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Clinical Trial Results:
A Prospective, Open-Label, Multicenter Randomized Phase III Trial to Compare The Efficacy and Safety of A Combined Regimen of Obinutuzumab and Venetoclax (GDC-0199/ABT-199) Versus Obinutuzumab and Chlorambucil in Previously Untreated Patients With CLL and Coexisting Medical Conditions

Summary
EudraCT number	2014-001810-24
Trial protocol	DE DK GB EE AT BG ES HR IT FR PL
Global end of trial date

Results information
Results version number	v1(current)
This version publication date	01 Sep 2019
First version publication date	01 Sep 2019
Other versions

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

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Trial information

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Sponsor protocol code

BO25323

ISRCTN number

US NCT number

NCT02242942

WHO universal trial number (UTN)

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

Interim

Date of interim/final analysis

17 Aug 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

17 Aug 2018

Global end of trial reached?

Main objective of the trial

This study compared the efficacy and safety of a combined regimen of obinutuzumab and venetoclax versus obinutuzumab + chlorambucil in subjects with previously untreated chronic lymphocytic leukemia (CLL) and coexisting medical conditions. The study had a safety run-in phase and a main randomized phase with two treatment arms.

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

24 Dec 2014

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, 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

Australia: 47

Country: Number of subjects enrolled

New Zealand: 20

Country: Number of subjects enrolled

Austria: 6

Country: Number of subjects enrolled

Bulgaria: 33

Country: Number of subjects enrolled

Croatia: 12

Country: Number of subjects enrolled

Estonia: 5

Country: Number of subjects enrolled

Poland: 16

Country: Number of subjects enrolled

Romania: 7

Country: Number of subjects enrolled

Russian Federation: 41

Country: Number of subjects enrolled

Argentina: 1

Country: Number of subjects enrolled

Brazil: 22

Country: Number of subjects enrolled

Canada: 16

Country: Number of subjects enrolled

Mexico: 3

Country: Number of subjects enrolled

United States: 30

Country: Number of subjects enrolled

Denmark: 21

Country: Number of subjects enrolled

France: 39

Country: Number of subjects enrolled

Germany: 58

Country: Number of subjects enrolled

Italy: 26

Country: Number of subjects enrolled

Spain: 31

Country: Number of subjects enrolled

Switzerland: 3

Country: Number of subjects enrolled

United Kingdom: 8

Worldwide total number of subjects

445

EEA total number of subjects

262

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)

From 65 to 84 years

356

85 years and over

Subject disposition

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Recruitment details

A total of 445 subjects were enrolled in the study in 130 centers in 21 countries. The safety run-in cohort enrolled 13 subjects and the main randomized main part of the trial enrolled 432 subjects.

Screening details

Subjects with previously untreated CLL and coexisting medical conditions were enrolled in the study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Obinutuzumab + Chlorambucil

Arm description

Subjects received obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles comprised of 28 days.

Arm type

Experimental

Investigational medicinal product name

Chlorambucil

Investigational medicinal product code

RO0059978

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Chlorambucil was administered orally at a dose of 0.5 mg/kg on Day 1 and Day 15 of each 28-day cycle for 12 cycles.

Investigational medicinal product name

Obinutuzumab

Investigational medicinal product code

RO5072759

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received obinutuzumab 1000 mg on Days 1, 8 and 15 of Cycle 1 and 1000 mg on Day 1 through Cycles 2-6.

Obinutuzumab + Venetoclax

Arm description

Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.

Arm type

Experimental

Investigational medicinal product name

Obinutuzumab

Investigational medicinal product code

RO5072759

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received obinutuzumab 1000 mg on Days 1, 8 and 15 of Cycle 1 and 1000 mg on Day 1 through Cycles 2-6.

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

RO553-7382

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received venetoclax 400 mg daily orally for twelve 28-day cycles.

Safety Run-in Obinutuzumab + Venetoclax

Arm description

Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.

Arm type

Experimental

Investigational medicinal product name

Obinutuzumab

Investigational medicinal product code

RO5072759

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received obinutuzumab intravenously for six 28-day cycles.

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

RO553-7382

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received venetoclax 400 mg orally daily for twelve 28-day cycles.

Number of subjects in period 1	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax	Safety Run-in Obinutuzumab + Venetoclax
Started	216	216	13
Treated	214	212	13
Completed	0	0	0
Not completed	216	216	13
Adverse event, serious fatal	17	20	2
Physician decision	1	-	-
Consent withdrawn by subject	8	10	-
On-going in Study	190	186	11

Baseline characteristics

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Reporting group title

Obinutuzumab + Chlorambucil

Reporting group description

Subjects received obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles comprised of 28 days.

Reporting group title

Obinutuzumab + Venetoclax

Reporting group description

Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.

Reporting group title

Safety Run-in Obinutuzumab + Venetoclax

Reporting group description

Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.

Reporting group values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax	Safety Run-in Obinutuzumab + Venetoclax	Total
Number of subjects	216	216	13	445
Age categorical
Units: Subjects
Adults (18-64 years)	37	36	1	74
Elderly (From 65-84 years)	174	172	10	356
Elderly 85 years and over	5	8	2	15
Age Continuous
Units: Years
arithmetic mean (standard deviation)	71.1 ± 8.0	71.1 ± 8.2	75.4 ± 7.8	-
Sex: Female, Male
Units: Subjects
Female	73	70	5	148
Male	143	146	8	297

End points

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Reporting group title

Obinutuzumab + Chlorambucil

Reporting group description

Subjects received obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles comprised of 28 days.

Reporting group title

Obinutuzumab + Venetoclax

Reporting group description

Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.

Reporting group title

Safety Run-in Obinutuzumab + Venetoclax

Reporting group description

Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.

Primary: Progression Free Survival (PFS) Based on Investigator Assessment According to IWCLL Criteria

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End point title

Progression Free Survival (PFS) Based on Investigator Assessment According to IWCLL Criteria ^[1]

End point description

PFS was determined according to IWCLL 2008 criteria and defined as the time from randomisation to the first occurrence of PD or death from any cause. Disease progression was characterized by at least one of the following: 1) >/= 50% increase in the absolute number of circulating lymphocytes to at least 5*10^9/L, 2) Appearance of new palpable lymph nodes (> 15 mm in longest diameter) or any new extra-nodal lesion; 3) >/= 50% increase in the longest diameter of any previous site of lymphadenopathy; 4) >/= 50% increase in the enlargement of the liver and/or spleen; 5) Transformation to a more aggressive histology. Intent to treat (ITT) population was defined as all randomised subjects. Here, 9999 indicates that the data for the specific time point were not evaluable due to insufficient number of subjects with events.

End point type

Primary

End point timeframe

Baseline until disease progression or death up to approximately 3.75 years

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Efficacy data were analysed only for the randomised arms in the main study.

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Number of subjects analysed	216	216
Units: months
median (confidence interval 95%)	9999 (31.1 to 9999)	9999 (9999 to 9999)

Main study analysis

Comparison groups

Obinutuzumab + Venetoclax v Obinutuzumab + Chlorambucil

Number of subjects included in analysis

432

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.35

Confidence interval

level

95%

sides

2-sided

lower limit

0.23

upper limit

0.53

Secondary: Progression Free Survival (PFS) Based on Institutional Review Committee (IRC)-Assessments According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria

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End point title

Progression Free Survival (PFS) Based on Institutional Review Committee (IRC)-Assessments According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria ^[2]

End point description

PFS was determined according to IWCLL 2008 criteria and defined as the time from randomisation to the first occurrence of progressive disease (PD) or death from any cause. Disease progression was characterised by at least one of the following: 1) >/= 50% increase in the absolute number of circulating lymphocytes to at least 5*10^9/L, 2) Appearance of new palpable lymph nodes (> 15 mm in longest diameter) or any new extra-nodal lesion; 3) >/= 50% increase in the longest diameter of any previous site of lymphadenopathy; 4) >/= 50% increase in the enlargement of the liver and/or spleen; 5) Transformation to a more aggressive histology. ITT population was defined as all randomised subjects. Here, 9999 indicates that the data for the specific time point were not evaluable due to insufficient number of subjects with events.

End point type

Secondary

End point timeframe

Baseline until disease progression or death up to approximately 3.75 years

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Efficacy data were analysed only for the randomised arms in the main study.

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Number of subjects analysed	216	216
Units: months
median (confidence interval 95%)	9999 (31.1 to 9999)	9999 (9999 to 9999)

No statistical analyses for this end point

Secondary: Percentage of Subjects With an Overall Response (OR) at Completion of Treatment, as Determined by the Investigator According to IWCLL Criteria

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End point title

Percentage of Subjects With an Overall Response (OR) at Completion of Treatment, as Determined by the Investigator According to IWCLL Criteria ^[3]

End point description

OR: complete response (CR), CR with incomplete bone marrow recovery (CRi), or partial response (PR) according to IWCLL 2008 criteria. CR requires all of the following: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and computed tomography (CT) scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, bone marrow normocellular for age without clonal infiltrate (except for Cri). PR: two of the following for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following counts: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L. ITT population: all randomised subjects. 9999: data not evaluable due to insufficient number of events.

End point type

Secondary

End point timeframe

At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Efficacy data were analysed only for the randomised arms in the main study.

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Number of subjects analysed	216	216
Units: percentage of subjects
number (confidence interval 95%)	71.3 (64.77 to 77.23)	84.7 (79.22 to 89.24)

No statistical analyses for this end point

Secondary: Percentage of Subjects With a Complete Response Rate (CRR) at the Completion of Treatment Assessment as Determined by the Investigator According to IWCLL Criteria

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End point title

Percentage of Subjects With a Complete Response Rate (CRR) at the Completion of Treatment Assessment as Determined by the Investigator According to IWCLL Criteria ^[4]

End point description

CRR was defined as the rate of a clinical response of CR or CRi according to IWCLL 2008 criteria. CR requires all of the following: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and CT scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, bone marrow at least normocellular for age without clonal infiltrate (except for Cri). ITT population was defined as all randomised subjects.

End point type

Secondary

End point timeframe

At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Efficacy data were analysed only for the randomised arms in the main study.

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Number of subjects analysed	216	216
Units: percentage of subjects
number (confidence interval 95%)	23.1 (17.70 to 29.35)	49.5 (42.68 to 56.40)

No statistical analyses for this end point

Secondary: Percentage of Subjects With Minimal Residual Disease (MRD) Negativity in Peripheral Blood as Measured by Allele-Specific Oligonucleotide Polymerase Chain Reaction (ASO-PCR) at Completion of Treatment

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End point title

Percentage of Subjects With Minimal Residual Disease (MRD) Negativity in Peripheral Blood as Measured by Allele-Specific Oligonucleotide Polymerase Chain Reaction (ASO-PCR) at Completion of Treatment ^[5]

End point description

MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in peripheral blood. ITT population was defined as all randomised subjects.

End point type

Secondary

End point timeframe

At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Efficacy data were analysed only for the randomised arms in the main study.

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Number of subjects analysed	216	216
Units: percentage of subjects
number (confidence interval 95%)	35.2 (28.83 to 41.95)	75.5 (69.17 to 81.05)

No statistical analyses for this end point

Secondary: Percentage of Subjects With MRD Negativity in Bone marrow as Measured by ASO-PCR at Completion of Treatment

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End point title

Percentage of Subjects With MRD Negativity in Bone marrow as Measured by ASO-PCR at Completion of Treatment ^[6]

End point description

MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in bone marrow. ITT population was defined as all randomised subjects.

End point type

Secondary

End point timeframe

At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Efficacy data were analysed only for the randomised arms in the main study.

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Number of subjects analysed	216	216
Units: percentage of subjects
number (confidence interval 95%)	17.1 (12.36 to 22.83)	56.9 (50.05 to 63.64)

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS) ^[7]

End point description

OS was defined as the time between the date of randomization and the date of death due to any cause. ITT population was defined as all randomised subjects.

End point type

Secondary

End point timeframe

Baseline until death, up to approximately 5.75 years

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data will be analysed only for the randomised arms in the main study once data collection is complete.

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Number of subjects analysed	0 ^[8]	0 ^[9]
Units: months
median (confidence interval 95%)	( to )	( to )

Notes
[8] - Data to be reported upon study completion.
[9] - Data to be reported upon study completion.

No statistical analyses for this end point

Secondary: Percentage of Subjects With MRD Negativity in Peripheral Blood as Measured by ASO-PCR at Completion of Combination Treatment Assessment

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End point title

Percentage of Subjects With MRD Negativity in Peripheral Blood as Measured by ASO-PCR at Completion of Combination Treatment Assessment ^[10]

End point description

MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in peripheral blood. ITT population was defined as all randomised subjects.

End point type

Secondary

End point timeframe

Day 1 Cycle 9 or 3 months after last IV infusion, approximately 9 months

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Efficacy data were analysed only for the randomised arms in the main study.

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Number of subjects analysed	216	216
Units: percentage of subjects
number (confidence interval 95%)	38.4 (31.91 to 45.27)	71.3 (64.77 to 77.23)

No statistical analyses for this end point

Secondary: Percentage of Subjects With MRD Negativity in Bone Marrow as Measured by ASO-PCR at Completion of Combination Treatment Assessment

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End point title

Percentage of Subjects With MRD Negativity in Bone Marrow as Measured by ASO-PCR at Completion of Combination Treatment Assessment ^[11]

End point description

MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in bone marrow. ITT population was defined as all randomised subjects.

End point type

Secondary

End point timeframe

Day 1 Cycle 9 or 3 months after last IV infusion at approximately 9 months

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Efficacy data were analysed only for the randomised arms in the main study.

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Number of subjects analysed	216	216
Units: percentage of subjects
number (confidence interval 95%)	13.0 (8.79 to 18.19)	51.4 (44.51 to 58.23)

No statistical analyses for this end point

Secondary: Percentage of Subjects With OR at Completion of Combination Treatment Response Assessment

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End point title

Percentage of Subjects With OR at Completion of Combination Treatment Response Assessment ^[12]

End point description

OR was defined as CR, CRi or PR according to IWCLL 2008 criteria. CR required all of the following: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination, no hepatomegaly or splenomegaly, Absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L. PR: two of the following features for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L. ITT population was defined as all randomised subjects.

End point type

Secondary

End point timeframe

Day 1 Cycle 7 or 28 days after last IV infusion, approximately 6 months

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Efficacy data were analysed only for the randomised arms in the main study.

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Number of subjects analysed	216	216
Units: percentage of subjects
number (confidence interval 95%)	86.6 (81.29 to 90.82)	88.4 (83.39 to 92.37)

No statistical analyses for this end point

Secondary: Duration of Objective Response (DOR)

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End point title

Duration of Objective Response (DOR) ^[13]

End point description

PD was defined as lymphadenopathy, >=50% increase in liver or spleen size, >=50% increase in lymphocyte count, transformation to a more aggressive histology or occurrence of cytopenia. ITT population was defined as all randomised subjects.

End point type

Secondary

End point timeframe

Time from the first occurrence of a documented objective response to the time of PD as determined by the investigator or death from any cause, up to approximately 5.75 years

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data will be analysed only for the randomised arms in the main study once data collection is complete.

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Number of subjects analysed	0 ^[14]	0 ^[15]
Units: months
median (confidence interval 95%)	( to )	( to )

Notes
[14] - Data to be reported upon study completion.
[15] - Data to be reported upon study completion.

No statistical analyses for this end point

Secondary: Percentage of Subjects By Best Response Achieved (CR, CRi, PR, Stable Disease (SD), or PD)

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End point title

Percentage of Subjects By Best Response Achieved (CR, CRi, PR, Stable Disease (SD), or PD) ^[16]

End point description

CR: Peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and CT scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, bone marrow normocellular for age without clonal infiltrate (except for Cri). PR: any 2 for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L. PD: lymphadenopathy, >=50% increase in liver or spleen size, >=50% increase in lymphocyte count, transformation to a more aggressive histology or occurrence of cytopenia. SD: non-response used to characterize subjects who did not achieve a CR or a PR, and who have not exhibited PD. ITT population: all randomised subjects.

End point type

Secondary

End point timeframe

Baseline up to the completion of treatment assessment 3 months after treatment completion (up to approximately 15 months)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Efficacy data were analysed only for the randomised arms in the main study.

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Number of subjects analysed	216	216
Units: percentage of subjects
number (not applicable)
CR	56.0	70.4
CRi	5.6	7.9
PR	29.2	13.4
SD	1.9	0.5
PD	0.5	0.5

No statistical analyses for this end point

Secondary: Event-Free Survival

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End point title

Event-Free Survival ^[17]

End point description

ITT population was defined as all randomised subjects.

End point type

Secondary

End point timeframe

Time between date of randomisation and the date of disease progression/relapse on the basis of investigator-assessment, death, or start of a new anti-leukemic therapy, up to 5.75 years

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data will be analysed only for the randomised arms in the main study once data collection is complete.

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Number of subjects analysed	0 ^[18]	0 ^[19]
Units: months
median (confidence interval 95%)	( to )	( to )

Notes
[18] - Data to be reported upon study completion.
[19] - Data to be reported upon study completion.

No statistical analyses for this end point

Secondary: Time to Next Anti-Leukemic Treatment

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End point title

Time to Next Anti-Leukemic Treatment ^[20]

End point description

ITT population was defined as all randomised subjects.

End point type

Secondary

End point timeframe

Time between the date of randomization and the date of first intake of new anti-leukemic therapy, up to 5.75 years

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data will be analysed only for the randomised arms in the main study once data collection is complete.

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Number of subjects analysed	0 ^[21]	0 ^[22]
Units: months
median (confidence interval 95%)	( to )	( to )

Notes
[21] - Data to be reported upon study completion.
[22] - Data to be reported upon study completion.

No statistical analyses for this end point

Secondary: Number of Subjects With Adverse Events (AEs)

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End point title

Number of Subjects With Adverse Events (AEs) ^[23]

End point description

An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE 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 AEs. Safety population was defined as all subjects who received at least one dose of any study medication (i.e., obinutuzumab, venetoclax, or chlorambucil).

End point type

Secondary

End point timeframe

Up to approximately 5.75 years

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data will be analysed only for the randomised arms in the main study once data collection is complete.

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Number of subjects analysed	0 ^[24]	0 ^[25]
Units: subjects

Notes
[24] - Data to be reported upon study completion.
[25] - Data to be reported upon study completion.

No statistical analyses for this end point

Secondary: Percentage of Subjects With CD19 + /CD5+ B Cells or CD14+ monocytes

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End point title

Percentage of Subjects With CD19 + /CD5+ B Cells or CD14+ monocytes

End point description

ITT population was defined as all randomised subjects.

End point type

Secondary

End point timeframe

Baseline up to approximately 5.75 years

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax	Safety Run-in Obinutuzumab + Venetoclax
Number of subjects analysed	0 ^[26]	0 ^[27]	0 ^[28]
Units: percentage of subjects
number (not applicable)

Notes
[26] - Data to be reported upon study completion.
[27] - Data to be reported upon study completion.
[28] - Data to be reported upon study completion.

No statistical analyses for this end point

Secondary: Percentage of Subjects With Human-Anti-Human Antibodies

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End point title

Percentage of Subjects With Human-Anti-Human Antibodies

End point description

ITT population was defined as all randomised subjects.

End point type

Secondary

End point timeframe

Baseline up to approximately 5.75 years

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax	Safety Run-in Obinutuzumab + Venetoclax
Number of subjects analysed	0 ^[29]	0 ^[30]	0 ^[31]
Units: percentage of subjects
number (not applicable)

Notes
[29] - Data to be reported upon study completion.
[30] - Data to be reported upon study completion.
[31] - Data to be reported upon study completion.

No statistical analyses for this end point

Secondary: Percentage of Subjects Recorded as Premature Study Withdrawals

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End point title

Percentage of Subjects Recorded as Premature Study Withdrawals

End point description

ITT population was defined as all randomised subjects.

End point type

Secondary

End point timeframe

Up to approximately 5.75 years

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax	Safety Run-in Obinutuzumab + Venetoclax
Number of subjects analysed	0 ^[32]	0 ^[33]	0 ^[34]
Units: percentage of subjects
number (not applicable)

Notes
[32] - Data to be reported upon study completion.
[33] - Data to be reported upon study completion.
[34] - Data to be reported upon study completion.

No statistical analyses for this end point

Secondary: Plasma Concentrations of Venetoclax

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End point title

Plasma Concentrations of Venetoclax ^[35]

End point description

Analysis population consisted of those subjects from whom one or more plasma samples were collected and who had received at least one dose of venetoclax treatment.

End point type

Secondary

End point timeframe

Pre-venetoclax dose (0 hour) and 4 hours post- venetoclax dose on Day 1 Cycle 4

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Samples were only collected for the obinutuzumab + venetoclax arm in the study.

End point values	Obinutuzumab + Venetoclax
Number of subjects analysed	201
Units: μg/mL
arithmetic mean (standard deviation)
Pre-Dose (n=129)	0.578 ± 0.533
4 hours Post-Dose (n=142)	1.21 ± 0.765

No statistical analyses for this end point

Secondary: Serum Concentrations of Obinutuzumab

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End point title

Serum Concentrations of Obinutuzumab ^[36]

End point description

Analysis population consisted of subjects from whom one or more serum samples were collected and who had received at least one dose of obinutuzumab treatment.

End point type

Secondary

End point timeframe

Pre-obinutuzumab infusion (0 hour) and end of obinutuzumab infusion on Day 1 Cycle 4

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Samples were only collected for the obinutuzumab + venetoclax arm in the study.

End point values	Obinutuzumab + Venetoclax
Number of subjects analysed	201
Units: μg/mL
arithmetic mean (standard deviation)
Pre-Dose (n=133)	258 ± 140
4 hours Post-Dose (n=133)	568 ± 187

No statistical analyses for this end point

Secondary: Change From Baseline in M.D. Anderson Symptom Inventory-CLL (MDASI-CLL) score

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End point title

Change From Baseline in M.D. Anderson Symptom Inventory-CLL (MDASI-CLL) score ^[37]

End point description

MDASI-CLL: questionnaire of 25 items related to CLL specific symptoms that a subject may have experienced in the past 24 hours. Subjects were asked to rate the severity of 13 symptoms called mean core symptom severity (i.e., pain, fatigue, nausea, disturbed sleep, distressed, shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, sadness, vomiting, numbness or tingling), 6 disease-specific symptoms called mean module symptom severity (night sweats, fevers and chills, lymph node swelling, diarrhea, easy bruising or bleeding, constipation) and 6 mean interference on life questions (i.e., general activity, walking, work, mood, relations with other people, enjoyment of life) on a scale from 0 to 10 with 0 indicating that the symptom is “not present”/“did not interfere” with the subject’s activities and 10 indicating “as bad as you can imagine”/“interfered completely”. Scores were averaged (range 0 to 10) for each part.

End point type

Secondary

End point timeframe

Baseline up to approximately 5.75 years

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data will be analysed only for the randomised arms in the main study once data collection is complete.

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Number of subjects analysed	0 ^[38]	0 ^[39]
Units: score on a scale
arithmetic mean (standard deviation)	±	±

Notes
[38] - Data to be reported upon study completion.
[39] - Data to be reported upon study completion.

No statistical analyses for this end point

Secondary: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQC30)

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End point title

Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQC30)

End point description

The EORTC QLQ-C30 is a validated and reliable self-report measure consisting of 30 questions incorporated into five functional scales (physical, role, cognitive, emotional, and social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), and a global health status/global quality−of−life scale. The remaining single items (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) assess the additional symptoms experienced by patients with cancer and the perceived financial burden of treatment. The 28 function and symptom items were scored on a 4-point scale that ranged from “not at all” to “very much,” and the 2 global health status/global quality-of-life items were scored on a 7-point scale that ranged from “very poor” to “excellent.” Raw average scale scores were linearly transformed to range 0-100 with higher scores indicating higher response levels (i.e., higher functioning, higher symptom severity).

End point type

Secondary

End point timeframe

Baseline up to approximately 5.75 years

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax	Safety Run-in Obinutuzumab + Venetoclax
Number of subjects analysed	0 ^[40]	0 ^[41]	0 ^[42]
Units: score on a scale
arithmetic mean (standard deviation)	±	±	±

Notes
[40] - Data to be reported upon study completion.
[41] - Data to be reported upon study completion.
[42] - Data to be reported upon study completion.

No statistical analyses for this end point

Secondary: Change From Baseline in EuroQol 5 Dimension Questionnaire (EQ-5D-3L)

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End point title

Change From Baseline in EuroQol 5 Dimension Questionnaire (EQ-5D-3L) ^[43]

End point description

The EQ-5D-3L questionnaire is a generic, preference based health utility measure that assesses 5 health states (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and is used to build a composite of the patient’s health status. The EQ-5D-3L was employed in this study to calculate health utilities for economic modeling, which ranged 0-1. The EQ-5D-3L also contained a visual analog scale (VAS) to assess the participant’s overall health, which ranged from 0-100 with a higher score indicating a worse health status.

End point type

Secondary

End point timeframe

Baseline up to approximately 5.75 years

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data will be analysed only for the randomised arms in the main study once data collection is complete.

End point values	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Number of subjects analysed	0 ^[44]	0 ^[45]
Units: score on a scale
arithmetic mean (standard deviation)	±	±

Notes
[44] - Data to be reported upon study completion.
[45] - Data to be reported upon study completion.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All AEs: up to 1 year, Grade 3-4 AEs: up to 1.5 years, Grade 3-4 major infections: up to 3 years (causality only if subject received leukemic treatment). SAEs: before PD up to 3.75 years, after PD only related SAEs and second primary malignancies.

Adverse event reporting additional description

Safety population was defined as all subjects who received at least one dose of any study medication (i.e., obinutuzumab, venetoclax, or chlorambucil).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Obinutuzumab + Chlorambucil

Reporting group description

Subjects received obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles comprised of 28 days.

Reporting group title

Obinutuzumab + Venetoclax

Reporting group description

Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.

Reporting group title

Safety Run-in Obinutuzumab + Venetoclax

Reporting group description

Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.

Serious adverse events	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax	Safety Run-in Obinutuzumab + Venetoclax
Total subjects affected by serious adverse events
subjects affected / exposed	90 / 214 (42.06%)	104 / 212 (49.06%)	10 / 13 (76.92%)
number of deaths (all causes)	9	16	2
number of deaths resulting from adverse events	1	5	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Anal squamous cell carcinoma
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder cancer
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Bladder cancer recurrent
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder neoplasm
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Invasive breast carcinoma
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Invasive ductal breast carcinoma
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung adenocarcinoma
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung adenocarcinoma stage IV
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	1 / 214 (0.47%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastatic malignant melanoma
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Myelodysplastic syndrome
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Pancreatic carcinoma metastatic
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Penile cancer
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 214 (0.00%)	2 / 212 (0.94%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostate cancer metastatic
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Salivary gland adenoma
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sarcoma of skin
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Skin squamous cell carcinoma metastatic
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	3 / 214 (1.40%)	2 / 212 (0.94%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
T-cell lymphoma
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic stenosis
subjects affected / exposed	0 / 214 (0.00%)	2 / 212 (0.94%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	2 / 214 (0.93%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombophlebitis superficial
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Aortic valve replacement
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Medical device removal
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Adverse drug reaction
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chills
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device related thrombosis
subjects affected / exposed	1 / 214 (0.47%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	1 / 214 (0.47%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Pyrexia
subjects affected / exposed	7 / 214 (3.27%)	8 / 212 (3.77%)	2 / 13 (15.38%)
occurrences causally related to treatment / all	5 / 8	3 / 8	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Cystocele
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis chronic
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchopneumopathy
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchospasm
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	2 / 214 (0.93%)	3 / 212 (1.42%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 2	1 / 10	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	1 / 214 (0.47%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 214 (0.00%)	2 / 212 (0.94%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	1 / 214 (0.47%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	2 / 214 (0.93%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pulmonary oedema
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Delirium
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	3 / 214 (1.40%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	4 / 214 (1.87%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	4 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood urea increased
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prothrombin time prolonged
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
White blood cell count decreased
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Chillblains
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clavicle fracture
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	13 / 214 (6.07%)	9 / 212 (4.25%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	12 / 13	9 / 9	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Limb injury
subjects affected / exposed	2 / 214 (0.93%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Overdose
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subcutaneous haematoma
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thoracic vertebral fracture
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transfusion reaction
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Traumatic haemothorax
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vasoplegia syndrome
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound evisceration
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Gilbert's syndrome
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 214 (0.00%)	2 / 212 (0.94%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	3 / 214 (1.40%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 3	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	2 / 214 (0.93%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 214 (0.47%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Cardiac failure
subjects affected / exposed	1 / 214 (0.47%)	3 / 212 (1.42%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Mitral valve incompetence
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	3 / 214 (1.40%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	1 / 4	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	2 / 214 (0.93%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radiculopathy
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	2 / 214 (0.93%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 214 (0.47%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vertebrobasilar insufficiency
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 214 (0.47%)	2 / 212 (0.94%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Autoimmune haemolytic anaemia
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coombs negative haemolytic anaemia
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	8 / 214 (3.74%)	11 / 212 (5.19%)	3 / 13 (23.08%)
occurrences causally related to treatment / all	9 / 10	11 / 12	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune thrombocytopenic purpura
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 214 (0.47%)	3 / 212 (1.42%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Splenic infarction
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Splenomegaly
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	5 / 214 (2.34%)	2 / 212 (0.94%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	5 / 5	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 214 (0.00%)	2 / 212 (0.94%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Amaurosis fugax
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye inflammation
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Keratitis
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 214 (0.00%)	2 / 212 (0.94%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Duodenal ulcer haemorrhage
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Faecaloma
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric ulcer perforation
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 214 (0.47%)	2 / 212 (0.94%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Large intestine polyp
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Blister
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic foot
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urticaria
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion
subjects affected / exposed	2 / 214 (0.93%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spondylitis
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Atypical pneumonia
subjects affected / exposed	1 / 214 (0.47%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	2 / 214 (0.93%)	2 / 212 (0.94%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	2 / 2	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchopulmonary aspergillosis
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Candida infection
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 214 (0.00%)	3 / 212 (1.42%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis infective
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic sinusitis
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cytomegalovirus infection
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 214 (0.00%)	2 / 212 (0.94%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eczema infected
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	2 / 214 (0.93%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal infection
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatitis E
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	2 / 214 (0.93%)	2 / 212 (0.94%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 2	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Infectious pleural effusion
subjects affected / exposed	1 / 214 (0.47%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	2 / 214 (0.93%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Listeriosis
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	2 / 214 (0.93%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscle abscess
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenic infection
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ophthalmic herpes zoster
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	1 / 214 (0.47%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	9 / 214 (4.21%)	10 / 212 (4.72%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	6 / 11	3 / 10	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Pneumonia fungal
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Pneumonia haemophilus
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia respiratory syncytial viral
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pseudomembranous colitis
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 214 (0.47%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 214 (0.47%)	2 / 212 (0.94%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 214 (0.93%)	6 / 212 (2.83%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	1 / 2	3 / 7	0 / 2
deaths causally related to treatment / all	0 / 1	2 / 5	0 / 1
Septic shock
subjects affected / exposed	2 / 214 (0.93%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Sinusitis aspergillus
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 214 (0.47%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 214 (0.47%)	2 / 212 (0.94%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 2	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Varicella zoster virus infection
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound infection fungal
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	2 / 214 (0.93%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 214 (0.47%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tumour lysis syndrome
subjects affected / exposed	4 / 214 (1.87%)	1 / 212 (0.47%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	4 / 4	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax	Safety Run-in Obinutuzumab + Venetoclax
Total subjects affected by non serious adverse events
subjects affected / exposed	205 / 214 (95.79%)	193 / 212 (91.04%)	12 / 13 (92.31%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	5 / 214 (2.34%)	6 / 212 (2.83%)	1 / 13 (7.69%)
occurrences all number	6	6	1
Benign breast neoplasm
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	1
Seborrhoeic keratosis
subjects affected / exposed	0 / 214 (0.00%)	2 / 212 (0.94%)	1 / 13 (7.69%)
occurrences all number	0	2	1
Skin papilloma
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences all number	0	1	1
Vascular disorders
Flushing
subjects affected / exposed	3 / 214 (1.40%)	2 / 212 (0.94%)	2 / 13 (15.38%)
occurrences all number	3	2	2
Hypertension
subjects affected / exposed	11 / 214 (5.14%)	12 / 212 (5.66%)	0 / 13 (0.00%)
occurrences all number	12	17	0
Hypotension
subjects affected / exposed	8 / 214 (3.74%)	11 / 212 (5.19%)	2 / 13 (15.38%)
occurrences all number	10	15	2
Thrombophlebitis
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	1
General disorders and administration site conditions
Adverse drug reaction
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	1
Asthenia
subjects affected / exposed	17 / 214 (7.94%)	14 / 212 (6.60%)	0 / 13 (0.00%)
occurrences all number	20	20	0
Chills
subjects affected / exposed	10 / 214 (4.67%)	12 / 212 (5.66%)	1 / 13 (7.69%)
occurrences all number	13	14	1
Extravasation
subjects affected / exposed	2 / 214 (0.93%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	2	0	1
Fatigue
subjects affected / exposed	29 / 214 (13.55%)	32 / 212 (15.09%)	3 / 13 (23.08%)
occurrences all number	36	40	6
Influenza like illness
subjects affected / exposed	3 / 214 (1.40%)	4 / 212 (1.89%)	1 / 13 (7.69%)
occurrences all number	3	4	1
Oedema
subjects affected / exposed	7 / 214 (3.27%)	3 / 212 (1.42%)	1 / 13 (7.69%)
occurrences all number	7	3	1
Oedema peripheral
subjects affected / exposed	16 / 214 (7.48%)	17 / 212 (8.02%)	1 / 13 (7.69%)
occurrences all number	18	20	2
Pyrexia
subjects affected / exposed	26 / 214 (12.15%)	40 / 212 (18.87%)	3 / 13 (23.08%)
occurrences all number	28	53	4
Sensation of foreign body
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	24 / 214 (11.21%)	33 / 212 (15.57%)	6 / 13 (46.15%)
occurrences all number	27	37	6
Dyspnoea
subjects affected / exposed	11 / 214 (5.14%)	11 / 212 (5.19%)	1 / 13 (7.69%)
occurrences all number	12	12	2
Epistaxis
subjects affected / exposed	4 / 214 (1.87%)	3 / 212 (1.42%)	1 / 13 (7.69%)
occurrences all number	5	3	1
Pharyngeal paraesthesia
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	1
Productive cough
subjects affected / exposed	3 / 214 (1.40%)	6 / 212 (2.83%)	1 / 13 (7.69%)
occurrences all number	3	6	2
Rhinorrhoea
subjects affected / exposed	3 / 214 (1.40%)	3 / 212 (1.42%)	1 / 13 (7.69%)
occurrences all number	3	3	1
Throat irritation
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	1
Psychiatric disorders
Depression
subjects affected / exposed	1 / 214 (0.47%)	8 / 212 (3.77%)	1 / 13 (7.69%)
occurrences all number	1	8	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	13 / 214 (6.07%)	11 / 212 (5.19%)	0 / 13 (0.00%)
occurrences all number	15	15	0
Aspartate aminotransferase increased
subjects affected / exposed	17 / 214 (7.94%)	12 / 212 (5.66%)	0 / 13 (0.00%)
occurrences all number	20	14	0
Blood albumin decreased
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	1
Blood creatinine increased
subjects affected / exposed	6 / 214 (2.80%)	7 / 212 (3.30%)	1 / 13 (7.69%)
occurrences all number	6	9	2
Blood glucose increased
subjects affected / exposed	1 / 214 (0.47%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences all number	1	1	1
Blood lactate dehydrogenase increased
subjects affected / exposed	2 / 214 (0.93%)	2 / 212 (0.94%)	2 / 13 (15.38%)
occurrences all number	2	2	2
Blood magnesium decreased
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences all number	0	1	1
Blood phosphorus increased
subjects affected / exposed	1 / 214 (0.47%)	2 / 212 (0.94%)	1 / 13 (7.69%)
occurrences all number	1	4	1
C-reactive protein increased
subjects affected / exposed	2 / 214 (0.93%)	4 / 212 (1.89%)	1 / 13 (7.69%)
occurrences all number	2	4	1
Neutrophil count decreased
subjects affected / exposed	11 / 214 (5.14%)	10 / 212 (4.72%)	0 / 13 (0.00%)
occurrences all number	32	27	0
Procalcitonin increased
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	1
Protein total decreased
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	1
Transaminases increased
subjects affected / exposed	2 / 214 (0.93%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	2	0	1
Weight decreased
subjects affected / exposed	5 / 214 (2.34%)	5 / 212 (2.36%)	1 / 13 (7.69%)
occurrences all number	5	5	1
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences all number	0	1	1
Eye contusion
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences all number	0	1	1
Fall
subjects affected / exposed	8 / 214 (3.74%)	5 / 212 (2.36%)	1 / 13 (7.69%)
occurrences all number	11	7	1
Head injury
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	1
Infusion related reaction
subjects affected / exposed	103 / 214 (48.13%)	89 / 212 (41.98%)	9 / 13 (69.23%)
occurrences all number	131	122	10
Limb injury
subjects affected / exposed	4 / 214 (1.87%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	4	0	1
Skin abrasion
subjects affected / exposed	0 / 214 (0.00%)	2 / 212 (0.94%)	1 / 13 (7.69%)
occurrences all number	0	2	1
Cardiac disorders
Coronary artery disease
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	1
Tachycardia
subjects affected / exposed	1 / 214 (0.47%)	5 / 212 (2.36%)	1 / 13 (7.69%)
occurrences all number	1	5	1
Ventricular extrasystoles
subjects affected / exposed	1 / 214 (0.47%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences all number	1	1	1
Nervous system disorders
Dizziness
subjects affected / exposed	17 / 214 (7.94%)	16 / 212 (7.55%)	4 / 13 (30.77%)
occurrences all number	20	18	5
Headache
subjects affected / exposed	21 / 214 (9.81%)	23 / 212 (10.85%)	3 / 13 (23.08%)
occurrences all number	24	29	3
Paraesthesia
subjects affected / exposed	1 / 214 (0.47%)	4 / 212 (1.89%)	1 / 13 (7.69%)
occurrences all number	1	4	1
Presyncope
subjects affected / exposed	1 / 214 (0.47%)	1 / 212 (0.47%)	2 / 13 (15.38%)
occurrences all number	1	1	3
Somnolence
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences all number	0	1	1
Syncope
subjects affected / exposed	4 / 214 (1.87%)	5 / 212 (2.36%)	2 / 13 (15.38%)
occurrences all number	4	5	2
Tremor
subjects affected / exposed	3 / 214 (1.40%)	6 / 212 (2.83%)	1 / 13 (7.69%)
occurrences all number	4	6	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	39 / 214 (18.22%)	33 / 212 (15.57%)	2 / 13 (15.38%)
occurrences all number	55	53	2
Leukopenia
subjects affected / exposed	13 / 214 (6.07%)	12 / 212 (5.66%)	1 / 13 (7.69%)
occurrences all number	19	23	1
Neutropenia
subjects affected / exposed	122 / 214 (57.01%)	121 / 212 (57.08%)	8 / 13 (61.54%)
occurrences all number	294	370	12
Thrombocytopenia
subjects affected / exposed	49 / 214 (22.90%)	49 / 212 (23.11%)	2 / 13 (15.38%)
occurrences all number	76	86	5
Ear and labyrinth disorders
Excessive cerumen production
subjects affected / exposed	0 / 214 (0.00%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences all number	0	1	1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	10 / 214 (4.67%)	11 / 212 (5.19%)	2 / 13 (15.38%)
occurrences all number	11	15	2
Abdominal pain upper
subjects affected / exposed	4 / 214 (1.87%)	7 / 212 (3.30%)	1 / 13 (7.69%)
occurrences all number	4	7	1
Constipation
subjects affected / exposed	19 / 214 (8.88%)	28 / 212 (13.21%)	5 / 13 (38.46%)
occurrences all number	23	32	6
Diarrhoea
subjects affected / exposed	32 / 214 (14.95%)	59 / 212 (27.83%)	5 / 13 (38.46%)
occurrences all number	42	99	8
Dry mouth
subjects affected / exposed	4 / 214 (1.87%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	4	0	1
Dyspepsia
subjects affected / exposed	3 / 214 (1.40%)	7 / 212 (3.30%)	1 / 13 (7.69%)
occurrences all number	3	7	1
Epigastric discomfort
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	1
Haemorrhoids
subjects affected / exposed	0 / 214 (0.00%)	2 / 212 (0.94%)	1 / 13 (7.69%)
occurrences all number	0	2	1
Nausea
subjects affected / exposed	46 / 214 (21.50%)	40 / 212 (18.87%)	4 / 13 (30.77%)
occurrences all number	62	61	7
Stomatitis
subjects affected / exposed	2 / 214 (0.93%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences all number	2	1	2
Vomiting
subjects affected / exposed	18 / 214 (8.41%)	21 / 212 (9.91%)	3 / 13 (23.08%)
occurrences all number	22	27	3
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	6 / 214 (2.80%)	4 / 212 (1.89%)	2 / 13 (15.38%)
occurrences all number	7	4	2
Erythema
subjects affected / exposed	4 / 214 (1.87%)	2 / 212 (0.94%)	2 / 13 (15.38%)
occurrences all number	4	2	2
Pruritus
subjects affected / exposed	9 / 214 (4.21%)	18 / 212 (8.49%)	6 / 13 (46.15%)
occurrences all number	9	20	6
Rash
subjects affected / exposed	12 / 214 (5.61%)	12 / 212 (5.66%)	2 / 13 (15.38%)
occurrences all number	13	12	3
Urticaria
subjects affected / exposed	5 / 214 (2.34%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	5	0	1
Renal and urinary disorders
Dysuria
subjects affected / exposed	2 / 214 (0.93%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences all number	2	1	1
Renal failure
subjects affected / exposed	1 / 214 (0.47%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences all number	1	1	3
Renal impairment
subjects affected / exposed	0 / 214 (0.00%)	2 / 212 (0.94%)	1 / 13 (7.69%)
occurrences all number	0	2	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	18 / 214 (8.41%)	16 / 212 (7.55%)	1 / 13 (7.69%)
occurrences all number	23	19	1
Back pain
subjects affected / exposed	20 / 214 (9.35%)	21 / 212 (9.91%)	2 / 13 (15.38%)
occurrences all number	21	24	2
Groin pain
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	1
Intervertebral disc protrusion
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	1
Muscle spasms
subjects affected / exposed	11 / 214 (5.14%)	10 / 212 (4.72%)	1 / 13 (7.69%)
occurrences all number	11	11	1
Musculoskeletal chest pain
subjects affected / exposed	0 / 214 (0.00%)	2 / 212 (0.94%)	2 / 13 (15.38%)
occurrences all number	0	4	2
Musculoskeletal pain
subjects affected / exposed	4 / 214 (1.87%)	7 / 212 (3.30%)	1 / 13 (7.69%)
occurrences all number	4	8	2
Pain in extremity
subjects affected / exposed	13 / 214 (6.07%)	10 / 212 (4.72%)	1 / 13 (7.69%)
occurrences all number	14	11	1
Infections and infestations
Bronchitis
subjects affected / exposed	5 / 214 (2.34%)	11 / 212 (5.19%)	1 / 13 (7.69%)
occurrences all number	6	14	2
Cystitis
subjects affected / exposed	2 / 214 (0.93%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences all number	2	1	1
Ear infection
subjects affected / exposed	0 / 214 (0.00%)	2 / 212 (0.94%)	1 / 13 (7.69%)
occurrences all number	0	2	1
Eye infection
subjects affected / exposed	1 / 214 (0.47%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	1	0	3
Herpes zoster
subjects affected / exposed	6 / 214 (2.80%)	9 / 212 (4.25%)	1 / 13 (7.69%)
occurrences all number	7	9	1
Influenza
subjects affected / exposed	4 / 214 (1.87%)	3 / 212 (1.42%)	1 / 13 (7.69%)
occurrences all number	4	3	1
Localised infection
subjects affected / exposed	3 / 214 (1.40%)	1 / 212 (0.47%)	1 / 13 (7.69%)
occurrences all number	3	1	1
Nasopharyngitis
subjects affected / exposed	14 / 214 (6.54%)	16 / 212 (7.55%)	0 / 13 (0.00%)
occurrences all number	16	16	0
Oral herpes
subjects affected / exposed	4 / 214 (1.87%)	5 / 212 (2.36%)	1 / 13 (7.69%)
occurrences all number	5	7	4
Paronychia
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	1
Pneumonia
subjects affected / exposed	3 / 214 (1.40%)	6 / 212 (2.83%)	1 / 13 (7.69%)
occurrences all number	3	9	1
Respiratory tract infection
subjects affected / exposed	6 / 214 (2.80%)	10 / 212 (4.72%)	1 / 13 (7.69%)
occurrences all number	7	14	3
Rhinitis
subjects affected / exposed	5 / 214 (2.34%)	2 / 212 (0.94%)	1 / 13 (7.69%)
occurrences all number	6	3	1
Sinusitis
subjects affected / exposed	6 / 214 (2.80%)	8 / 212 (3.77%)	1 / 13 (7.69%)
occurrences all number	6	8	1
Upper respiratory tract infection
subjects affected / exposed	15 / 214 (7.01%)	16 / 212 (7.55%)	2 / 13 (15.38%)
occurrences all number	17	19	4
Urinary tract infection
subjects affected / exposed	9 / 214 (4.21%)	10 / 212 (4.72%)	1 / 13 (7.69%)
occurrences all number	10	13	1
Viral skin infection
subjects affected / exposed	0 / 214 (0.00%)	0 / 212 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	6 / 214 (2.80%)	10 / 212 (4.72%)	1 / 13 (7.69%)
occurrences all number	8	10	1
Gout
subjects affected / exposed	1 / 214 (0.47%)	3 / 212 (1.42%)	1 / 13 (7.69%)
occurrences all number	2	4	1
Hyperglycaemia
subjects affected / exposed	7 / 214 (3.27%)	14 / 212 (6.60%)	2 / 13 (15.38%)
occurrences all number	7	16	4
Hyperkalaemia
subjects affected / exposed	5 / 214 (2.34%)	4 / 212 (1.89%)	5 / 13 (38.46%)
occurrences all number	6	13	7
Hyperphosphataemia
subjects affected / exposed	3 / 214 (1.40%)	4 / 212 (1.89%)	1 / 13 (7.69%)
occurrences all number	3	5	1
Tumour lysis syndrome
subjects affected / exposed	1 / 214 (0.47%)	2 / 212 (0.94%)	2 / 13 (15.38%)
occurrences all number	1	2	2

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Were there any global substantial amendments to the protocol? Yes

21 Oct 2014

Correction of inclusion criterion and clarification of adverse event (AE) reporting.

07 Nov 2014

Alignment of contraceptive requirements with product information for obinutuzumab in the inclusion criteria.

21 May 2015

Modification/correction of tumor lysis syndrome (TLS) laboratory assessments. Correction/modification of inclusion and exclusion criteria regarding infection and timing of CYP3A inhibitors/inducers relative to venetoclax dosing. Reporting of AEs and serious adverse events (SAEs) during follow-up period was modified in accordance with German Ethics Committee Chairman recommendation. Contraception and pregnancy testing requirements were updated to comply with International Conference for Harmonization (ICH) and health authority guidance.

02 Nov 2015

Inclusion of new safety data for obinutuzumab relating to subjects with previous history of gastrointestinal bleeding. Cytogenetic sample moved to screening visit so that results are available prior to randomization of the subject into the trial, allowing investigators to decide whether alternative treatment should be considered, particularly for subjects with 17p deletion and/or TP53 mutation. Clarification of eligibility of subjects with previous infections and timing of CYP3A inhibitors/inducers relative to venetoclax dosing, and clarification that subjects with previous deep vein thrombosis or pulmonary embolism could continue treatment if they did not revert to > Grade 1.

29 Mar 2017

Modification of timing of the interim analysis for efficacy to introduce a date-based stopping rule for PFS. Amendment of PFS analysis assumptions. Clarification that all response assessments to be made according to iwCLL criteria. In addition, clarification of response criteria for stable disease. Removal of requirement for first meal of day to be a low-fat meal.

12 Feb 2018

Addition of the option to add an additional earlier interim efficacy analysis to mitigate the potential for an undue delay in delivery of the study read-out. Prolongation of blood sample collection to characterize MRD kinetics in subjects responding longer than originally expected. Addition of complete response as a stand-alone secondary endpoint. Clarification of time windows for assessment of blood sampling for B-cell recovery and removal of an inconsistency in reporting instructions for unrelated SAEs.

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) Based on Investigator Assessment According to IWCLL Criteria

Primary: Progression Free Survival (PFS) Based on Investigator Assessment According to IWCLL Criteria

Secondary: Progression Free Survival (PFS) Based on Institutional Review Committee (IRC)-Assessments According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria

Secondary: Progression Free Survival (PFS) Based on Institutional Review Committee (IRC)-Assessments According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria

Secondary: Percentage of Subjects With an Overall Response (OR) at Completion of Treatment, as Determined by the Investigator According to IWCLL Criteria

Secondary: Percentage of Subjects With an Overall Response (OR) at Completion of Treatment, as Determined by the Investigator According to IWCLL Criteria

Secondary: Percentage of Subjects With a Complete Response Rate (CRR) at the Completion of Treatment Assessment as Determined by the Investigator According to IWCLL Criteria

Secondary: Percentage of Subjects With a Complete Response Rate (CRR) at the Completion of Treatment Assessment as Determined by the Investigator According to IWCLL Criteria

Secondary: Percentage of Subjects With Minimal Residual Disease (MRD) Negativity in Peripheral Blood as Measured by Allele-Specific Oligonucleotide Polymerase Chain Reaction (ASO-PCR) at Completion of Treatment

Secondary: Percentage of Subjects With Minimal Residual Disease (MRD) Negativity in Peripheral Blood as Measured by Allele-Specific Oligonucleotide Polymerase Chain Reaction (ASO-PCR) at Completion of Treatment

Secondary: Percentage of Subjects With MRD Negativity in Bone marrow as Measured by ASO-PCR at Completion of Treatment

Secondary: Percentage of Subjects With MRD Negativity in Bone marrow as Measured by ASO-PCR at Completion of Treatment

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Percentage of Subjects With MRD Negativity in Peripheral Blood as Measured by ASO-PCR at Completion of Combination Treatment Assessment

Secondary: Percentage of Subjects With MRD Negativity in Peripheral Blood as Measured by ASO-PCR at Completion of Combination Treatment Assessment

Secondary: Percentage of Subjects With MRD Negativity in Bone Marrow as Measured by ASO-PCR at Completion of Combination Treatment Assessment

Secondary: Percentage of Subjects With MRD Negativity in Bone Marrow as Measured by ASO-PCR at Completion of Combination Treatment Assessment

Secondary: Percentage of Subjects With OR at Completion of Combination Treatment Response Assessment

Secondary: Percentage of Subjects With OR at Completion of Combination Treatment Response Assessment

Secondary: Duration of Objective Response (DOR)

Secondary: Duration of Objective Response (DOR)

Secondary: Percentage of Subjects By Best Response Achieved (CR, CRi, PR, Stable Disease (SD), or PD)

Secondary: Percentage of Subjects By Best Response Achieved (CR, CRi, PR, Stable Disease (SD), or PD)

Secondary: Event-Free Survival

Secondary: Event-Free Survival

Secondary: Time to Next Anti-Leukemic Treatment

Secondary: Time to Next Anti-Leukemic Treatment

Secondary: Number of Subjects With Adverse Events (AEs)

Secondary: Number of Subjects With Adverse Events (AEs)

Secondary: Percentage of Subjects With CD19 + /CD5+ B Cells or CD14+ monocytes

Secondary: Percentage of Subjects With CD19 + /CD5+ B Cells or CD14+ monocytes

Secondary: Percentage of Subjects With Human-Anti-Human Antibodies

Secondary: Percentage of Subjects With Human-Anti-Human Antibodies

Secondary: Percentage of Subjects Recorded as Premature Study Withdrawals

Secondary: Percentage of Subjects Recorded as Premature Study Withdrawals

Secondary: Plasma Concentrations of Venetoclax

Secondary: Plasma Concentrations of Venetoclax

Secondary: Serum Concentrations of Obinutuzumab

Secondary: Serum Concentrations of Obinutuzumab

Secondary: Change From Baseline in M.D. Anderson Symptom Inventory-CLL (MDASI-CLL) score

Secondary: Change From Baseline in M.D. Anderson Symptom Inventory-CLL (MDASI-CLL) score

Secondary: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQC30)

Secondary: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQC30)

Secondary: Change From Baseline in EuroQol 5 Dimension Questionnaire (EQ-5D-3L)

Secondary: Change From Baseline in EuroQol 5 Dimension Questionnaire (EQ-5D-3L)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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