.

End point type

Secondary

End point timeframe

Baseline (Induction Cycle 1, Day 1), end of study (up to approximately 5 years and 2 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	601	601
Units: Units on a scale
arithmetic mean (standard deviation)
Physical Well-being (PW), Baseline (n=557, n=566)	23.36 ± 4.77	23.14 ± 4.85
PW Change, Cycle 3, Day 1 (n=511,496)	-0.91 ± 4.54	-0.21 ± 4.59
PW Change, End Induction (n=482, 480)	-0.06 ± 4.83	0.56 ± 5.14
PW Change, Maint Month 2 (n=362, 398)	0.83 ± 4.76	1.42 ± 5.09
PW Change, Maint Month 12 (n=362, 406)	1.14 ± 4.29	1.34 ± 4.74
PW Change, End Maint (n=411, 437)	0.88 ± 4.54	1.33 ± 5.00
Social/Family Well-being , Baseline (n=555, 563)	22.84 ± 4.92	23.28 ± 4.77
S/FW Change, Cycle 3 Day 1 (n=506, 492)	-0.52 ± 4.03	-0.67 ± 3.92
S/FW Change, End Induction (n=482, 475)	-0.46 ± 4.77	-0.56 ± 5.00
S/FW Change, Maint Month 2 (n=359, 396)	-0.39 ± 4.72	-0.67 ± 4.68
S/FW Change, Maint Month 12 (n=359, 403)	-0.61 ± 5.56	-0.97 ± 5.34
S/FW Change, End Maint (n=410, 436)	-0.93 ± 5.67	-0.71 ± 5.54
Emotional Well-being (EW), Baseline (n=556, 563)	17.64 ± 4.19	17.87 ± 4.13
EW Change, Cycle 3 Day 1 (n=503, 490)	1.49 ± 3.40	1.35 ± 3.35
EW Change, End Induction (n=478, 476)	1.16 ± 3.90	1.14 ± 3.87
EW Change, Maint Month 2 (n=359, 396)	1.77 ± 3.88	1.49 ± 4.16
EW Change, Maint Month 12 (n=360, 402)	1.45 ± 3.92	1.46 ± 3.88
EW Change, End Maint (n=405, 435)	1.43 ± 3.98	1.49 ± 3.99
Functional Well-being (FW), Baseline (n=556, 563)	18.66 ± 6.19	18.76 ± 5.98
FW Change, Cycle 3 Day 1 (n=504, 488)	-0.30 ± 5.30	-0.07 ± 5.24
FW Change, End Induction (n=480, 476)	0.44 ± 5.63	0.93 ± 5.85
FW Change, Maint Month 2 (n=359, 396)	1.04 ± 5.31	1.25 ± 6.02
FW Change, Maint Month 12 (n=360, 402)	1.84 ± 5.54	1.65 ± 5.95
FW Change, End Maint (n=406, 436)	1.40 ± 6.12	1.72 ± 6.16

No statistical analyses for this end point

Secondary: Change From Baseline in FACT-Lym Total Outcome Index (TOI) Score (Follicular Lymphoma Population)

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End point title

Change From Baseline in FACT-Lym Total Outcome Index (TOI) Score (Follicular Lymphoma Population)

End point description

The FACT-Lym TOI Score for the follicular lymphoma population was derived from the following 3 individual FACT-Lym questionnaire subscale scores: Physical Well-being (range: 0-28), Functional Well-being (range: 0-28) and Lymphoma (range: 0-60). The FACT-Lym TOI Score is the sum of the 3 individual subscales (range 0-116). Higher scores indicate better outcomes. A positive change from baseline indicates an improvement. The FL ITT population was defined as all randomised subjects with follicular histology grouped according to their randomised treatment arm regardless of what treatments were actually received.

End point type

Secondary

End point timeframe

Baseline (Induction Cycle 1, Day 1), end of study (up to approximately 5 years and 2 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	601	601
Units: Units on a scale
arithmetic mean (standard deviation)
TOI Score, Baseline (n=559, 567)	86.61 ± 18.16	86.94 ± 18.05
TOI Score Change, Cycle 3 Day 1 (n=514, 497)	0.46 ± 15.03	2.18 ± 15.95
TOI Score Change, End Induction (n=485, 481)	2.91 ± 17.00	4.57 ± 16.71
TOI Score Change, Maint Month 2 (n=363, 400)	6.22 ± 16.16	7.17 ± 16.57
TOI Score Change, Maint Month 12 (n=362, 408)	7.61 ± 15.62	7.20 ± 16.75
TOI Score Change, End Maint (n=412, 440)	6.23 ± 17.06	7.44 ± 16.96

No statistical analyses for this end point

Secondary: Change From Baseline in FACT-Lym Individual Subscale Lymphoma Score (Follicular Population)

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End point title

Change From Baseline in FACT-Lym Individual Subscale Lymphoma Score (Follicular Population)

End point description

The FACT-Lym Individual Subscale Lymphoma Score for the follicular lymphoma population was derived from the Lymphoma subscale questionnaire (range: 0-60). Higher scores indicate better outcomes. A positive change from baseline indicates an improvement. The FL ITT population was defined as all randomised subjects with follicular histology grouped according to their randomised treatment arm regardless of what treatments were actually received.

End point type

Secondary

End point timeframe

Baseline (Induction Cycle 1, Day 1), end of study (up to approximately 5 years and 2 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	601	601
Units: Units on a scale
arithmetic mean (standard deviation)
Lymphoma, Baseline (n=556, 563)	45.01 ± 9.37	45.54 ± 9.29
Lymphoma Change, Cycle 3 Day 1 (n=509, 491)	2.04 ± 7.18	2.71 ± 7.46
Lymphoma Change, End Induction (n=477, 478)	2.99 ± 8.63	3.01 ± 8.36
Lymphoma Change, Maint Month 2 (n=360, 395)	4.80 ± 8.29	4.52 ± 8.32
Lymphoma Change, Maint Month 12 (n=360, 404)	4.93 ± 8.34	4.27 ± 8.31
Lymphoma Change, End Maint (n=407, 438)	4.31 ± 8.81	4.57 ± 8.54

No statistical analyses for this end point

Secondary: Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Total Score (Follicular Population)

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End point title

Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Total Score (Follicular Population)

End point description

The FACT-Lym Total Score for the follicular lymphoma population was derived from the following 5 individual FACT-Lym questionnaire subscale scores: Physical Well-being (range: 0-28), Social/Family Well-being (range: 0-28), Emotional Well-being (range: 0-24),Functional Well-being (range: 0-28) and Lymphoma (range: 0-60). The FACT-Lym Total Score is the sum of all 5 individual subscales (range 0-168). Higher scores indicate better outcomes. A positive change from baseline indicates an improvement. The FL ITT population was defined as all randomised subjects with follicular histology grouped according to their randomised treatment arm regardless of what treatments were actually received.

End point type

Secondary

End point timeframe

Baseline (Induction Cycle 1, Day 1), end of study (up to approximately 5 years and 2 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	601	601
Units: Units on a scale
arithmetic mean (standard deviation)
Total Score, Baseline (n=552, 559)	127.40 ± 22.43	128.42 ± 22.16
Total Score Change, Cycle 3 Day 1 (n=499, 484)	1.98 ± 17.01	3.21 ± 17.12
Total Score Change, End Induction (n=471, 471)	4.18 ± 19.75	5.10 ± 20.03
Total Score Change, Maint Month 2 (n=356, 392)	8.40 ± 19.16	8.13 ± 19.80
Total Score Change, Maint Month 12 (n=358, 396)	8.87 ± 19.31	7.90 ± 19.55
Total Score Change, End Maint (n=401, 433)	7.43 ± 19.88	8.80 ± 20.57

No statistical analyses for this end point

Secondary: Change From Baseline in Euro-Quality of Life-5 Dimensions (EQ-5D) Questionnaire Summary Score (Follicular Lymphoma Population) During Induction Phase

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End point title

Change From Baseline in Euro-Quality of Life-5 Dimensions (EQ-5D) Questionnaire Summary Score (Follicular Lymphoma Population) During Induction Phase

End point description

The EQ-5D is a quality of life questionnaire with five questions, each with three categories (no problem, moderate problem, severe problems) and a visual analogue scale (VAS) from 0 (worst possible health state) to 100 (best possible health state. Summary score ranges from 0 to 1. Higher scores indicate better outcomes. A positive change from baseline indicates an improvement. The FL ITT population was defined as all randomised subjects with follicular histology grouped according to their randomised treatment arm regardless of what treatments were actually received. 9999=NE=Not estimable based on 0 or 1 subject evaluated.

End point type

Secondary

End point timeframe

Induction: Cycle 1 Day 1 (Baseline), Cycle 3 Day 1, End of Induction (up to 7 months) (1 Cycle=21 or 28 days); Maintenance: 2, 12, 25 months after Day 1 of last induction cycle (Cycle 6 or 8), Follow-up; up to data cut-off (up to 5 years and 2 months)

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	601	601
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline Induction (n=558, 559)	0.80 ± 0.24	0.81 ± 0.21
Change Baseline, Cycle 1 Day 1 (n=0, 0)	9999 ± 9999	9999 ± 9999
Change Baseline, Cycle 3 Day 1 (n=505, 487)	0.03 ± 0.21	0.03 ± 0.20
Change Baseline, Induction Completion (n=468, 466)	0.04 ± 0.23	0.03 ± 0.22
Change Baseline, Maint/Obs Month 2 (n=348, 377)	0.05 ± 0.23	0.06 ± 0.22
Change Baseline, Maint/Obs Month 12 (n=2, 1)	0.00 ± 0.00	-0.20 ± 9999
Change Baseline, Maint/Obs Completion (n=0, 1)	9999 ± 9999	-0.10 ± 9999

No statistical analyses for this end point

Secondary: Change From Baseline in EQ-5D Questionnaire Summary Score (Follicular Lymphoma Population) During Maintenance/Observation Phase

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End point title

Change From Baseline in EQ-5D Questionnaire Summary Score (Follicular Lymphoma Population) During Maintenance/Observation Phase

End point description

End point type

Secondary

End point timeframe

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	601	601
Units: Units on a scale
arithmetic mean (standard deviation)
Change Baseline, Maint/Obs Month 2 (n=11, 14)	0.04 ± 0.34	0.04 ± 0.14
Change Baseline, Maint/Obs Month 12 (n=354, 395)	0.06 ± 0.24	0.06 ± 0.21
Change Baseline, Maint/Obs Completion (n=402, 421)	0.03 ± 0.23	0.05 ± 0.23

No statistical analyses for this end point

Secondary: Change From Baseline in EQ-5D Questionnaire Summary Score (Follicular Lymphoma Population) During Follow Up Phase

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End point title

Change From Baseline in EQ-5D Questionnaire Summary Score (Follicular Lymphoma Population) During Follow Up Phase

End point description

End point type

Secondary

End point timeframe

End point values	Rituximab+Chemotherapy	Obinutuzumab+Chemotherapy
Number of subjects analysed	601	601
Units: Units on a scale
arithmetic mean (standard deviation)
Change Baseline, Follow-up Month 36 (n=238, 248)	0.05 ± 0.24	0.06 ± 0.23
Change Baseline, Follow-up Month 48 (n=73, 80)	0.05 ± 0.20	0.06 ± 0.23

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to 10 years

Adverse event reporting additional description

The safety analysis population included all subjects who received any amount of any study drug and subjects were analysed according to the treatment received.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

Obinutuzumab+Chemotherapy

Reporting group description

Participants will receive either 8 cycles of obinutuzumab along with 6 cycles of CHOP (21-day cycle) or 8 cycles of obinutuzumab along with 8 cycles of CVP (21-day cycles) or 6 cycles of obinutuzumab along with 6 cycles of bendamustine (28-day cycle) during induction period. The induction period will be followed by either a maintenance or observation period for responders or non-responders, respectively. Responders will receive obinutuzumab monotherapy every 2 months for 2 years during the maintenance period. Non-responders will receive no protocol specified treatment during the 2-year observation period. Finally, participants will be followed during a 5-year follow-up period. The chemotherapy regimen (CHOP or CVP or bendamustine) for individual participant will be chosen by the site prior to initiation of the study.

Reporting group title

Rituximab+Chemotherapy

Reporting group description

Participants will receive either 8 cycles of rituximab along with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (21-day cycle) or 8 cycles of rituximab along with 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) (21-day cycles) or 6 cycles of rituximab along with 6 cycles of bendamustine (28-day cycle) during the induction period. The induction period will be followed by either a maintenance or observation period for responders or non-responders, respectively. Responders will receive rituximab monotherapy every 2 months for 2 years during the maintenance period. Non-responders will receive no protocol specified treatment during the 2-year observation period. Finally, participants will be followed during a 5-year follow-up period. The chemotherapy regimen (CHOP or CVP or bendamustine) for individual participant will be chosen by the site prior to initiation of the study.

Serious adverse events	Obinutuzumab+Chemotherapy	Rituximab+Chemotherapy
Total subjects affected by serious adverse events
subjects affected / exposed	361 / 698 (51.72%)	309 / 692 (44.65%)
number of deaths (all causes)	104	111
number of deaths resulting from adverse events	14	6
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ADENOCARCINOMA OF COLON
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CHOLANGIOCARCINOMA
subjects affected / exposed	0 / 698 (0.00%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	1 / 2
RENAL CANCER
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATIC CANCER
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
KERATOACANTHOMA
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SQUAMOUS CELL BREAST CARCINOMA
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ADENOCARCINOMA METASTATIC
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
LENTIGO MALIGNA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
LARYNGEAL SQUAMOUS CELL CARCINOMA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SQUAMOUS CELL CARCINOMA
subjects affected / exposed	2 / 698 (0.29%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PITUITARY TUMOUR BENIGN
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
GASTRIC CANCER
subjects affected / exposed	2 / 698 (0.29%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	1 / 2	0 / 1
DUCTAL ADENOCARCINOMA OF PANCREAS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
INTRADUCTAL PROLIFERATIVE BREAST LESION
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
MYELODYSPLASTIC SYNDROME
subjects affected / exposed	4 / 698 (0.57%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	4 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PAPILLARY THYROID CANCER
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
VULVOVAGINAL WARTS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
TRANSITIONAL CELL CARCINOMA
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HODGKIN'S DISEASE NODULAR SCLEROSIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
BASAL CELL CARCINOMA
subjects affected / exposed	6 / 698 (0.86%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	1 / 7	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
BENIGN LARYNGEAL NEOPLASM
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
NEUROENDOCRINE CARCINOMA OF THE SKIN
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
ACUTE MYELOID LEUKAEMIA
subjects affected / exposed	2 / 698 (0.29%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	2 / 4	1 / 1
deaths causally related to treatment / all	1 / 2	1 / 1
TUMOUR FLARE
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SCHWANNOMA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INVASIVE DUCTAL BREAST CARCINOMA
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
NON-SMALL CELL LUNG CANCER
subjects affected / exposed	2 / 698 (0.29%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 2
COLORECTAL CANCER
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SQUAMOUS CELL CARCINOMA OF SKIN
subjects affected / exposed	5 / 698 (0.72%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
BOWEN'S DISEASE
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HODGKIN'S DISEASE
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PROSTATE CANCER
subjects affected / exposed	5 / 698 (0.72%)	4 / 692 (0.58%)
occurrences causally related to treatment / all	1 / 5	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
OESOPHAGEAL CARCINOMA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
BLADDER TRANSITIONAL CELL CARCINOMA METASTATIC
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
LUNG NEOPLASM MALIGNANT
subjects affected / exposed	0 / 698 (0.00%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 3
NON-HODGKIN'S LYMPHOMA
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
CANCER PAIN
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PANCREATIC CARCINOMA
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
MALIGNANT MELANOMA
subjects affected / exposed	1 / 698 (0.14%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1
INTRAOCULAR MELANOMA
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ADENOCARCINOMA
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
RECTAL ADENOCARCINOMA
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ACUTE LYMPHOCYTIC LEUKAEMIA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
TONGUE NEOPLASM MALIGNANT STAGE UNSPECIFIED
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
GASTRIC ADENOMA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
BREAST CANCER
subjects affected / exposed	6 / 698 (0.86%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	2 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
THYROID ADENOMA
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
COLON CANCER
subjects affected / exposed	1 / 698 (0.14%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	0 / 1	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
HORMONE RECEPTOR POSITIVE BREAST CANCER
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ACOUSTIC NEUROMA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROINTESTINAL NEOPLASM
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
MENINGIOMA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
BLADDER TRANSITIONAL CELL CARCINOMA
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
LUNG ADENOCARCINOMA
subjects affected / exposed	2 / 698 (0.29%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 1	1 / 1
HODGKIN'S DISEASE STAGE II
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
NON-SMALL CELL LUNG CANCER STAGE IV
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
UTERINE CANCER
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
RENAL CELL CARCINOMA
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
EMBOLISM
subjects affected / exposed	0 / 698 (0.00%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
DEEP VEIN THROMBOSIS
subjects affected / exposed	1 / 698 (0.14%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
PERIPHERAL ARTERY ANEURYSM
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PERIPHERAL ISCHAEMIA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PELVIC VENOUS THROMBOSIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
AXILLARY VEIN THROMBOSIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (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	7 / 698 (1.00%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	5 / 7	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
HYPERTENSIVE URGENCY
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CIRCULATORY COLLAPSE
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HYPERTENSIVE CRISIS
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
ABORTION
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (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
CHILLS
subjects affected / exposed	4 / 698 (0.57%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	4 / 4	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
HYPERTHERMIA
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CHEST DISCOMFORT
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PYREXIA
subjects affected / exposed	37 / 698 (5.30%)	23 / 692 (3.32%)
occurrences causally related to treatment / all	23 / 43	11 / 24
deaths causally related to treatment / all	0 / 0	0 / 0
MUCOSAL INFLAMMATION
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
MULTIPLE ORGAN DYSFUNCTION SYNDROME
subjects affected / exposed	0 / 698 (0.00%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 2
DEATH
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 1
HYPERPLASIA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ILL-DEFINED DISORDER
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
INFUSION SITE EXTRAVASATION
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ADVERSE DRUG REACTION
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
STENT-GRAFT ENDOLEAK
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
NON-CARDIAC CHEST PAIN
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PAIN
subjects affected / exposed	0 / 698 (0.00%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
INFLUENZA LIKE ILLNESS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CHEST PAIN
subjects affected / exposed	1 / 698 (0.14%)	4 / 692 (0.58%)
occurrences causally related to treatment / all	0 / 1	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
SWELLING FACE
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CYST RUPTURE
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
GENERAL PHYSICAL HEALTH DETERIORATION
subjects affected / exposed	3 / 698 (0.43%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	1 / 3	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1
OEDEMA PERIPHERAL
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
HYPOGAMMAGLOBULINAEMIA
subjects affected / exposed	0 / 698 (0.00%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
CYTOKINE RELEASE SYNDROME
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ANAPHYLACTIC SHOCK
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DRUG HYPERSENSITIVITY
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ALLERGY TO ARTHROPOD BITE
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (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 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HYPERSENSITIVITY
subjects affected / exposed	0 / 698 (0.00%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
PROSTATITIS
subjects affected / exposed	1 / 698 (0.14%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
OVARIAN MASS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
OVARIAN CYST
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
VULVOVAGINAL PAIN
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
VAGINAL ULCERATION
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
PLEURISY
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
BRONCHOSPASM
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DYSPNOEA
subjects affected / exposed	10 / 698 (1.43%)	8 / 692 (1.16%)
occurrences causally related to treatment / all	8 / 12	4 / 8
deaths causally related to treatment / all	0 / 1	0 / 0
ACUTE LUNG INJURY
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
ACUTE RESPIRATORY DISTRESS SYNDROME
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
LUNG DISORDER
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HYPOXIA
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
RESPIRATORY ARREST
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INTERSTITIAL LUNG DISEASE
subjects affected / exposed	2 / 698 (0.29%)	4 / 692 (0.58%)
occurrences causally related to treatment / all	2 / 2	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
PHARYNGEAL PARAESTHESIA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PULMONARY ARTERIAL HYPERTENSION
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (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	5 / 698 (0.72%)	5 / 692 (0.72%)
occurrences causally related to treatment / all	1 / 5	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
EMPHYSEMA
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
EPISTAXIS
subjects affected / exposed	1 / 698 (0.14%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
LUNG CONSOLIDATION
subjects affected / exposed	0 / 698 (0.00%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMONIA ASPIRATION
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
ASTHMA
subjects affected / exposed	2 / 698 (0.29%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMONITIS
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PARANASAL CYST
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
COUGH
subjects affected / exposed	0 / 698 (0.00%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
DYSPNOEA EXERTIONAL
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
RESPIRATORY DISORDER
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PULMONARY OEDEMA
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PHARYNGEAL INFLAMMATION
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HAEMOPTYSIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PULMONARY CONGESTION
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMOTHORAX
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PULMONARY EMBOLISM
subjects affected / exposed	8 / 698 (1.15%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	2 / 11	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
subjects affected / exposed	1 / 698 (0.14%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	0 / 1	0 / 6
deaths causally related to treatment / all	0 / 1	0 / 1
PLEURITIC PAIN
subjects affected / exposed	1 / 698 (0.14%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
ACUTE RESPIRATORY FAILURE
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
RESPIRATORY FAILURE
subjects affected / exposed	3 / 698 (0.43%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Psychiatric disorders
SUBSTANCE-INDUCED PSYCHOTIC DISORDER
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DEPRESSION
subjects affected / exposed	3 / 698 (0.43%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
CONFUSIONAL STATE
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DELIRIUM
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SUICIDE ATTEMPT
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ANXIETY
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ALCOHOL PROBLEM
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
EMOTIONAL DISORDER
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
MENTAL STATUS CHANGES
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PSYCHOTIC DISORDER
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
DEVICE BREAKAGE
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
INTERNATIONAL NORMALISED RATIO INCREASED
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATIC ENZYME INCREASED
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
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	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS WORSENED
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ASPARTATE AMINOTRANSFERASE INCREASED
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
WHITE BLOOD CELLS URINE POSITIVE
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
RESPIROVIRUS TEST POSITIVE
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
MENISCUS INJURY
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CARTILAGE INJURY
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
BRAIN CONTUSION
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMOTHORAX TRAUMATIC
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
LUMBAR VERTEBRAL FRACTURE
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
THORACIC VERTEBRAL FRACTURE
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HUMERUS FRACTURE
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (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	3 / 698 (0.43%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
MULTIPLE FRACTURES
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ANASTOMOTIC STENOSIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
COMPRESSION FRACTURE
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
LIGAMENT SPRAIN
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INFUSION RELATED REACTION
subjects affected / exposed	36 / 698 (5.16%)	19 / 692 (2.75%)
occurrences causally related to treatment / all	42 / 42	21 / 21
deaths causally related to treatment / all	0 / 0	0 / 0
FOOT FRACTURE
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ACCIDENT
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
FEMUR FRACTURE
subjects affected / exposed	2 / 698 (0.29%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
UPPER LIMB FRACTURE
subjects affected / exposed	1 / 698 (0.14%)	4 / 692 (0.58%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
FACIAL BONES FRACTURE
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
POST PROCEDURAL HAEMORRHAGE
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
MEDICATION ERROR
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SPINAL COMPRESSION FRACTURE
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ANKLE FRACTURE
subjects affected / exposed	1 / 698 (0.14%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
HAND FRACTURE
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ALCOHOL POISONING
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SEROMA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
HEREDITARY MOTOR AND SENSORY NEUROPATHY
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
CARDIOGENIC SHOCK
subjects affected / exposed	2 / 698 (0.29%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 2	0 / 0
SINUS TACHYCARDIA
subjects affected / exposed	3 / 698 (0.43%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
TACHYCARDIA
subjects affected / exposed	3 / 698 (0.43%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CORONARY ARTERY DISEASE
subjects affected / exposed	1 / 698 (0.14%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
BRADYCARDIA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ARRHYTHMIA
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SUPRAVENTRICULAR TACHYCARDIA
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
VENTRICULAR TACHYCARDIA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PALPITATIONS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
AORTIC VALVE STENOSIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
MYOCARDIAL ISCHAEMIA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
RIGHT VENTRICULAR FAILURE
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (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 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ACUTE MYOCARDIAL INFARCTION
subjects affected / exposed	4 / 698 (0.57%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CARDIO-RESPIRATORY ARREST
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CORONARY ARTERY STENOSIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CARDIAC ARREST
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
ATRIAL FIBRILLATION
subjects affected / exposed	9 / 698 (1.29%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	1 / 11	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
CARDIAC FAILURE CONGESTIVE
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
MYOCARDIAL INFARCTION
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
SINUS BRADYCARDIA
subjects affected / exposed	5 / 698 (0.72%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	5 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CARDIAC FAILURE
subjects affected / exposed	2 / 698 (0.29%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	2 / 3	3 / 3
deaths causally related to treatment / all	0 / 1	0 / 0
ANGINA PECTORIS
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
HAEMORRHAGIC STROKE
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CEREBRAL ISCHAEMIA
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
LOSS OF CONSCIOUSNESS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DEMENTIA
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
LETHARGY
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
TRANSIENT ISCHAEMIC ATTACK
subjects affected / exposed	5 / 698 (0.72%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DYSDIADOCHOKINESIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DIZZINESS POSTURAL
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SUBARACHNOID HAEMORRHAGE
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CEREBRAL DISORDER
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PRESYNCOPE
subjects affected / exposed	0 / 698 (0.00%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
MONOPARESIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CEREBRAL INFARCTION
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
EPILEPSY
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
FACIAL PARALYSIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ISCHAEMIC STROKE
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
HAEMORRHAGE INTRACRANIAL
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
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 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
NEURALGIA
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SYNCOPE
subjects affected / exposed	4 / 698 (0.57%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	1 / 4	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
POLYNEUROPATHY
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	1 / 1
BRACHIAL PLEXOPATHY
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DIZZINESS
subjects affected / exposed	1 / 698 (0.14%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
ATAXIA
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CAROTID ARTERY STENOSIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ENCEPHALOPATHY
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
TREMOR
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ORTHOSTATIC INTOLERANCE
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HYPERAMMONAEMIC ENCEPHALOPATHY
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
AMYOTROPHIC LATERAL SCLEROSIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
PARKINSON'S DISEASE
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ORTHOSTATIC TREMOR
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HYPOTONIA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SEIZURE
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CEREBROVASCULAR ACCIDENT
subjects affected / exposed	0 / 698 (0.00%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2
CEREBRAL HAEMATOMA
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
NERVOUS SYSTEM DISORDER
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
NEUROPATHY PERIPHERAL
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
HAEMOLYSIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
AUTOIMMUNE HAEMOLYTIC ANAEMIA
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
HAEMOLYTIC ANAEMIA
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
MYELOSUPPRESSION
subjects affected / exposed	3 / 698 (0.43%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	4 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
NEUTROPENIA
subjects affected / exposed	28 / 698 (4.01%)	33 / 692 (4.77%)
occurrences causally related to treatment / all	30 / 31	43 / 46
deaths causally related to treatment / all	0 / 0	0 / 0
IMMUNE THROMBOCYTOPENIA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ANAEMIA
subjects affected / exposed	6 / 698 (0.86%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	6 / 7	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DISSEMINATED INTRAVASCULAR COAGULATION
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
FEBRILE NEUTROPENIA
subjects affected / exposed	36 / 698 (5.16%)	23 / 692 (3.32%)
occurrences causally related to treatment / all	45 / 48	28 / 31
deaths causally related to treatment / all	0 / 0	0 / 0
GRANULOCYTOPENIA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
THROMBOCYTOPENIA
subjects affected / exposed	5 / 698 (0.72%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	12 / 12	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
SPLENOMEGALY
subjects affected / exposed	2 / 698 (0.29%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
LEUKOPENIA
subjects affected / exposed	4 / 698 (0.57%)	6 / 692 (0.87%)
occurrences causally related to treatment / all	2 / 4	8 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
VERTIGO
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
EAR PAIN
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DEAFNESS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
CORNEAL OPACITY
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
MELAENA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
VOMITING
subjects affected / exposed	5 / 698 (0.72%)	9 / 692 (1.30%)
occurrences causally related to treatment / all	4 / 5	10 / 13
deaths causally related to treatment / all	0 / 0	0 / 0
CONSTIPATION
subjects affected / exposed	3 / 698 (0.43%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ASCITES
subjects affected / exposed	1 / 698 (0.14%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
PANCREATITIS ACUTE
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
GASTRITIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INTESTINAL OBSTRUCTION
subjects affected / exposed	4 / 698 (0.57%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ILEUS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INTESTINAL ISCHAEMIA
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
RECTAL HAEMORRHAGE
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (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	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HAEMORRHOIDS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INTESTINAL POLYP
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SWOLLEN TONGUE
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
GASTRITIS EROSIVE
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
UPPER GASTROINTESTINAL HAEMORRHAGE
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
GASTRIC HAEMORRHAGE
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
COLITIS
subjects affected / exposed	3 / 698 (0.43%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	1 / 3	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
PANCREATITIS
subjects affected / exposed	4 / 698 (0.57%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DIARRHOEA
subjects affected / exposed	11 / 698 (1.58%)	7 / 692 (1.01%)
occurrences causally related to treatment / all	7 / 12	3 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
ENTEROVESICAL FISTULA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROOESOPHAGEAL REFLUX DISEASE
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HIATUS HERNIA
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
FAECALOMA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
OBSTRUCTIVE PANCREATITIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROENTERITIS EOSINOPHILIC
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
INTESTINAL VILLI ATROPHY
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HAEMATEMESIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
MIKULICZ'S SYNDROME
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
LARGE INTESTINAL OBSTRUCTION
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
GASTRIC ULCER
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
UMBILICAL HERNIA
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ABDOMINAL PAIN UPPER
subjects affected / exposed	0 / 698 (0.00%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
SUBACUTE PANCREATITIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
LARGE INTESTINE POLYP
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INGUINAL HERNIA
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CROHN'S DISEASE
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SMALL INTESTINAL OBSTRUCTION
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
NAUSEA
subjects affected / exposed	5 / 698 (0.72%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	5 / 5	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
ABDOMINAL PAIN
subjects affected / exposed	10 / 698 (1.43%)	6 / 692 (0.87%)
occurrences causally related to treatment / all	1 / 11	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
DYSPEPSIA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
HEPATIC FUNCTION ABNORMAL
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DRUG-INDUCED LIVER INJURY
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
BILE DUCT STONE
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CHOLECYSTITIS ACUTE
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATITIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
BILE DUCT STENOSIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CHOLANGITIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
CHOLELITHIASIS
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATITIS ACUTE
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATIC CIRRHOSIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CHOLECYSTITIS
subjects affected / exposed	5 / 698 (0.72%)	6 / 692 (0.87%)
occurrences causally related to treatment / all	0 / 6	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
BILIARY COLIC
subjects affected / exposed	3 / 698 (0.43%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
RASH
subjects affected / exposed	5 / 698 (0.72%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	3 / 5	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
DERMATITIS EXFOLIATIVE GENERALISED
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (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	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
RASH MACULO-PAPULAR
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ACTINIC KERATOSIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DERMATITIS CONTACT
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
URTICARIA
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
NEPHROLITHIASIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
RENAL PELVIS FISTULA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ACUTE KIDNEY INJURY
subjects affected / exposed	4 / 698 (0.57%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
RENAL PAIN
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
RENAL INFARCT
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
RENAL COLIC
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
RENAL FAILURE
subjects affected / exposed	1 / 698 (0.14%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
URETERIC OBSTRUCTION
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
FLANK PAIN
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PATHOLOGICAL FRACTURE
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
TEMPOROMANDIBULAR JOINT SYNDROME
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ARTHROPATHY
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
NECK PAIN
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
MYOPATHY
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ROTATOR CUFF SYNDROME
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
MYOSITIS
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PAIN IN EXTREMITY
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SPINAL PAIN
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SYNOVITIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
MUSCULAR WEAKNESS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
OSTEITIS DEFORMANS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
INTERVERTEBRAL DISC PROTRUSION
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SPINAL STENOSIS
subjects affected / exposed	0 / 698 (0.00%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
BACK PAIN
subjects affected / exposed	2 / 698 (0.29%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
HAEMARTHROSIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
OSTEOARTHRITIS
subjects affected / exposed	2 / 698 (0.29%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
SERONEGATIVE ARTHRITIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
GASTROENTERITIS VIRAL
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ENTEROCOCCAL INFECTION
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
BRONCHITIS
subjects affected / exposed	9 / 698 (1.29%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	2 / 9	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
POST PROCEDURAL INFECTION
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
NEUTROPENIC SEPSIS
subjects affected / exposed	6 / 698 (0.86%)	5 / 692 (0.72%)
occurrences causally related to treatment / all	8 / 9	7 / 8
deaths causally related to treatment / all	1 / 1	0 / 1
INFLUENZA
subjects affected / exposed	4 / 698 (0.57%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
BREAST ABSCESS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
MUCOSAL INFECTION
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
OOPHORITIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CHRONIC SINUSITIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (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 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
RHINITIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ORAL HERPES
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (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	1 / 698 (0.14%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
INFECTED CYST
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PYELONEPHRITIS
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PERITONSILLAR ABSCESS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
COMPLICATED APPENDICITIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HERPES ZOSTER OTICUS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INFECTION
subjects affected / exposed	6 / 698 (0.86%)	10 / 692 (1.45%)
occurrences causally related to treatment / all	2 / 7	3 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
PULMONARY SEPSIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DIVERTICULITIS
subjects affected / exposed	1 / 698 (0.14%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
PARAPHARYNGEAL SPACE INFECTION
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (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	8 / 698 (1.15%)	7 / 692 (1.01%)
occurrences causally related to treatment / all	2 / 8	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
NEUROBORRELIOSIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
INTERVERTEBRAL DISCITIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SINUSITIS
subjects affected / exposed	1 / 698 (0.14%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
SCROTAL ABSCESS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CATHETER SITE CELLULITIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DISSEMINATED VARICELLA ZOSTER VIRUS INFECTION
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SINUSITIS FUNGAL
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
EPIGLOTTITIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HERPES ZOSTER
subjects affected / exposed	9 / 698 (1.29%)	9 / 692 (1.30%)
occurrences causally related to treatment / all	6 / 9	5 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
ESCHERICHIA URINARY TRACT INFECTION
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
OTITIS MEDIA CHRONIC
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
MASTOIDITIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SEPSIS
subjects affected / exposed	14 / 698 (2.01%)	9 / 692 (1.30%)
occurrences causally related to treatment / all	8 / 18	5 / 9
deaths causally related to treatment / all	0 / 2	0 / 1
STAPHYLOCOCCAL BACTERAEMIA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
CYSTITIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CELLULITIS
subjects affected / exposed	4 / 698 (0.57%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	1 / 4	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
CYTOMEGALOVIRUS INFECTION
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SEPTIC SHOCK
subjects affected / exposed	0 / 698 (0.00%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Q FEVER
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CAMPYLOBACTER INFECTION
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
VARICELLA ZOSTER SEPSIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
VIRAL INFECTION
subjects affected / exposed	1 / 698 (0.14%)	4 / 692 (0.58%)
occurrences causally related to treatment / all	0 / 1	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
ABDOMINAL SEPSIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
ENCEPHALITIS ENTEROVIRAL
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ESCHERICHIA INFECTION
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SINUSITIS BACTERIAL
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ATYPICAL PNEUMONIA
subjects affected / exposed	1 / 698 (0.14%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	0 / 1	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
NEUTROPENIC INFECTION
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
TUBERCULOSIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ABSCESS INTESTINAL
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROENTERITIS
subjects affected / exposed	7 / 698 (1.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 7	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMOCYSTIS JIROVECII PNEUMONIA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
TUBO-OVARIAN ABSCESS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ABSCESS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
FEBRILE INFECTION
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SUBCUTANEOUS ABSCESS
subjects affected / exposed	0 / 698 (0.00%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
PERIODONTITIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (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 / 698 (0.14%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
DEVICE RELATED SEPSIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
BK VIRUS INFECTION
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
RHINOVIRUS INFECTION
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
VASCULAR DEVICE INFECTION
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
OESOPHAGEAL CANDIDIASIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
VIRAL MYOSITIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
LOWER RESPIRATORY TRACT INFECTION
subjects affected / exposed	13 / 698 (1.86%)	9 / 692 (1.30%)
occurrences causally related to treatment / all	8 / 23	2 / 9
deaths causally related to treatment / all	1 / 2	0 / 0
OESOPHAGEAL INFECTION
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ARTHRITIS BACTERIAL
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMONIA BACTERIAL
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
UROSEPSIS
subjects affected / exposed	4 / 698 (0.57%)	5 / 692 (0.72%)
occurrences causally related to treatment / all	4 / 5	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	5 / 698 (0.72%)	3 / 692 (0.43%)
occurrences causally related to treatment / all	2 / 7	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMONIA FUNGAL
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
OVARIAN BACTERIAL INFECTION
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed	51 / 698 (7.31%)	43 / 692 (6.21%)
occurrences causally related to treatment / all	24 / 61	24 / 51
deaths causally related to treatment / all	2 / 7	0 / 2
SOFT TISSUE INFECTION
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ARTHRITIS INFECTIVE
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
BACTERIAL TRACHEITIS
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DEVICE RELATED INFECTION
subjects affected / exposed	1 / 698 (0.14%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROENTERITIS ESCHERICHIA COLI
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMONIA PNEUMOCOCCAL
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
RESPIRATORY TRACT INFECTION
subjects affected / exposed	6 / 698 (0.86%)	5 / 692 (0.72%)
occurrences causally related to treatment / all	3 / 7	9 / 11
deaths causally related to treatment / all	0 / 1	0 / 0
MENINGITIS ENTEROVIRAL
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INFECTIVE EXACERBATION OF CHRONIC OBSTRUCTIVE AIRWAYS DISEASE
subjects affected / exposed	3 / 698 (0.43%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
STAPHYLOCOCCAL INFECTION
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HERPES ZOSTER INFECTION NEUROLOGICAL
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ENDOCARDITIS
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PELVIC ABSCESS
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMOCYSTIS JIROVECII INFECTION
subjects affected / exposed	0 / 698 (0.00%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
HYPONATRAEMIA
subjects affected / exposed	4 / 698 (0.57%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	1 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HYPERCALCAEMIA
subjects affected / exposed	2 / 698 (0.29%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
HYPERGLYCAEMIA
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DEHYDRATION
subjects affected / exposed	4 / 698 (0.57%)	2 / 692 (0.29%)
occurrences causally related to treatment / all	2 / 4	1 / 2
deaths causally related to treatment / all	1 / 1	0 / 0
HYPOKALAEMIA
subjects affected / exposed	1 / 698 (0.14%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
FLUID OVERLOAD
subjects affected / exposed	1 / 698 (0.14%)	0 / 692 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
TUMOUR LYSIS SYNDROME
subjects affected / exposed	3 / 698 (0.43%)	1 / 692 (0.14%)
occurrences causally related to treatment / all	3 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DIABETES MELLITUS
subjects affected / exposed	2 / 698 (0.29%)	0 / 692 (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	Obinutuzumab+Chemotherapy	Rituximab+Chemotherapy
Total subjects affected by non serious adverse events
subjects affected / exposed	690 / 698 (98.85%)	675 / 692 (97.54%)
Vascular disorders
FLUSHING
subjects affected / exposed	46 / 698 (6.59%)	40 / 692 (5.78%)
occurrences all number	56	44
HOT FLUSH
subjects affected / exposed	38 / 698 (5.44%)	25 / 692 (3.61%)
occurrences all number	43	28
HYPOTENSION
subjects affected / exposed	44 / 698 (6.30%)	28 / 692 (4.05%)
occurrences all number	48	32
HYPERTENSION
subjects affected / exposed	64 / 698 (9.17%)	50 / 692 (7.23%)
occurrences all number	100	70
General disorders and administration site conditions
PAIN
subjects affected / exposed	26 / 698 (3.72%)	35 / 692 (5.06%)
occurrences all number	28	40
PYREXIA
subjects affected / exposed	200 / 698 (28.65%)	150 / 692 (21.68%)
occurrences all number	277	231
CHILLS
subjects affected / exposed	126 / 698 (18.05%)	74 / 692 (10.69%)
occurrences all number	172	99
CHEST DISCOMFORT
subjects affected / exposed	43 / 698 (6.16%)	36 / 692 (5.20%)
occurrences all number	45	43
FATIGUE
subjects affected / exposed	275 / 698 (39.40%)	277 / 692 (40.03%)
occurrences all number	390	392
INFLUENZA LIKE ILLNESS
subjects affected / exposed	34 / 698 (4.87%)	35 / 692 (5.06%)
occurrences all number	38	36
ASTHENIA
subjects affected / exposed	47 / 698 (6.73%)	44 / 692 (6.36%)
occurrences all number	56	55
MUCOSAL INFLAMMATION
subjects affected / exposed	36 / 698 (5.16%)	44 / 692 (6.36%)
occurrences all number	41	55
OEDEMA PERIPHERAL
subjects affected / exposed	46 / 698 (6.59%)	40 / 692 (5.78%)
occurrences all number	50	47
Respiratory, thoracic and mediastinal disorders
PRODUCTIVE COUGH
subjects affected / exposed	42 / 698 (6.02%)	35 / 692 (5.06%)
occurrences all number	53	41
OROPHARYNGEAL PAIN
subjects affected / exposed	82 / 698 (11.75%)	73 / 692 (10.55%)
occurrences all number	98	87
DYSPNOEA
subjects affected / exposed	112 / 698 (16.05%)	88 / 692 (12.72%)
occurrences all number	131	101
THROAT IRRITATION
subjects affected / exposed	27 / 698 (3.87%)	37 / 692 (5.35%)
occurrences all number	27	40
COUGH
subjects affected / exposed	221 / 698 (31.66%)	185 / 692 (26.73%)
occurrences all number	305	248
Psychiatric disorders
INSOMNIA
subjects affected / exposed	113 / 698 (16.19%)	89 / 692 (12.86%)
occurrences all number	131	98
ANXIETY
subjects affected / exposed	44 / 698 (6.30%)	29 / 692 (4.19%)
occurrences all number	47	31
Investigations
WEIGHT DECREASED
subjects affected / exposed	35 / 698 (5.01%)	45 / 692 (6.50%)
occurrences all number	37	49
Injury, poisoning and procedural complications
INFUSION RELATED REACTION
subjects affected / exposed	416 / 698 (59.60%)	347 / 692 (50.14%)
occurrences all number	699	569
Nervous system disorders
DYSGEUSIA
subjects affected / exposed	38 / 698 (5.44%)	40 / 692 (5.78%)
occurrences all number	42	44
PERIPHERAL SENSORY NEUROPATHY
subjects affected / exposed	59 / 698 (8.45%)	47 / 692 (6.79%)
occurrences all number	68	50
HEADACHE
subjects affected / exposed	155 / 698 (22.21%)	123 / 692 (17.77%)
occurrences all number	229	185
DIZZINESS
subjects affected / exposed	75 / 698 (10.74%)	57 / 692 (8.24%)
occurrences all number	88	69
PARAESTHESIA
subjects affected / exposed	62 / 698 (8.88%)	51 / 692 (7.37%)
occurrences all number	71	68
NEUROPATHY PERIPHERAL
subjects affected / exposed	51 / 698 (7.31%)	49 / 692 (7.08%)
occurrences all number	62	52
Blood and lymphatic system disorders
NEUTROPENIA
subjects affected / exposed	348 / 698 (49.86%)	307 / 692 (44.36%)
occurrences all number	885	777
ANAEMIA
subjects affected / exposed	75 / 698 (10.74%)	72 / 692 (10.40%)
occurrences all number	88	95
THROMBOCYTOPENIA
subjects affected / exposed	90 / 698 (12.89%)	52 / 692 (7.51%)
occurrences all number	150	79
LEUKOPENIA
subjects affected / exposed	87 / 698 (12.46%)	91 / 692 (13.15%)
occurrences all number	222	267
Gastrointestinal disorders
DIARRHOEA
subjects affected / exposed	207 / 698 (29.66%)	168 / 692 (24.28%)
occurrences all number	318	253
VOMITING
subjects affected / exposed	182 / 698 (26.07%)	151 / 692 (21.82%)
occurrences all number	242	211
CONSTIPATION
subjects affected / exposed	249 / 698 (35.67%)	221 / 692 (31.94%)
occurrences all number	326	301
DRY MOUTH
subjects affected / exposed	36 / 698 (5.16%)	23 / 692 (3.32%)
occurrences all number	40	25
ABDOMINAL PAIN
subjects affected / exposed	69 / 698 (9.89%)	78 / 692 (11.27%)
occurrences all number	84	95
STOMATITIS
subjects affected / exposed	54 / 698 (7.74%)	55 / 692 (7.95%)
occurrences all number	72	71
NAUSEA
subjects affected / exposed	354 / 698 (50.72%)	338 / 692 (48.84%)
occurrences all number	594	577
ABDOMINAL PAIN UPPER
subjects affected / exposed	57 / 698 (8.17%)	53 / 692 (7.66%)
occurrences all number	64	60
DYSPEPSIA
subjects affected / exposed	65 / 698 (9.31%)	50 / 692 (7.23%)
occurrences all number	82	56
Skin and subcutaneous tissue disorders
RASH
subjects affected / exposed	127 / 698 (18.19%)	131 / 692 (18.93%)
occurrences all number	162	170
PRURITUS
subjects affected / exposed	102 / 698 (14.61%)	94 / 692 (13.58%)
occurrences all number	124	116
DRY SKIN
subjects affected / exposed	40 / 698 (5.73%)	36 / 692 (5.20%)
occurrences all number	44	39
ERYTHEMA
subjects affected / exposed	37 / 698 (5.30%)	37 / 692 (5.35%)
occurrences all number	40	43
NIGHT SWEATS
subjects affected / exposed	32 / 698 (4.58%)	38 / 692 (5.49%)
occurrences all number	35	46
ALOPECIA
subjects affected / exposed	90 / 698 (12.89%)	77 / 692 (11.13%)
occurrences all number	94	78
Musculoskeletal and connective tissue disorders
MUSCLE SPASMS
subjects affected / exposed	40 / 698 (5.73%)	42 / 692 (6.07%)
occurrences all number	46	49
BACK PAIN
subjects affected / exposed	99 / 698 (14.18%)	115 / 692 (16.62%)
occurrences all number	127	143
BONE PAIN
subjects affected / exposed	40 / 698 (5.73%)	44 / 692 (6.36%)
occurrences all number	46	56
ARTHRALGIA
subjects affected / exposed	144 / 698 (20.63%)	127 / 692 (18.35%)
occurrences all number	180	160
MYALGIA
subjects affected / exposed	53 / 698 (7.59%)	38 / 692 (5.49%)
occurrences all number	63	43
PAIN IN EXTREMITY
subjects affected / exposed	66 / 698 (9.46%)	65 / 692 (9.39%)
occurrences all number	75	79
Infections and infestations
RHINITIS
subjects affected / exposed	59 / 698 (8.45%)	36 / 692 (5.20%)
occurrences all number	71	49
SINUSITIS
subjects affected / exposed	68 / 698 (9.74%)	47 / 692 (6.79%)
occurrences all number	92	58
ORAL HERPES
subjects affected / exposed	46 / 698 (6.59%)	43 / 692 (6.21%)
occurrences all number	54	48
BRONCHITIS
subjects affected / exposed	47 / 698 (6.73%)	42 / 692 (6.07%)
occurrences all number	69	53
LOWER RESPIRATORY TRACT INFECTION
subjects affected / exposed	59 / 698 (8.45%)	71 / 692 (10.26%)
occurrences all number	97	105
RESPIRATORY TRACT INFECTION
subjects affected / exposed	39 / 698 (5.59%)	35 / 692 (5.06%)
occurrences all number	67	43
CONJUNCTIVITIS
subjects affected / exposed	35 / 698 (5.01%)	26 / 692 (3.76%)
occurrences all number	42	30
NASOPHARYNGITIS
subjects affected / exposed	135 / 698 (19.34%)	143 / 692 (20.66%)
occurrences all number	200	224
HERPES ZOSTER
subjects affected / exposed	70 / 698 (10.03%)	40 / 692 (5.78%)
occurrences all number	75	46
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	153 / 698 (21.92%)	132 / 692 (19.08%)
occurrences all number	217	189
PNEUMONIA
subjects affected / exposed	47 / 698 (6.73%)	46 / 692 (6.65%)
occurrences all number	63	59
URINARY TRACT INFECTION
subjects affected / exposed	75 / 698 (10.74%)	66 / 692 (9.54%)
occurrences all number	111	100
Metabolism and nutrition disorders
HYPOKALAEMIA
subjects affected / exposed	48 / 698 (6.88%)	29 / 692 (4.19%)
occurrences all number	72	43
DECREASED APPETITE
subjects affected / exposed	98 / 698 (14.04%)	91 / 692 (13.15%)
occurrences all number	114	103

More information

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Were there any global substantial amendments to the protocol? Yes

26 Jul 2011

Allow for an early futility analysis of the first 170 randomized patients with follicular lymphoma based on the end-of-induction treatment complete response rates. The statistical methods sections were updated accordingly. Positron emission tomography (PET) was also made mandatory at screening and at end of induction therapy for the first 170 subjects with follicular lymphoma at all sites where PET scanners were available. The determination of minimal residual disease (MRD) based on polymerase chain reaction detection of BCL2/IgH-rearrangements within the malignant clone for all subjects with follicular lymphoma was also implemented.

16 Jul 2012

Implementation of a deoxyribonucleic acid (DNA) substudy in those subjects who give consent to the Roche Clinical Repository (RCR) and to DNA collection.

28 May 2013

Clarification of measuring and assessing the spleen and splenic response for marginal zone lymphoma (MZL) subjects.

22 Mar 2014

The Sponsor issued a Dear Investigator Letter (DIL) on 3 February 2014 to inform investigators about a higher incidence of thrombocytopenia and hemorrhagic events during the first cycle in participants with chronic lymphocytic leukemia (CLL) treated with obinutuzumab plus chlorambucil (GClb) as compared with participants treated with rituximab plus chlorambucil (RClb) or chlorambucil alone. Updates to guidelines regarding management of participants with thrombocytopenia. Evaluation of medical resource utilization was removed from the secondary objectives. The name of the study drug was updated from GA101 to obinutuzumab.

09 Jun 2017

The protocol was amended to consider second malignancies as an adverse event of special interest (AESI). The Medical Monitor for the study changed. Biomarker sample storage changed from 15 to 5 years after the completion of the study.

15 Feb 2020

The protocol was amended to collect response after progression and administration of new anti-lymphoma treatment (NALT). The Medical Monitor changed. Reference safety information was added.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression-Free Survival (PFS) in the Follicular Lymphoma Population, Investigator-Assessed

Primary: Progression-Free Survival (PFS) in the Follicular Lymphoma Population, Investigator-Assessed

Secondary: Progression-Free Survival in the Follicular Lymphoma Population, Investigator-Assessed

Secondary: Progression-Free Survival in the Follicular Lymphoma Population, Investigator-Assessed

Secondary: Progression-Free Survival in the Overall Study Population, Investigator-Assessed

Secondary: Progression-Free Survival in the Overall Study Population, Investigator-Assessed

Secondary: Progression-Free Survival (PFS) (Follicular Lymphoma Population), IRC-Assessed

Secondary: Progression-Free Survival (PFS) (Follicular Lymphoma Population), IRC-Assessed

Secondary: Progression-Free Survival (PFS) (Overall Study Population), Assessed by Independent Review Committee (IRC)

Secondary: Progression-Free Survival (PFS) (Overall Study Population), Assessed by Independent Review Committee (IRC)

Secondary: Overall Response (Follicular Lymphoma Population), Investigator-Assessed

Secondary: Overall Response (Follicular Lymphoma Population), Investigator-Assessed

Secondary: Overall Response (Overall Study Population), Investigator-Assessed

Secondary: Overall Response (Overall Study Population), Investigator-Assessed

Secondary: Complete Response (Follicular Lymphoma Population), Investigator-Assessed

Secondary: Complete Response (Follicular Lymphoma Population), Investigator-Assessed

Secondary: Complete Response (Overall Study Population), Investigator-Assessed

Secondary: Complete Response (Overall Study Population), Investigator-Assessed

Secondary: Overall Response (Follicular Lymphoma Population), IRC-Assessed

Secondary: Overall Response (Follicular Lymphoma Population), IRC-Assessed

Secondary: Overall Response (Overall Study Population), IRC-Assessed

Secondary: Overall Response (Overall Study Population), IRC-Assessed

Secondary: Complete Response (Follicular Lymphoma Population), IRC-Assessed

Secondary: Complete Response (Follicular Lymphoma Population), IRC-Assessed

Secondary: Complete Response (Overall Study Population), IRC-Assessed

Secondary: Complete Response (Overall Study Population), IRC-Assessed

Secondary: Overall Survival (Follicular Lymphoma Population)

Secondary: Overall Survival (Follicular Lymphoma Population)

Secondary: Overall Survival (Overall Study Population)

Secondary: Overall Survival (Overall Study Population)

Secondary: Event-Free Survival (Follicular Lymphoma Population)

Secondary: Event-Free Survival (Follicular Lymphoma Population)

Secondary: Event-Free Survival (Overall Study Population)

Secondary: Event-Free Survival (Overall Study Population)

Secondary: Disease-Free Survival (DFS), (Follicular Lymphoma Population)

Secondary: Disease-Free Survival (DFS), (Follicular Lymphoma Population)

Secondary: Disease-Free Survival (DFS) (Overall Study Population)

Secondary: Disease-Free Survival (DFS) (Overall Study Population)

Secondary: Duration of Response (DOR) (Follicular Lymphoma Population), Investigator-Assessed

Secondary: Duration of Response (DOR) (Follicular Lymphoma Population), Investigator-Assessed

Secondary: Duration of Response (DOR) (Overall Study Population), Investigator-Assessed

Secondary: Duration of Response (DOR) (Overall Study Population), Investigator-Assessed

Secondary: Time to Next Anti-Lymphoma Treatment (Follicular Lymphoma Population)

Secondary: Time to Next Anti-Lymphoma Treatment (Follicular Lymphoma Population)

Secondary: Time to Next Anti-Lymphoma Treatment (Overall Study Population)

Secondary: Time to Next Anti-Lymphoma Treatment (Overall Study Population)

Secondary: Percentage of Subjects With Adverse Events

Secondary: Percentage of Subjects With Adverse Events

Secondary: Change from Baseline in All Domains of FACT-G (Follicular Lymphoma Population)

Secondary: Change from Baseline in All Domains of FACT-G (Follicular Lymphoma Population)

Secondary: Change From Baseline in FACT-Lym Total Outcome Index (TOI) Score (Follicular Lymphoma Population)

Secondary: Change From Baseline in FACT-Lym Total Outcome Index (TOI) Score (Follicular Lymphoma Population)

Secondary: Change From Baseline in FACT-Lym Individual Subscale Lymphoma Score (Follicular Population)

Secondary: Change From Baseline in FACT-Lym Individual Subscale Lymphoma Score (Follicular Population)

Secondary: Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Total Score (Follicular Population)

Secondary: Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Total Score (Follicular Population)

Secondary: Change From Baseline in Euro-Quality of Life-5 Dimensions (EQ-5D) Questionnaire Summary Score (Follicular Lymphoma Population) During Induction Phase

Secondary: Change From Baseline in Euro-Quality of Life-5 Dimensions (EQ-5D) Questionnaire Summary Score (Follicular Lymphoma Population) During Induction Phase

Secondary: Change From Baseline in EQ-5D Questionnaire Summary Score (Follicular Lymphoma Population) During Maintenance/Observation Phase

Secondary: Change From Baseline in EQ-5D Questionnaire Summary Score (Follicular Lymphoma Population) During Maintenance/Observation Phase

Secondary: Change From Baseline in EQ-5D Questionnaire Summary Score (Follicular Lymphoma Population) During Follow Up Phase

Secondary: Change From Baseline in EQ-5D Questionnaire Summary Score (Follicular Lymphoma Population) During Follow Up Phase

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information