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Clinical Trial Results:
A Multicenter, Phase III, Open-Label, Randomized Study in Relapsed/Refractory Patients With Chronic Lymphocytic Leukemia to Evaluate the Benefit of Venetoclax (GDC-0199/ABT-199) Plus Rituximab Compared With Bendamustine Plus Rituximab

Summary
EudraCT number	2013-002110-12
Trial protocol	CZ SE BE GB AT IT FR NL HU DK DE ES PL
Global end of trial date	03 Aug 2022

Results information
Results version number	v3(current)
This version publication date	28 Oct 2023
First version publication date	19 May 2018
Other versions	v1 , v2
Version creation reason

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

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Trial information

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Sponsor protocol code

GO28667

ISRCTN number

US NCT number

NCT02005471

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com

Scientific contact

Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

03 Aug 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

08 May 2017

Global end of trial reached?

Yes

Global end of trial date

03 Aug 2022

Was the trial ended prematurely?

Main objective of the trial

To evaluate the efficacy of venetoclax (V) and rituximab (R) compared with bendamustine (B) and rituximab in participants with relapsed or refractory chronic lymphocytic leukemia (CLL) as measured by investigator-assessed progression-free survival (PFS)

Protection of trial subjects

This study was conducted in full conformance with the International Council on Harmonization (ICH) E6 guideline for Good Clinical Practice (GCP) and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The study complied with the requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). The study complied with U.S. FDA regulations and applicable local, state, and federal laws. In the EU/EEA the study complied with the EU Clinical Trial Directive (2001/20/EC).

Background therapy

Evidence for comparator

Actual start date of recruitment

17 Mar 2014

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

3 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Korea, Republic of: 5

Country: Number of subjects enrolled

Taiwan: 3

Country: Number of subjects enrolled

Australia: 73

Country: Number of subjects enrolled

New Zealand: 13

Country: Number of subjects enrolled

Czechia: 44

Country: Number of subjects enrolled

Hungary: 26

Country: Number of subjects enrolled

Poland: 46

Country: Number of subjects enrolled

Russian Federation: 14

Country: Number of subjects enrolled

Canada: 25

Country: Number of subjects enrolled

United States: 9

Country: Number of subjects enrolled

Austria: 10

Country: Number of subjects enrolled

Belgium: 14

Country: Number of subjects enrolled

Germany: 8

Country: Number of subjects enrolled

Denmark: 7

Country: Number of subjects enrolled

Spain: 14

Country: Number of subjects enrolled

France: 29

Country: Number of subjects enrolled

United Kingdom: 10

Country: Number of subjects enrolled

Italy: 20

Country: Number of subjects enrolled

Netherlands: 16

Country: Number of subjects enrolled

Sweden: 3

Worldwide total number of subjects

389

EEA total number of subjects

237

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)

186

From 65 to 84 years

201

85 years and over

Subject disposition

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Recruitment details

A total 389 participants took part in the study across 109 investigative sites in 20 countries from 17 March 2014 to 03 August 2022. The trial consisted of a main study and an optional Retreatment/Crossover (R/C) sub study.

Screening details

Of the 389 participants enrolled 7 participants in the bendamustine + rituximab (BR) arm did not receive a valid dose of study treatment.

Period 1 title

Main Study

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Bendamustine + Rituximab

Arm description

Participants received bendamustine at a dose of 70 milligrams per meter squared (mg/m^2) via intravenous (IV) infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.

Arm type

Active comparator

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab was administered at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.

Investigational medicinal product name

Bendamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Bendamustine was administered at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle, for 6 cycles.

Venetoclax + Rituximab

Arm description

Participants were initially placed on a venetoclax ramp-up period of 5 weeks and received an initial dose of 20 mg via tablet orally once daily (QD) for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg, orally, QD. Participants continued receiving venetoclax at a dose of 400 mg, orally, QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.

Arm type

Experimental

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab was administered at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

Other name

GDC-0199, ABT-199

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Venetoclax was administered at an initial dose of 20 mg via tablet orally QD, incremented weekly up to a maximum dose of 400 mg during 4-5 weeks ramp-up period. Venetoclax was continued at 400 mg QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first.

Number of subjects in period 1	Bendamustine + Rituximab	Venetoclax + Rituximab
Started	195	194
Safety evaluable (SE) population	188	194
Completed	71	118
Not completed	124	76
Physician decision	3	1
Consent withdrawn by subject	26	11
Adverse Event	-	1
Death	83	52
Randomized but not Dosed	8	-
Lost to follow-up	4	5
Reason not Specified	-	6

Period 2 title

Re-treatment/Crossover (R/C) Substudy

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Bendamustine + Rituximab Crossover Substudy

Arm description

Participants who entered the crossover substudy had a 5-week venetoclax dose ramp-up period to reach the target dose of 400 mg QD. Following the venetoclax ramp-up period, participants received 6 cycles of rituximab, 375 mg/m^2, as IV infusion on the Day 1 of each 28-day cycle. Participants who did not progress following the completion of the 6 cycles continued to receive venetoclax monotherapy until disease progression or for a maximum of 2 years from Cycle 1 crossover Day 1 of the substudy.

Arm type

Experimental

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

Other name

GDC-0199, ABT-199

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Venetoclax was administered at an initial dose of 20 mg via tablet orally QD, incremented weekly to reach the target dose of 400 mg during 5 weeks ramp-up period. Venetoclax was continued at 400 mg QD Day 1 of Cycle 1 of substudy up to PD or 2 years, whichever occurred first.

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab was administered at a dose of 375 mg/m^2, single IV infusion for 6 cycles on the first day of each 28-day cycle.

Venetoclax + Rituximab Re-Treatment Substudy

Arm description

Participants who entered the re-treatment substudy had a 5-week venetoclax dose ramp-up period to reach the target dose of 400 mg QD. Following the venetoclax ramp-up period, participants received 6 cycles of rituximab consisting of a single infusion on the first day of each 28-day cycle. Participants who did not progress following the completion of the 6 cycles continued to receive venetoclax monotherapy until disease progression or for a maximum of 2 year from Cycle 1 re-treatment Day 1 of the substudy.

Arm type

Experimental

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

Other name

GDC-0199, ABT-199

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab was administered at a dose of 375 mg/m^2, single IV infusion for 6 cycles on the first day of each 28-day cycle.

Number of subjects in period 2 ^[1]	Bendamustine + Rituximab Crossover Substudy	Venetoclax + Rituximab Re-Treatment Substudy
Started	9	25
Completed	7	15
Not completed	2	10
Consent withdrawn by subject	-	1
Death	1	8
Lost to follow-up	1	1

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: 9 participants from BR arm and 25 participants from VR arm entered R/C substudy.

Baseline characteristics

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Reporting group title

Bendamustine + Rituximab

Reporting group description

Reporting group title

Venetoclax + Rituximab

Reporting group description

Reporting group values	Bendamustine + Rituximab	Venetoclax + Rituximab	Total
Number of subjects	195	194	389
Age Categorical
Units: Subjects
Age Continuous
Intent-to-treat (ITT) population, included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.
Units: years
arithmetic mean (standard deviation)	64.4 ( 9.6 )	63.9 ( 10.5 )	-
Gender Categorical
Units: Subjects
Female	44	58	102
Male	151	136	287

End points

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Reporting group title

Bendamustine + Rituximab

Reporting group description

Reporting group title

Venetoclax + Rituximab

Reporting group description

Reporting group title

Bendamustine + Rituximab Crossover Substudy

Reporting group description

Reporting group title

Venetoclax + Rituximab Re-Treatment Substudy

Reporting group description

Subject analysis set title

Bendamustine + Rituximab 17p Del. Population

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. Only participants with 17p deletion as identified by Fluorescence in-situ Hybridization (FISH) test were included.

Subject analysis set title

Venetoclax + Rituximab 17p Del. Population

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. Only participants with 17p deletion as identified by FISH test were included.

Primary: Percentage of Participants With PD as Assessed by the Investigator Using Standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines or Death

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End point title

Percentage of Participants With PD as Assessed by the Investigator Using Standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines or Death ^[1]

End point description

Assessment of response was performed by the investigator according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (greater than [>] 1.5 centimeters [cm]); unequivocal progression of non-target lesion; an increase of greater than or equal to (>/=) 50 percent (%) compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000 per microliter (mcL), or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 gram per deciliter (g/dL) or to less than [<] 10 g/dL. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.

End point type

Primary

End point timeframe

Baseline up to PD or death from any cause, whichever occurred first (up to approximately 8 years 5 months)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive analysis was planned to be analyzed for this endpoint.

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195	194
Units: percentage of participants
number (not applicable)	88.7	70.1

No statistical analyses for this end point

Primary: PFS as Assessed by the Investigator Using Standard iwCLL Guidelines

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End point title

PFS as Assessed by the Investigator Using Standard iwCLL Guidelines

End point description

PFS= time from randomization until first occurrence of PD/relapse as assessed by the investigator using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet/neutrophil count, hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.

End point type

Primary

End point timeframe

Baseline up to PD or death, whichever occurred first (up to approximately 8 years 5 months)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195 ^[2]	194
Units: months
median (confidence interval 95%)	17.0 (15.5 to 21.7)	54.7 (52.3 to 59.9)

Notes
[2] - Analysis was performed on ITT population.

Statistical Analysis 2

Statistical analysis description

Unstratified Analysis

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

0.19

upper limit

0.31

Notes
[3] - Hazard ratio was estimated by Cox regression model.

Statistical Analysis 1

Statistical analysis description

Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region.

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.23

Confidence interval

level

95%

sides

2-sided

lower limit

0.18

upper limit

0.29

Notes
[4] - Hazard ratio was estimated by Cox regression model.

Secondary: PFS as Assessed by the IRC Using Standard iwCLL Guidelines

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End point title

PFS as Assessed by the IRC Using Standard iwCLL Guidelines

End point description

End point type

Secondary

End point timeframe

Baseline up to PD or death, whichever occurred first (up to approximately 3 years)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195 ^[5]	194 ^[6]
Units: months
median (confidence interval 95%)	18.1 (15.8 to 22.3)	99999 (99999 to 99999)

Notes
[5] - Analysis was performed on ITT population.
[6] - ‘99999’ signifies that data could not be estimated due to low number of participants with an event.

Statistical Analysis 1

Statistical analysis description

Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region.

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.19

Confidence interval

level

95%

sides

2-sided

lower limit

0.13

upper limit

0.28

Notes
[7] - Hazard ratio was estimated by Cox regression model.

Statistical Analysis 2

Statistical analysis description

Unstratified Analysis

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[8]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

0.14

upper limit

0.3

Notes
[8] - Hazard ratio was estimated by Cox regression model.

Secondary: Percentage of Participants With PD or Death as Assessed by the Independent Review Committee (IRC) Using Standard iwCLL Guidelines

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End point title

Percentage of Participants With PD or Death as Assessed by the Independent Review Committee (IRC) Using Standard iwCLL Guidelines

End point description

Assessment of response was performed by the IRC according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.

End point type

Secondary

End point timeframe

Baseline up to PD or death, whichever occurred first (up to approximately 3 years)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195	194
Units: percentage of participants
number (not applicable)	54.4	18.0

No statistical analyses for this end point

Secondary: Percentage of Participants With PD or Death as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

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End point title

Percentage of Participants With PD or Death as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

End point description

Assessment of response was performed by the IRC according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. Analysis was performed on ITT population participants with 17p deletion as identified by FISH test.

End point type

Secondary

End point timeframe

Baseline up to PD or death, whichever occurred first (up to approximately 3 years)

End point values	Bendamustine + Rituximab 17p Del. Population	Venetoclax + Rituximab 17p Del. Population
Number of subjects analysed	46	46
Units: percentage of participants
number (not applicable)	47.8	19.6

No statistical analyses for this end point

Secondary: Percentage of Participants With PD or Death as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by Fluorescence in-situ Hybridization (FISH) Test

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End point title

Percentage of Participants With PD or Death as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by Fluorescence in-situ Hybridization (FISH) Test

End point description

Assessment of response was performed by the investigator according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. Analysis was performed on ITT population participants with 17p deletion as identified by FISH test.

End point type

Secondary

End point timeframe

Baseline up to PD or death, whichever occurred first (up to approximately 8 years 5 months)

End point values	Bendamustine + Rituximab 17p Del. Population	Venetoclax + Rituximab 17p Del. Population
Number of subjects analysed	46	46
Units: percentage of participants
number (not applicable)	80.4	80.4

No statistical analyses for this end point

Secondary: PFS as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

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End point title

PFS as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

End point description

PFS = time from randomization until first occurrence of PD/relapse as assessed by the investigator using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. Analysis was performed on ITT population participants with 17p deletion as identified by FISH test.

End point type

Secondary

End point timeframe

Baseline up to PD or death, whichever occurred first (up to approximately 8 years 5 months)

End point values	Bendamustine + Rituximab 17p Del. Population	Venetoclax + Rituximab 17p Del. Population
Number of subjects analysed	46 ^[9]	46
Units: months
median (confidence interval 95%)	15.4 (10.0 to 21.0)	47.9 (37.4 to 59.9)

Notes
[9] - Analysis was performed on ITT population participants with 17p deletion as identified by FISH test.

Statistical Analysis 2

Statistical analysis description

Unstratified Analysis

Comparison groups

Bendamustine + Rituximab 17p Del. Population v Venetoclax + Rituximab 17p Del. Population

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[10]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.35

Confidence interval

level

95%

sides

2-sided

lower limit

0.22

upper limit

0.56

Notes
[10] - Hazard ratio was estimated by Cox regression model.

Statistical Analysis 1

Statistical analysis description

Stratified Analysis; Stratification factor: geographic region.

Comparison groups

Bendamustine + Rituximab 17p Del. Population v Venetoclax + Rituximab 17p Del. Population

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.35

Confidence interval

level

95%

sides

2-sided

lower limit

0.21

upper limit

0.57

Notes
[11] - Hazard ratio was estimated by Cox regression model.

Secondary: Percentage of Participants With Best Overall Response of Complete Response (CR), CR with Incomplete Bone Marrow Recovery (CRi), Nodular Partial Response (nPR), or Partial Response (PR) as Assessed by the Investigator Using iwCLL Guidelines

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End point title

Percentage of Participants With Best Overall Response of Complete Response (CR), CR with Incomplete Bone Marrow Recovery (CRi), Nodular Partial Response (nPR), or Partial Response (PR) as Assessed by the Investigator Using iwCLL Guidelines

End point description

Response per investigator per iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in two of the following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and one of the following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. ITT population = all randomized participants.

End point type

Secondary

End point timeframe

Baseline up to approximately 8 years 5 months

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195 ^[12]	194 ^[13]
Units: percentage of participants
number (confidence interval 95%)
CR	8.2 (4.76 to 12.98)	26.3 (20.24 to 33.07)
CRi	0.5 (0.01 to 2.82)	1.5 (0.32 to 4.45)
nPR	6.2 (3.22 to 10.50)	3.6 (1.46 to 7.29)
PR	52.8 (45.56 to 59.99)	61.9 (54.62 to 68.72)

Notes
[12] - Analysis was performed on ITT population.
[13] - Participants without post-baseline response assessment were considered as non-responders.

Statistical Analysis 2

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[14]

Method

Parameter type

Odds ratio (OR)

Point estimate

7.81

Confidence interval

level

95%

sides

2-sided

lower limit

3.97

upper limit

15.37

Notes
[14] - Odds Ratio (OR) was estimated using logistic regression model. The 95% CI was computed using Wald test.

Statistical Analysis 1

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Response Rates

Point estimate

25.61

Confidence interval

level

95%

sides

2-sided

lower limit

17.88

upper limit

33.33

Notes
[15] - 95% CI for rates were constructed using Pearson- Clopper method. 95% CI for difference in rates were constructed using Anderson-Hauck method.

Secondary: PFS as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

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End point title

PFS as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

End point description

PFS = time from randomization until first occurrence of PD/relapse as assessed by the IRC using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. Analysis was performed on ITT population participants with 17p deletion as identified by FISH test.

End point type

Secondary

End point timeframe

Baseline up to PD or death, whichever occurred first (up to approximately 3 years)

End point values	Bendamustine + Rituximab 17p Del. Population	Venetoclax + Rituximab 17p Del. Population
Number of subjects analysed	46 ^[16]	46 ^[17]
Units: months
median (confidence interval 95%)	16.1 (13.6 to 22.3)	99999 (27.6 to 99999)

Notes
[16] - Analysis was performed on ITT population participants with 17p deletion as identified by FISH test.
[17] - ‘99999’ signifies that data could not be estimated due to low number of participants with an event.

Statistical Analysis 1

Statistical analysis description

Stratified Analysis; Stratification factor: geographic region.

Comparison groups

Bendamustine + Rituximab 17p Del. Population v Venetoclax + Rituximab 17p Del. Population

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[18]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.09

upper limit

0.49

Notes
[18] - Hazard ratio was estimated by Cox regression model.

Statistical Analysis 2

Statistical analysis description

Unstratified Analysis

Comparison groups

Bendamustine + Rituximab 17p Del. Population v Venetoclax + Rituximab 17p Del. Population

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.09

upper limit

0.46

Notes
[19] - Hazard ratio was estimated by Cox regression model.

Secondary: Percentage of Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the IRC Using iwCLL Guidelines

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End point title

Percentage of Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the IRC Using iwCLL Guidelines

End point description

Response per IRC according to the iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in two of the following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and one of the following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. ITT population = all randomized participants.

End point type

Secondary

End point timeframe

Baseline up to last FUV (up to approximately 3 years)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195 ^[20]	194 ^[21]
Units: percentage of participants
number (confidence interval 95%)	67.7 (60.64 to 74.20)	93.3 (88.81 to 96.38)

Notes
[20] - Analysis was performed on ITT population.
[21] - Participants without post-baseline response assessment were considered as non-responders.

Statistical Analysis 2

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[22]

Method

Parameter type

Odds ratio (OR)

Point estimate

7.81

Confidence interval

level

95%

sides

2-sided

lower limit

3.97

upper limit

15.37

Notes
[22] - OR was estimated using logistic regression model. The 95% CI was computed using Wald test.

Statistical Analysis 1

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[23]

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Response Rates

Point estimate

25.61

Confidence interval

level

95%

sides

2-sided

lower limit

17.88

upper limit

33.33

Notes
[23] - 95% CI for rates were constructed using Pearson- Clopper method. 95% CI for difference in rates were constructed using Anderson-Hauck method.

Secondary: Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at end of Combination Treatment Visit as Assessed by the Investigator Using iwCLL Guidelines

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End point title

Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at end of Combination Treatment Visit as Assessed by the Investigator Using iwCLL Guidelines

End point description

Response per investigator according to the iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in two of the following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and one of the following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. ITT population = all randomized participants.

End point type

Secondary

End point timeframe

End of combination treatment response (EoCTR) visit (8 to 12 weeks after Cycle [C] 6 Day [1]); Cycle length = 28 days

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195 ^[24]	194 ^[25]
Units: percentage of participants
number (confidence interval 95%)	63.1 (55.89 to 69.86)	88.1 (82.74 to 92.33)

Notes
[24] - Analysis was performed on ITT population.
[25] - Participants without post-baseline response assessment were considered as non-responders.

Statistical Analysis 1

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[26]

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Response Rates

Point estimate

25.07

Confidence interval

level

95%

sides

2-sided

lower limit

16.63

upper limit

33.51

Notes
[26] - The 95% CI was computed using Anderson-Hauck method.

Statistical Analysis 2

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[27]

Method

Parameter type

Odds ratio (OR)

Point estimate

4.59

Confidence interval

level

95%

sides

2-sided

lower limit

2.68

upper limit

7.88

Notes
[27] - OR was estimated using logistic regression model. The 95% CI was computed using Wald test.

Secondary: Percentage of Participants Who Died

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End point title

Percentage of Participants Who Died

End point description

Percentage of participants who died from any cause, during the study, was reported. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.

End point type

Secondary

End point timeframe

Baseline up to approximately 8 years 5 months

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195	194
Units: percentage of participants
number (not applicable)	43.1	30.9

No statistical analyses for this end point

Secondary: Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at end of Combination Treatment Visit as Assessed by the IRC Using iwCLL Guidelines

Top of page

End point title

Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at end of Combination Treatment Visit as Assessed by the IRC Using iwCLL Guidelines

End point description

End point type

Secondary

End point timeframe

EoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195 ^[28]	194 ^[29]
Units: percentage of participants
number (confidence interval 95%)	62.6 (55.37 to 69.37)	87.1 (81.57 to 91.48)

Notes
[28] - Analysis was performed on ITT population.
[29] - Participants without post-baseline response assessment were considered as non-responders.

Statistical Analysis 2

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[30]

Method

Parameter type

Odds ratio (OR)

Point estimate

4.59

Confidence interval

level

95%

sides

2-sided

lower limit

2.68

upper limit

7.85

Notes
[30] - OR was estimated using logistic regression model. The 95% CI was computed using Wald test.

Statistical Analysis 1

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[31]

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Response Rates

Point estimate

24.55

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

33.1

Notes
[31] - The 95% CI was computed using Anderson-Hauck method.

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

OS was defined as the time from the date of randomization to the date of death from any cause. Participants alive at the time of the analysis were censored at the date when they were last known to be alive as documented by the investigator. The median OS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley. Analysis was performed on ITT population. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received. '9999' = upper limit was not estimable due to low number of participants with event. '99999' = median, lower limit and upper limit were not estimable due to low number of participants with event.

End point type

Secondary

End point timeframe

Baseline up to approximately 8 years 5 months

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195	194
Units: months
median (confidence interval 95%)	87.8 (70.1 to 9999)	99999 (99999 to 99999)

Statistical Analysis 2

Statistical analysis description

Unstratified Analysis

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[32]

P-value

= 0.0003

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.54

Confidence interval

level

95%

sides

2-sided

lower limit

0.39

upper limit

0.76

Notes
[32] - Hazard ratio was estimated by Cox regression model.

Statistical Analysis 1

Statistical analysis description

Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region.

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[33]

P-value

= 0.0002

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.53

Confidence interval

level

95%

sides

2-sided

lower limit

0.37

upper limit

0.74

Notes
[33] - Hazard ratio was estimated by Cox regression model.

Secondary: Percentage of Participants With PD/Relapse, Start of a new Anti-Chronic Lymphocytic Leukemia (CLL) Therapy, or Death as Assessed by the Investigator Using iwCLL Guidelines

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End point title

Percentage of Participants With PD/Relapse, Start of a new Anti-Chronic Lymphocytic Leukemia (CLL) Therapy, or Death as Assessed by the Investigator Using iwCLL Guidelines

End point description

Percentage of participants with PD/relapse, death from any cause, or start of a new non-protocol-specified anti-CLL therapy as assessed by the investigator, during the study, was reported. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.

End point type

Secondary

End point timeframe

Baseline up to PD/relapse, start of a new anti-CLL therapy, or death from any cause, whichever occurred first (approximately 8 years 5 months)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195	194
Units: percentage of participants
number (not applicable)	89.2	71.1

No statistical analyses for this end point

Secondary: Event-Free Survival (EFS) as Assessed by the Investigator Using iwCLL Guidelines

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End point title

Event-Free Survival (EFS) as Assessed by the Investigator Using iwCLL Guidelines

End point description

EFS was defined as the time from date of randomization until the date of PD/relapse, start of a new non-protocol-specified anti-CLL therapy, or death from any cause, whichever occurred first, as assessed by the investigator. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants without any of the specified event at the time of analysis were censored at the date of last adequate response assessment. In case of no post-baseline response assessment, participants were censored at the randomization date. ITT population = all randomized participants.

End point type

Secondary

End point timeframe

Baseline up to PD/relapse, start of a new anti-CLL therapy, or death from any cause, whichever occurred first (approximately 8 years 5 months)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195 ^[34]	194
Units: months
median (confidence interval 95%)	16.4 (14.2 to 21.0)	53.7 (48.5 to 59.3)

Notes
[34] - Analysis was performed on ITT population.

Statistical Analysis 2

Statistical analysis description

Unstratified Analysis

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[35]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.25

Confidence interval

level

95%

sides

2-sided

lower limit

0.19

upper limit

0.31

Notes
[35] - Hazard ratio was estimated by Cox regression model.

Statistical Analysis 1

Statistical analysis description

Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region.

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[36]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.22

Confidence interval

level

95%

sides

2-sided

lower limit

0.17

upper limit

0.29

Notes
[36] - Hazard ratio was estimated by Cox regression model.

Secondary: Percentage of Participants With Start of New Anti-CLL Treatment or Death as Assessed by the Investigator

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End point title

Percentage of Participants With Start of New Anti-CLL Treatment or Death as Assessed by the Investigator

End point description

Percentage of participants with start of new non-protocol-specified anti-CLL therapy, as assessed by the investigator, or death from any cause, during the study, was reported. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.

End point type

Secondary

End point timeframe

Baseline up to start of new ani-CLL therapy or death, whichever occurred first (up to approximately 8 years 5 months)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195	194
Units: percentage of participants
number (not applicable)	81.5	62.4

No statistical analyses for this end point

Secondary: Duration of Responses (DOR) as Assessed by the Investigator Using iwCLL Guidelines

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End point title

Duration of Responses (DOR) as Assessed by the Investigator Using iwCLL Guidelines

End point description

DOR was defined as the time from first occurrence of a documented response of CR, CRi, nPR, or PR until PD/relapse, as assessed by the investigator according to the iwCLL guidelines, or death from any cause. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants without PD or death after response were censored at the last date of adequate response assessment. Analysis was performed on ITT population participants who had best overall response of CR, CRi, nPR, or PR.

End point type

Secondary

End point timeframe

From time of achieving best overall response until PD or death from any cause, whichever occurred first (up to approximately 8 years 5 months)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	132	181
Units: months
median (confidence interval 95%)	19.1 (16.1 to 23.6)	53.6 (49.1 to 57.0)

No statistical analyses for this end point

Secondary: Percentage of Participants With PD or Death Among Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the Investigator Using iwCLL Guidelines

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End point title

Percentage of Participants With PD or Death Among Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the Investigator Using iwCLL Guidelines

End point description

Percentage of participants with PD as assessed by the investigator according to the iwCLL guidelines, or death from any cause, during the study, was reported. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. Analysis was performed on ITT population participants who had best overall response of CR, CRi, nPR, or PR.

End point type

Secondary

End point timeframe

From time of achieving best overall response until PD or death from any cause, whichever occurred first (up to approximately 8 years 5 months)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	132	181
Units: percentage of participants
number (not applicable)	95.5	68.5

No statistical analyses for this end point

Secondary: Percentage of Participants With MRD Negativity in Bone Marrow

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End point title

Percentage of Participants With MRD Negativity in Bone Marrow

End point description

MRD-negativity was defined as the presence of <1 malignant B-cell per 10000 normal B-cells in a sample of at least 200000 B-cells, as assessed flow cytometry technique. Percentage of participants with MRD-negativity was reported. The 95% CI was computed using Pearson-Clopper method. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.

End point type

Secondary

End point timeframe

EoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195	194
Units: participants
number (confidence interval 95%)	1.0 (0.12 to 3.66)	14.4 (9.81 to 20.18)

Statistical Analysis 2

Statistical analysis description

OR was estimated using logistic regression model. The 95% CI was computed using Wald test.

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Odds ratio (OR)

Point estimate

16.28

Confidence interval

level

95%

sides

2-sided

lower limit

3.82

upper limit

69.35

Statistical Analysis 1

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[37]

P-value

< 0.0001

Method

Chi-squared

Parameter type

Difference in MRD negative rates

Point estimate

16.41

Confidence interval

level

95%

sides

2-sided

lower limit

7.99

upper limit

18.82

Notes
[37] - The 95% CI was computed using Anderson-Hauck method.

Secondary: Time to New Anti-CLL Treatment (TTNT) as Assessed by the Investigator

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End point title

Time to New Anti-CLL Treatment (TTNT) as Assessed by the Investigator

End point description

TTNT was defined as the time from randomization until start of new non-protocol-specified anti-CLL treatment or death from any cause. Participants without the event at the time of analysis were censored at the last visit date for this outcome measure analysis. The median TTNT was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.

End point type

Secondary

End point timeframe

Baseline up to start of new ani-CLL therapy or death, whichever occurred first (up to approximately 8 years 5 months)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195	194
Units: months
median (confidence interval 95%)	24.0 (20.7 to 29.5)	63.0 (56.1 to 73.6)

Statistical Analysis 2

Statistical analysis description

Unstratified Analysis

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[38]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.32

Confidence interval

level

95%

sides

2-sided

lower limit

0.25

upper limit

0.41

Notes
[38] - Hazard ratio was estimated by Cox regression model.

Statistical Analysis 1

Statistical analysis description

Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region.

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[39]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.23

upper limit

0.39

Notes
[39] - Hazard ratio was estimated by Cox regression model.

Secondary: Percentage of Participants With Minimal Residual Disease (MRD) Negativity in Peripheral Blood

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End point title

Percentage of Participants With Minimal Residual Disease (MRD) Negativity in Peripheral Blood

End point description

MRD-negativity was defined as the presence of <1 malignant B-cell per 10000 normal B-cells in a sample of at least 200000 B-cells, as assessed by the allele specific oligonucleotide polymerase chain reaction (ASO-PCR) and/or flow cytometry technique. Percentage of participants with MRD-negativity at the EoCTR visit was reported. The 95% CI was computed using Pearson-Clopper method. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.

End point type

Secondary

End point timeframe

EoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195	194
Units: percentage of participants
number (confidence interval 95%)	13.3 (8.90 to 18.92)	62.4 (55.15 to 69.21)

Statistical Analysis 2

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[40]

Method

Parameter type

Odds ratio (OR)

Point estimate

10.77

Confidence interval

level

95%

sides

2-sided

lower limit

6.5

upper limit

17.85

Notes
[40] - OR was estimated using logistic regression model. The 95% CI was computed using Wald test.

Statistical Analysis 1

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[41]

P-value

< 0.0001

Method

Chi-squared

Parameter type

Difference in MRD Negativity Rates

Point estimate

49.04

Confidence interval

level

95%

sides

2-sided

lower limit

40.44

upper limit

57.64

Notes
[41] - The 95% CI was computed using Anderson-Hauck method.

Secondary: Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Inventory (MDASI) Core Symptom Severity, Module Symptom Severity, and Interference Scores

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End point title

Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Inventory (MDASI) Core Symptom Severity, Module Symptom Severity, and Interference Scores

End point description

MDASI is a 25-item validated questionnaire consisting of 2 parts. Part 1: 19-items divided into 2 scales, Core Symptom Severity (average of Questions 1 to 13) and Module Symptom Severity (average of Questions 14 to 19). Part 2: 6-items to assess Interference (symptom distress) (average of Questions 20 to 25). Each item was rated from 0 to 10, with lower scores indicating better outcome. Total score for Core Symptom Severity, Module Symptom Severity, and Interference are reported which range from 0 to 10, with lower scores indicating better health-related quality of life (HRQoL). Patient reported outcome (PRO) evaluable population, included all participants with baseline and at least one post-baseline PRO assessment.

End point type

Secondary

End point timeframe

Baseline, Days 1, 8, and 15 of Cycles 1, 2, and 3; Cycle length = 28 days

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	117 ^[42]	42 ^[43]
Units: units on a scale
arithmetic mean (standard deviation)
Baseline; Core symptom severity (n=116,42)	1.76 ( 1.55 )	1.55 ( 1.31 )
Change at C1D1; Core symptom severity (n=116,36)	0.0 ( 0.0 )	-0.08 ( 0.98 )
Change at C1D8; Core symptom severity (n=107,36)	0.26 ( 1.34 )	-0.30 ( 0.84 )
Change at C1D15; Core symptom severity (n=104,33)	0.00 ( 1.31 )	-0.27 ( 0.93 )
Change at C2D1; Core symptom severity (n=101,35)	-0.23 ( 1.30 )	-0.33 ( 0.91 )
Change at C2D8; Core symptom severity (n=91,36)	0.17 ( 1.59 )	-0.45 ( 0.91 )
Change at C2D15; Core symptom severity (n=90,37)	-0.13 ( 1.53 )	-0.53 ( 0.90 )
Change at C3D1; Core symptom severity (n=89,36)	-0.26 ( 1.60 )	-0.40 ( 1.13 )
Change at C3D8; Core symptom severity (n=72,30)	-0.13 ( 1.63 )	-0.66 ( 1.20 )
Change at C3D15; Core symptom severity (n=73,32)	-0.42 ( 1.52 )	-0.53 ( 1.05 )
Baseline; Module symptom severity (n=116,42)	1.60 ( 1.46 )	1.57 ( 1.11 )
Change at C1D1; Module symptom severity (n=116,36)	0.00 ( 0.00 )	-0.19 ( 0.96 )
Change at C1D8;Module symptom severity(n=107,36)	-0.22 ( 1.40 )	-0.53 ( 0.96 )
Change atC1D15;Module symptom severity(n=104,33)	-0.43 ( 1.51 )	-0.73 ( 1.13 )
Change at C2D1; Module symptom severity (n=101,34)	-0.49 ( 1.46 )	-0.65 ( 0.92 )
Change at C2D8; Module symptom severity (n=91,35)	-0.46 ( 1.63 )	-0.77 ( 0.87 )
Change at C2D15; Module symptom severity (n=90,36)	-0.69 ( 1.47 )	-0.94 ( 0.93 )
Change at C3D1; Module symptom severity (n=86,35)	-0.65 ( 1.48 )	-0.81 ( 0.97 )
Change at C3D8; Module symptom severity (n=72,30)	-0.51 ( 1.58 )	-0.83 ( 0.97 )
Change at C3D15; Module symptom severity (n=73,32)	-0.83 ( 1.51 )	-0.92 ( 0.97 )
Baseline; Interference (n=116,41)	1.81 ( 2.05 )	1.90 ( 2.25 )
Change at C1D1; Interference (n=116,35)	0.00 ( 0.00 )	-0.13 ( 1.49 )
Change at C1D8; Interference (n=107,33)	0.45 ( 1.78 )	-0.29 ( 2.14 )
Change at C1D15; Interference (n=104,32)	0.36 ( 1.85 )	0.01 ( 2.04 )
Change at C2D1; Interference (n=101,33)	0.01 ( 1.73 )	-0.34 ( 1.78 )
Change at C2D8; Interference (n=91,34)	0.58 ( 2.20 )	-0.58 ( 1.81 )
Change at C2D15; Interference (n=89,35)	0.06 ( 1.84 )	-0.64 ( 1.59 )
Change at C3D1; Interference (n=86,34)	-0.02 ( 2.02 )	-0.73 ( 2.06 )
Change at C3D8; Interference (n=72,29)	0.15 ( 1.91 )	-0.82 ( 2.09 )
Change at C3D15; Interference (n=72,30)	-0.07 ( 2.01 )	-0.55 ( 2.18 )

Notes
[42] - 'Number of Subject Analysed' = participants evaluable for this outcome measure
[43] - 'n' = participants evaluable at specified time point, for each arm respectively

No statistical analyses for this end point

Secondary: Plasma Venetoclax Concentrations

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End point title

Plasma Venetoclax Concentrations ^[44]

End point description

Pharmacokinetic (PK) evaluable population, included all participants in the ‘Venetoclax + Rituximab’ arm who received at least one dose of venetoclax with at least one post-dose PK concentration result available. Here, 'Number of Subject Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point.

End point type

Secondary

End point timeframe

Pre-dose (0 hour, anytime before venetoclax administration) and 4 hours post-dose on D1 of Cycles 1 and 4; Cycle length = 28 days

Notes
[44] - 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: Plasma venetoclax concentrations was only analyzed for VR arm of the study.

End point values	Venetoclax + Rituximab
Number of subjects analysed	184
Units: micrograms per milliliter (mcg/mL)
arithmetic mean (standard deviation)
C1D1, Pre-dose (n=151)	0.626 ( 0.540 )
C1D1, 4 hours Post-Dose (n=159)	1.34 ( 0.881 )
C4D1, Pre-dose (n=112)	0.681 ( 0.745 )
C4D1, 4 hours Post-Dose (n=121)	1.34 ( 0.905 )

No statistical analyses for this end point

Secondary: Change from Baseline in HRQoL as Measured by European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scales Score and Global Health Status/Global Quality-of-Life (QoL) Scale Score

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End point title

Change from Baseline in HRQoL as Measured by European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scales Score and Global Health Status/Global Quality-of-Life (QoL) Scale Score

End point description

EORTC QLQ-C30 is a validated self-report measure consisting of 30 questions incorporated into 5 functional scales (Physical, Role, Cognitive, Emotional, and Social), 3 symptom scales (fatigue, pain, nausea, and vomiting), a global health status/global QoL scale, and single items (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea). Most questions used 4-point scale (1='Not at all' to 4='Very much'), while 2 questions used 7-point scale (1='very poor' to 7='Excellent'). Scores were averaged, transformed to 0-100 scale; where higher score for functional scales=poor level of functioning; higher score for global health status/global QoL=better HRQoL. PRO evaluable population = all participants with baseline and at least one post-baseline PRO assessment. ‘99999’=either data were not available because no participant was evaluable or SD was not available because only 1 participant was evaluable at indicated time point.

End point type

Secondary

End point timeframe

Baseline, D1 of Cycles 1, 2, 3, 4, 5, 6, STC/EW visit (up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	177 ^[45]	69 ^[46]
Units: units on a scale
arithmetic mean (standard deviation)
Baseline; Physical functioning (n=177,69)	82.59 ( 17.46 )	83.77 ( 15.27 )
Change at C1D1; Physical functioning (n=177,67)	0.0 ( 0.0 )	1.39 ( 12.90 )
Change at C2D1; Physical functioning (n=172,67)	0.31 ( 15.81 )	2.99 ( 12.83 )
Change at C3D1; Physical functioning (n=160,64)	0.22 ( 16.43 )	1.46 ( 14.76 )
Change at C4D1; Physical functioning (n=154,65)	2.11 ( 14.95 )	5.54 ( 14.17 )
Change at C5D1; Physical functioning (n=149,65)	2.44 ( 18.19 )	4.62 ( 15.27 )
Change at C6D1; Physical functioning (n=143,65)	2.25 ( 16.82 )	4.51 ( 16.59 )
Change at STC/EW; Physical functioning (n=162,64)	1.68 ( 18.76 )	4.53 ( 16.04 )
Change at EoCTR; Physical functioning (n=142,63)	2.92 ( 18.03 )	4.34 ( 16.12 )
Change at FUV1; Physical functioning (n=124,63)	2.27 ( 18.86 )	3.81 ( 16.27 )
Change at FUV2; Physical functioning (n=114,63)	2.40 ( 19.21 )	2.75 ( 17.17 )
Change at FUV3; Physical functioning (n=95,62)	2.54 ( 17.83 )	3.44 ( 17.31 )
Change at FUV4; Physical functioning (n=77,47)	4.74 ( 20.14 )	0.85 ( 21.06 )
Change at FUV5; Physical functioning (n=57,19)	1.90 ( 17.68 )	-1.75 ( 19.35 )
Change at FUV6; Physical functioning (n=33,5)	-1.41 ( 15.34 )	1.33 ( 5.58 )
Change at FUV7; Physical functioning (n=13,1)	-3.08 ( 11.74 )	0.00 ( 99999 )
Change at FUV8; Physical functioning (n=5,1)	-9.33 ( 23.38 )	0.00 ( 99999 )
Change at FUV9; Physical functioning (n=2,0)	-10.00 ( 33.0 )	99999 ( 99999 )
Baseline; Role functioning (n=177,69)	78.25 ( 25.67 )	83.82 ( 21.00 )
Change at C1D1; Role functioning (n=177,67)	0.0 ( 0.0 )	-1.74 ( 23.23 )
Change at C2D1; Role functioning (n=172,67)	-1.26 ( 27.45 )	2.49 ( 23.07 )
Change at C3D1; Role functioning (n=160,64)	-0.10 ( 29.64 )	1.82 ( 26.08 )
Change at C4D1; Role functioning (n=154,65)	0.87 ( 29.01 )	5.13 ( 22.03 )
Change at C5D1; Role functioning (n=149,65)	0.45 ( 30.75 )	4.36 ( 23.44 )
Change at C6D1; Role functioning (n=143,65)	0.70 ( 29.92 )	1.79 ( 25.71 )
Change at STC/EW; Role functioning (n=162,64)	-0.41 ( 32.91 )	2.60 ( 25.58 )
Change at EoCTR; Role functioning (n=143,63)	3.26 ( 29.95 )	2.12 ( 26.69 )
Change at FUV1; Role functioning (n=125,63)	2.93 ( 32.31 )	2.65 ( 27.47 )
Change at FUV2; Role functioning (n=114,63)	3.07 ( 32.63 )	-1.85 ( 31.84 )
Change at FUV3; Role functioning (n=95,62)	5.26 ( 31.16 )	1.88 ( 28.17 )
Change at FUV4; Role functioning (n=77,47)	5.41 ( 33.16 )	-0.35 ( 30.39 )
Change at FUV5; Role functioning (n=57,19)	2.34 ( 29.79 )	1.75 ( 34.20 )
Change at FUV6; Role functioning (n=33,5)	-4.04 ( 27.01 )	-13.33 ( 32.06 )
Change at FUV7; Role functioning (n=13,1)	2.56 ( 29.54 )	-16.67 ( 99999 )
Change at FUV8; Role functioning (n=5,1)	0.00 ( 23.57 )	16.67 ( 99999 )
Change at FUV9; Role functioning (n=2,0)	-16.67 ( 23.57 )	99999 ( 99999 )
Baseline; Emotional functioning (n=176,69)	78.98 ( 22.47 )	82.13 ( 15.80 )
Change at C1D1; Emotional functioning (n=176,67)	0.0 ( 0.0 )	4.35 ( 15.17 )
Change at C2D1; Emotional functioning (n=171,67)	2.24 ( 20.07 )	5.60 ( 14.68 )
Change at C3D1; Emotional functioning (n=158,64)	2.99 ( 20.06 )	5.34 ( 19.09 )
Change at C4D1; Emotional functioning (n=151,65)	2.61 ( 18.35 )	4.19 ( 15.45 )
Change at C5D1; Emotional functioning (n=146,65)	1.14 ( 18.79 )	3.97 ( 17.37 )
Change at C6D1; Emotional functioning (n=143,65)	2.06 ( 18.74 )	3.08 ( 17.96 )
Change at STC/EW; Emotional functioning (n=160,64)	2.43 ( 20.61 )	5.34 ( 18.69 )
Change at EoCTR; Emotional functioning (n=142,62)	2.58 ( 19.45 )	3.49 ( 17.83 )
Change at FUV1; Emotional functioning (n=124,63)	3.49 ( 20.91 )	4.37 ( 18.50 )
Change at FUV2; Emotional functioning (n=114,63)	4.39 ( 20.33 )	0.66 ( 21.02 )
Change at FUV3; Emotional functioning (n=92,62)	0.63 ( 19.97 )	2.82 ( 17.66 )
Change at FUV4; Emotional functioning (n=76,47)	4.82 ( 19.73 )	1.95 ( 18.41 )
Change at FUV5; Emotional functioning (n=56,19)	3.13 ( 17.95 )	2.63 ( 20.61 )
Change at FUV6; Emotional functioning (n=33,5)	2.27 ( 21.78 )	5.00 ( 17.28 )
Change at FUV7; Emotional functioning (n=13,1)	5.77 ( 17.48 )	-8.33 ( 99999 )
Change at FUV8; Emotional functioning (n=5,1)	3.33 ( 28.01 )	0.00 ( 99999 )
Change at FUV9; Emotional functioning (n=2,0)	-16.67 ( 11.79 )	99999 ( 99999 )
Baseline; Cognitive functioning (n=176,69)	86.55 ( 16.78 )	89.86 ( 14.91 )
Change at C1D1; Cognitive functioning (n=176,67)	0.0 ( 0.0 )	-1.24 ( 14.01 )
Change at C2D1; Cognitive functioning (n=171,67)	-0.19 ( 15.34 )	0.25 ( 14.06 )
Change at C3D1; Cognitive functioning (n=158,64)	-0.32 ( 16.34 )	-1.56 ( 17.50 )
Change at C4D1; Cognitive functioning (n=152,65)	-1.54 ( 17.41 )	-0.26 ( 17.05 )
Change at C5D1; Cognitive functioning (n=146,65)	-1.94 ( 18.10 )	-0.26 ( 14.28 )
Change at C6D1; Cognitive functioning (n=143,65)	-2.68 ( 16.97 )	-0.77 ( 15.98 )
Change at STC/EW; Cognitive functioning (n=160,64)	-2.19 ( 17.65 )	1.04 ( 18.28 )
Change at EoCTR; Cognitive functioning (n=142,62)	-2.23 ( 18.11 )	-0.27 ( 16.94 )
Change at FUV1; Cognitive functioning (n=124,63)	-2.02 ( 17.21 )	-0.26 ( 15.98 )
Change at FUV2; Cognitive functioning (n=114,63)	1.32 ( 16.16 )	-2.38 ( 18.17 )
Change at FUV3; Cognitive functioning (n=92,62)	-1.63 ( 14.84 )	-2.96 ( 18.24 )
Change at FUV4; Cognitive functioning (n=76,47)	0.44 ( 17.63 )	-1.77 ( 19.11 )
Change at FUV5; Cognitive functioning (n=56,19)	-1.49 ( 15.66 )	-6.14 ( 21.67 )
Change at FUV6; Cognitive functioning (n=33,5)	-0.51 ( 14.72 )	0.00 ( 0.00 )
Change at FUV7; Cognitive functioning (n=13,1)	-1.28 ( 14.37 )	0.00 ( 99999 )
Change at FUV8; Cognitive functioning (n=5,1)	0.00 ( 23.57 )	0.00 ( 99999 )
Change at FUV9; Cognitive functioning (n=2,0)	16.67 ( 23.57 )	99999 ( 99999 )
Baseline; Social functioning (n=176,69)	82.48 ( 22.06 )	85.51 ( 21.18 )
Change at C1D1; Social functioning (n=176,67)	0.0 ( 0.0 )	-1.74 ( 19.92 )
Change at C2D1; Social functioning (n=171,67)	-2.44 ( 21.44 )	0.25 ( 18.46 )
Change at C3D1; Social functioning (n=158,64)	-2.32 ( 22.61 )	3.65 ( 25.45 )
Change at C4D1; Social functioning (n=151,65)	-0.55 ( 22.15 )	4.62 ( 20.09 )
Change at C5D1; Social functioning (n=146,65)	-5.48 ( 26.49 )	2.56 ( 20.46 )
Change at C6D1; Social functioning (n=143,65)	-5.13 ( 24.80 )	3.85 ( 24.61 )
Change at STC/EW; Social functioning (n=160,64)	-4.06 ( 27.71 )	1.04 ( 19.22 )
Change at EoCTR; Social functioning (n=142,62)	-0.47 ( 24.95 )	1.88 ( 20.49 )
Change at FUV1; Social functioning (n=124,63)	-1.08 ( 26.09 )	1.59 ( 24.27 )
Change at FUV2; Social functioning (n=114,63)	0.58 ( 24.68 )	1.32 ( 27.97 )
Change at FUV3; Social functioning (n=92,62)	-0.91 ( 24.00 )	1.88 ( 25.98 )
Change at FUV4; Social functioning (n=76,47)	1.97 ( 27.35 )	1.06 ( 32.12 )
Change at FUV5; Social functioning (n=56,19)	1.79 ( 26.72 )	0.00 ( 33.79 )
Change at FUV6; Social functioning (n=33,5)	1.52 ( 29.27 )	10.00 ( 14.91 )
Change at FUV7; Social functioning (n=13,1)	-2.56 ( 23.42 )	33.33 ( 99999 )
Change at FUV8; Social functioning (n=5,1)	-10.00 ( 22.36 )	33.33 ( 99999 )
Change at FUV9; Social functioning (n=2,0)	-25.00 ( 35.36 )	99999 ( 99999 )
Baseline; Global health status/QoL (n=176,69)	63.02 ( 21.45 )	67.39 ( 22.17 )
Change at C1D1;Global health status/QoL(n=176,67)	0.0 ( 0.0 )	6.34 ( 18.41 )
Change at C2D1;Global health status/QoL (n=171,67)	2.73 ( 21.69 )	5.35 ( 20.14 )
Change at C3D1;Global health status/QoL (n=157,64)	2.34 ( 24.66 )	2.21 ( 23.58 )
Change at C4D1;Global health status/QoL (n=152,65)	3.84 ( 22.26 )	7.05 ( 21.05 )
Change at C5D1;Global health status/QoL (n=146,65)	7.36 ( 24.20 )	7.18 ( 21.94 )
Change at C6D1;Global health status/QoL (n=143,65)	4.25 ( 25.00 )	5.90 ( 25.16 )
Change at STC/EW;Global health status/QoL;n=160,64	4.32 ( 26.20 )	6.51 ( 23.22 )
Change at EoCTR;Global health status/QoL(n=142,62)	6.10 ( 23.65 )	7.66 ( 24.11 )
Change at FUV1;Global health status/QoL (n=124,63)	5.91 ( 24.57 )	7.01 ( 25.01 )
Change at FUV2;Global health status/QoL (n=114,63)	6.94 ( 24.81 )	4.50 ( 26.51 )
Change at FUV3; Global health status/QoL (n=92,62)	4.80 ( 25.30 )	6.32 ( 27.36 )
Change at FUV4; Global health status/QoL (n=76,47)	7.35 ( 26.77 )	6.38 ( 27.60 )
Change at FUV5; Global health status/QoL (n=56,19)	4.46 ( 23.89 )	4.39 ( 18.08 )
Change at FUV6; Global health status/QoL (n=33,5)	1.01 ( 24.00 )	5.00 ( 7.45 )
Change at FUV7; Global health status/QoL (n=13,1)	8.33 ( 25.69 )	16.67 ( 99999 )
Change at FUV8; Global health status/QoL (n=5,1)	6.67 ( 16.03 )	8.33 ( 99999 )
Change at FUV9; Global health status/QoL (n=2,0)	0.00 ( 0.00 )	99999 ( 99999 )

Notes
[45] - 'Number of Subject Analysed' = participants evaluable for this outcome measure
[46] - 'n' = participants evaluable at specified time point, for each arm respectively

No statistical analyses for this end point

Secondary: Change From Baseline in HRQoL as Measured by Quality of Life Questionnaire Associated CLL Module (QLQ-CLL16) Multi-Item Scales Score

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End point title

Change From Baseline in HRQoL as Measured by Quality of Life Questionnaire Associated CLL Module (QLQ-CLL16) Multi-Item Scales Score

End point description

The EORTC QLQ-CLL16 module is designed for participants with Stage 0 to Stage 4 CLL. It is composed of 16 questions and there are four multi-item scales on Fatigue (2 items), Treatment-related side effects (TRSE, 4 items), Disease-related symptoms (DRS, 4 items), and Infection (4 items); and two single-item scales on social activities and future health worries. Multi-item scales score are reported and the total score for each multi-item scale was transformed to result in a total score range of 0 to 100, where higher score = poor HRQoL. PRO evaluable population, included all participants with baseline and at least one post-baseline PRO assessment. 'Number of Subject Analysed' = participants evaluable for this outcome measure; 'n' = participants evaluable at specified time point; ‘99999’ = either mean was not available because no participant was evaluable or SD was not available because only 1 participant was evaluable at indicated time points.

End point type

Secondary

End point timeframe

Baseline, D1 of Cycles 1, 2, 3, 4, 5, 6, STC/EW visit (up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	175	69
Units: units on a scale
arithmetic mean (standard deviation)
Baseline; TRSE (n=175,69)	14.29 ( 13.95 )	9.42 ( 8.80 )
Change at C1D1; TRSE (n=175,67)	0.0 ( 0.0 )	0.12 ( 10.10 )
Change at C2D1; TRSE (n=170,67)	1.62 ( 13.82 )	0.62 ( 12.76 )
Change at C3D1; TRSE (n=159,63)	-0.26 ( 13.76 )	1.98 ( 14.72 )
Change at C4D1; TRSE (n=152,64)	-0.49 ( 13.97 )	0.52 ( 11.87 )
Change at C5D1; TRSE (n=147,65)	-0.51 ( 14.57 )	0.64 ( 10.02 )
Change at C6D1; TRSE (n=144,65)	0.46 ( 15.51 )	-0.13 ( 10.04 )
Change at STC/EW; TRSE (n=161,64)	0.81 ( 18.11 )	0.13 ( 10.76 )
Change at EoCTR; TRSE (n=142,63)	-0.88 ( 16.06 )	0.26 ( 12.61 )
Change at FUV1; TRSE (n=123,63)	-1.20 ( 14.87 )	1.19 ( 12.24 )
Change at FUV2; TRSE (n=113,63)	-1.70 ( 15.28 )	2.65 ( 14.03 )
Change at FUV3; TRSE (n=95,62)	-2.08 ( 12.64 )	-0.13 ( 13.70 )
Change at FUV4; TRSE (n=76,47)	-1.97 ( 12.76 )	2.84 ( 15.18 )
Change at FUV5; TRSE (n=56,19)	-2.68 ( 11.02 )	1.32 ( 10.49 )
Change at FUV6; TRSE (n=33,5)	-1.01 ( 12.10 )	-1.67 ( 3.73 )
Change at FUV7; TRSE (n=13,1)	2.56 ( 22.67 )	-8.33 ( 99999 )
Change at FUV8; TRSE (n=5,1)	1.67 ( 13.69 )	0.00 ( 99999 )
Change at FUV9; TRSE (n=2,0)	8.33 ( 11.79 )	99999 ( 99999 )
Baseline; DRS (n=175,69)	19.57 ( 16.81 )	16.95 ( 17.37 )
Change at C1D1; DRS (n=175,67)	0.0 ( 0.0 )	-2.74 ( 16.18 )
Change at C2D1; DRS (n=170,67)	-3.33 ( 16.05 )	-4.77 ( 16.84 )
Change at C3D1; DRS (n=159,63)	-4.77 ( 16.49 )	-3.35 ( 17.48 )
Change at C4D1; DRS (n=152,64)	-6.03 ( 16.51 )	-5.12 ( 17.72 )
Change at C5D1; DRS (n=147,65)	-5.90 ( 16.73 )	-4.79 ( 17.50 )
Change at C6D1; DRS (n=144,65)	-6.40 ( 17.26 )	-5.30 ( 16.72 )
Change at STC/EW; DRS (n=161,64)	-5.80 ( 18.52 )	-6.51 ( 18.45 )
Change at EoCTR; DRS (n=142,63)	-6.57 ( 17.21 )	-5.86 ( 20.38 )
Change at FUV1; DRS (n=123,63)	-6.55 ( 15.73 )	-5.82 ( 19.20 )
Change at FUV2; DRS (n=113,63)	-8.63 ( 14.39 )	-3.57 ( 18.31 )
Change at FUV3; DRS (n=95,62)	-7.37 ( 14.88 )	-3.76 ( 19.25 )
Change at FUV4; DRS (n=76,47)	-8.55 ( 18.56 )	-2.66 ( 20.49 )
Change at FUV5; DRS (n=56,19)	-8.33 ( 16.13 )	-2.19 ( 19.41 )
Change at FUV6; DRS (n=33,5)	-6.31 ( 16.01 )	-3.33 ( 13.94 )
Change at FUV7; DRS (n=13,1)	-15.38 ( 20.08 )	-8.33 ( 99999 )
Change at FUV8; DRS (n=5,1)	-10.00 ( 16.03 )	-8.33 ( 99999 )
Change at FUV9; DRS (n=2,0)	-4.17 ( 5.89 )	99999 ( 99999 )
Baseline; Fatigue (n=175,69)	28.76 ( 24.66 )	21.74 ( 20.67 )
Change at C1D1; Fatigue (n=175,67)	0.0 ( 0.0 )	-2.24 ( 20.29 )
Change at C2D1; Fatigue (n=170,67)	-2.55 ( 22.86 )	-5.47 ( 21.40 )
Change at C3D1; Fatigue (n=159,63)	-2.83 ( 25.17 )	-3.17 ( 23.73 )
Change at C4D1; Fatigue (n=152,64)	-3.18 ( 23.23 )	-4.17 ( 22.02 )
Change at C5D1; Fatigue (n=147,65)	-2.38 ( 27.52 )	-4.36 ( 20.89 )
Change at C6D1; Fatigue (n=144,65)	-2.66 ( 26.35 )	-2.31 ( 21.42 )
Change at STC/EW; Fatigue (n=161,64)	-3.11 ( 28.64 )	-4.69 ( 21.30 )
Change at EoCTR; Fatigue (n=142,63)	-6.69 ( 26.78 )	-3.97 ( 24.27 )
Change at FUV1; Fatigue (n=123,63)	-6.37 ( 26.61 )	-4.23 ( 22.99 )
Change at FUV2; Fatigue (n=113,63)	-6.64 ( 24.55 )	-1.85 ( 24.70 )
Change at FUV3; Fatigue (n=95,62)	-5.79 ( 23.29 )	-2.42 ( 23.73 )
Change at FUV4; Fatigue (n=76,47)	-9.65 ( 26.84 )	-0.35 ( 25.18 )
Change at FUV5; Fatigue (n=56,19)	-6.55 ( 25.56 )	3.51 ( 23.95 )
Change at FUV6; Fatigue (n=33,5)	-5.05 ( 24.82 )	3.33 ( 24.72 )
Change at FUV7; Fatigue (n=13,1)	-10.26 ( 30.08 )	-33.33 ( 99999 )
Change at FUV8; Fatigue (n=5,1)	-6.67 ( 19.00 )	0.00 ( 99999 )
Change at FUV9; Fatigue (n=2,0)	-8.33 ( 11.79 )	99999 ( 99999 )
Baseline; Infection (n=175,69)	15.92 ( 17.63 )	14.01 ( 18.99 )
Change at C1D1; Infection (n=175,67)	0.0 ( 0.0 )	-2.24 ( 20.03 )
Change at C2D1; Infection (n=170,67)	-0.02 ( 19.98 )	-3.61 ( 21.72 )
Change at C3D1; Infection (n=159,63)	-1.66 ( 19.21 )	-1.32 ( 20.48 )
Change at C4D1; Infection (n=152,64)	-1.44 ( 22.07 )	-3.13 ( 21.28 )
Change at C5D1; Infection (n=147,65)	-1.91 ( 24.00 )	-2.56 ( 23.47 )
Change at C6D1; Infection (n=143,65)	-1.09 ( 20.66 )	-2.95 ( 20.54 )
Change at STC/EW; Infection (n=161,64)	-0.12 ( 23.28 )	-1.69 ( 23.34 )
Change at EoCTR; Infection (n=142,63)	-0.55 ( 21.73 )	-3.44 ( 25.78 )
Change at FUV1; Infection (n=121,63)	1.08 ( 18.77 )	-2.65 ( 26.51 )
Change at FUV2; Infection (n=113,63)	0.05 ( 23.29 )	-0.53 ( 25.74 )
Change at FUV3; Infection (n=95,62)	-1.90 ( 16.97 )	-0.54 ( 26.48 )
Change at FUV4; Infection (n=76,47)	-4.24 ( 16.71 )	0.53 ( 25.56 )
Change at FUV5; Infection (n=56,19)	-4.51 ( 22.66 )	7.46 ( 27.20 )
Change at FUV6; Infection (n=33,5)	-1.60 ( 18.90 )	8.33 ( 15.59 )
Change at FUV7; Infection (n=13,1)	-0.43 ( 21.84 )	-16.67 ( 99999 )
Change at FUV8; Infection (n=5,1)	8.89 ( 23.36 )	-25.00 ( 99999 )
Change at FUV9; Infection (n=2,0)	-2.78 ( 3.93 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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End point title

Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

End point description

An AE was defined as any untoward medical occurrence in a participant administered with Mircera and which does not necessarily have a causal relationship with Mircera. A Serious Adverse Event (SAE) is any significant hazard, contraindication, side effect that is fatal or life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is medically significant or requires intervention to prevent one or other of the outcomes listed above. AEs were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE, v4.0). SE population included all randomized participants who received at least one dose of study treatment with participants grouped according to the actual treatment received.

End point type

Secondary

End point timeframe

From signing of informed consent form up to approximately 8 years 5 months

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	188	194
Units: participants
AEs	185	194
SAEs	84	101

No statistical analyses for this end point

Secondary: Number of Participants with Grade 3 or higher Tumor Lysis Syndrome (TLS) and Infusion-related Reactions (IRRs)

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End point title

Number of Participants with Grade 3 or higher Tumor Lysis Syndrome (TLS) and Infusion-related Reactions (IRRs)

End point description

An AE was defined as any untoward medical occurrence in a participant administered with Mircera and which does not necessarily have a causal relationship with Mircera. A SAE is any significant hazard, contraindication, side effect that is fatal or life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is medically significant or requires intervention to prevent one or other of the outcomes listed above. TLS and IRRs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe or medically significant; Grade 4 = Life-threatening; Grade 5 = Death. A higher grade indicates a worse outcome. SE population.

End point type

Secondary

End point timeframe

From signing of informed consent form up to approximately 8 years 5 months

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	188	194
Units: participants
TLS	2	6
IRRs	10	4

No statistical analyses for this end point

Post-hoc: Euro QoL 5 Dimension (EQ-5D) Questionnaire Score

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End point title

Euro QoL 5 Dimension (EQ-5D) Questionnaire Score

End point description

PRO evaluable population included all participants with baseline and at least one post-baseline PRO assessment. Here, 'Overall Number of Participants Analyzed’ = participants evaluable for this outcome measure and 'Number Analyzed' = participants evaluable at specified time point.

End point type

Post-hoc

End point timeframe

Baseline, D1 of Cycles 1, 2, 3, 4, 5, 6, STC/EW visit (up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	0 ^[47]	0 ^[48]
Units: units on a scale
arithmetic mean (standard deviation)	( )	( )

Notes
[47] - Data were not presented as this is not an primary or secondary endpoint.
[48] - Data were not presented as this is not an primary or secondary endpoint.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From signing of informed consent form up to approximately 8 years 5 months

Adverse event reporting additional description

SE population included all randomized participants who received at least one dose of study treatment with participants grouped according to the actual treatment received.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Bendamustine + Rituximab Main Study

Reporting group description

Reporting group title

Venetoclax + Rituximab Re-Treatment Substudy

Reporting group description

Reporting group title

Bendamustine + Rituximab Crossover Substudy

Reporting group description

Reporting group title

Venetoclax + Rituximab Main Study

Reporting group description

Participants were initially placed on a venetoclax ramp-up period of 5 weeks and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg, orally, QD. Participants continued receiving venetoclax at a dose of 400 mg, orally, QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.

Serious adverse events	Bendamustine + Rituximab Main Study	Venetoclax + Rituximab Re-Treatment Substudy	Bendamustine + Rituximab Crossover Substudy	Venetoclax + Rituximab Main Study
Total subjects affected by serious adverse events
subjects affected / exposed	84 / 188 (44.68%)	13 / 25 (52.00%)	5 / 9 (55.56%)	101 / 194 (52.06%)
number of deaths (all causes)	84	8	1	60
number of deaths resulting from adverse events	4	0	0	4
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Adenocarcinoma gastric
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	3 / 188 (1.60%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
Basal cell carcinoma
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	2 / 194 (1.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Colorectal cancer
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	2 / 194 (1.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
Adenocarcinoma of colon
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphoma
subjects affected / exposed	1 / 188 (0.53%)	1 / 25 (4.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	2 / 194 (1.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Medullary thyroid cancer
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastatic malignant melanoma
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	2 / 194 (1.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
Myelodysplastic syndrome
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	2 / 194 (1.03%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
Prostate cancer
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prostatic adenoma
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transitional cell carcinoma
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	3 / 194 (1.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	3 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of lung
subjects affected / exposed	0 / 188 (0.00%)	1 / 25 (4.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastasis
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sebaceous adenoma
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Plasma cell myeloma
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin squamous cell carcinoma recurrent
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to lung
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Colorectal adenocarcinoma
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic stenosis
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	5 / 188 (2.66%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	4 / 5	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma
subjects affected / exposed	0 / 188 (0.00%)	1 / 25 (4.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperpyrexia
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	13 / 188 (6.91%)	0 / 25 (0.00%)	0 / 9 (0.00%)	5 / 194 (2.58%)
occurrences causally related to treatment / all	11 / 15	0 / 0	0 / 0	2 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sudden cardiac death
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Sudden death
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Reproductive system and breast disorders
Cervical dysplasia
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine haemorrhage
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Bronchiectasis
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Investigations
Body temperature increased
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Medical observation
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
SARS-CoV-2 test positive
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	1 / 9 (11.11%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	1 / 9 (11.11%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Humerus fracture
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	6 / 188 (3.19%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	8 / 8	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Scar
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ulna fracture
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Coronary artery disease
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	2 / 194 (1.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
Ventricular tachycardia
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 188 (0.00%)	1 / 25 (4.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 188 (0.00%)	1 / 25 (4.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic stroke
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Lacunar infarction
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Polyneuropathy
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Syncope
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	5 / 188 (2.66%)	1 / 25 (4.00%)	0 / 9 (0.00%)	3 / 194 (1.55%)
occurrences causally related to treatment / all	4 / 6	1 / 1	0 / 0	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	3 / 188 (1.60%)	0 / 25 (0.00%)	1 / 9 (11.11%)	3 / 194 (1.55%)
occurrences causally related to treatment / all	3 / 3	0 / 0	1 / 1	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	2 / 188 (1.06%)	0 / 25 (0.00%)	0 / 9 (0.00%)	2 / 194 (1.03%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
Autoimmune haemolytic anaemia
subjects affected / exposed	3 / 188 (1.60%)	0 / 25 (0.00%)	0 / 9 (0.00%)	3 / 194 (1.55%)
occurrences causally related to treatment / all	2 / 4	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	16 / 188 (8.51%)	1 / 25 (4.00%)	0 / 9 (0.00%)	7 / 194 (3.61%)
occurrences causally related to treatment / all	14 / 16	0 / 1	0 / 0	7 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune thrombocytopenia
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Deafness
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vertigo
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Eye haemorrhage
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Anal fistula
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 188 (0.00%)	1 / 25 (4.00%)	1 / 9 (11.11%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Crohn's disease
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	2 / 194 (1.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal obstruction
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Biliary obstruction
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 188 (0.00%)	1 / 25 (4.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice cholestatic
subjects affected / exposed	0 / 188 (0.00%)	1 / 25 (4.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis allergic
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic foot
subjects affected / exposed	0 / 188 (0.00%)	1 / 25 (4.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Actinic keratosis
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	0 / 188 (0.00%)	1 / 25 (4.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	0 / 188 (0.00%)	1 / 25 (4.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	2 / 194 (1.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	2 / 188 (1.06%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopulmonary aspergillosis
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Campylobacter gastroenteritis
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abscess neck
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 188 (0.53%)	1 / 25 (4.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemophilus infection
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis B
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes simplex otitis externa
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	2 / 188 (1.06%)	0 / 25 (0.00%)	0 / 9 (0.00%)	3 / 194 (1.55%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Listeria sepsis
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Localised infection
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumococcal bacteraemia
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Parainfluenzae virus infection
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peritoneal tuberculosis
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	2 / 188 (1.06%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Moraxella infection
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	15 / 188 (7.98%)	3 / 25 (12.00%)	1 / 9 (11.11%)	19 / 194 (9.79%)
occurrences causally related to treatment / all	5 / 17	0 / 4	2 / 2	7 / 23
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
Pneumonia influenzal
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia legionella
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia streptococcal
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	2 / 194 (1.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection viral
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rhinovirus infection
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	1 / 9 (11.11%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Scedosporium infection
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	4 / 188 (2.13%)	0 / 25 (0.00%)	1 / 9 (11.11%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	2 / 4	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	1 / 2	0 / 0	0 / 0	1 / 1
Respiratory tract infection fungal
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	2 / 194 (1.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tooth abscess
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	2 / 188 (1.06%)	0 / 25 (0.00%)	0 / 9 (0.00%)	4 / 194 (2.06%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection pseudomonal
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Varicella zoster virus infection
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	0 / 188 (0.00%)	1 / 25 (4.00%)	1 / 9 (11.11%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Atypical mycobacterial infection
subjects affected / exposed	0 / 188 (0.00%)	1 / 25 (4.00%)	0 / 9 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia pseudomonal
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	1 / 9 (11.11%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	1 / 9 (11.11%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Tumour lysis syndrome
subjects affected / exposed	1 / 188 (0.53%)	1 / 25 (4.00%)	0 / 9 (0.00%)	4 / 194 (2.06%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	2 / 194 (1.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	2 / 194 (1.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperphosphataemia
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	2 / 194 (1.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypervolaemia
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Bendamustine + Rituximab Main Study	Venetoclax + Rituximab Re-Treatment Substudy	Bendamustine + Rituximab Crossover Substudy	Venetoclax + Rituximab Main Study
Total subjects affected by non serious adverse events
subjects affected / exposed	177 / 188 (94.15%)	9 / 25 (36.00%)	5 / 9 (55.56%)	190 / 194 (97.94%)
Vascular disorders
Hypertension
subjects affected / exposed	7 / 188 (3.72%)	0 / 25 (0.00%)	0 / 9 (0.00%)	15 / 194 (7.73%)
occurrences all number	7	0	0	15
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	33 / 188 (17.55%)	0 / 25 (0.00%)	0 / 9 (0.00%)	27 / 194 (13.92%)
occurrences all number	44	0	0	41
Oedema peripheral
subjects affected / exposed	7 / 188 (3.72%)	0 / 25 (0.00%)	0 / 9 (0.00%)	10 / 194 (5.15%)
occurrences all number	11	0	0	14
Fatigue
subjects affected / exposed	39 / 188 (20.74%)	1 / 25 (4.00%)	0 / 9 (0.00%)	35 / 194 (18.04%)
occurrences all number	44	1	0	41
Chills
subjects affected / exposed	16 / 188 (8.51%)	1 / 25 (4.00%)	0 / 9 (0.00%)	8 / 194 (4.12%)
occurrences all number	20	1	0	10
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	31 / 188 (16.49%)	0 / 25 (0.00%)	0 / 9 (0.00%)	36 / 194 (18.56%)
occurrences all number	37	0	0	51
Dyspnoea
subjects affected / exposed	14 / 188 (7.45%)	0 / 25 (0.00%)	0 / 9 (0.00%)	11 / 194 (5.67%)
occurrences all number	17	0	0	14
Oropharyngeal pain
subjects affected / exposed	7 / 188 (3.72%)	0 / 25 (0.00%)	0 / 9 (0.00%)	10 / 194 (5.15%)
occurrences all number	7	0	0	12
Productive cough
subjects affected / exposed	4 / 188 (2.13%)	0 / 25 (0.00%)	0 / 9 (0.00%)	12 / 194 (6.19%)
occurrences all number	5	0	0	14
Psychiatric disorders
Insomnia
subjects affected / exposed	12 / 188 (6.38%)	0 / 25 (0.00%)	0 / 9 (0.00%)	21 / 194 (10.82%)
occurrences all number	13	0	0	22
Investigations
Alanine aminotransferase increased
subjects affected / exposed	10 / 188 (5.32%)	0 / 25 (0.00%)	0 / 9 (0.00%)	10 / 194 (5.15%)
occurrences all number	11	0	0	17
Neutrophil count decreased
subjects affected / exposed	13 / 188 (6.91%)	0 / 25 (0.00%)	1 / 9 (11.11%)	11 / 194 (5.67%)
occurrences all number	27	0	1	27
Blood creatinine increased
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	1 / 9 (11.11%)	5 / 194 (2.58%)
occurrences all number	1	0	2	6
White blood cell count decreased
subjects affected / exposed	3 / 188 (1.60%)	0 / 25 (0.00%)	1 / 9 (11.11%)	1 / 194 (0.52%)
occurrences all number	4	0	1	1
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	40 / 188 (21.28%)	0 / 25 (0.00%)	0 / 9 (0.00%)	16 / 194 (8.25%)
occurrences all number	54	0	0	21
Cardiac disorders
Supraventricular tachycardia
subjects affected / exposed	1 / 188 (0.53%)	0 / 25 (0.00%)	1 / 9 (11.11%)	0 / 194 (0.00%)
occurrences all number	1	0	1	0
Nervous system disorders
Dizziness
subjects affected / exposed	11 / 188 (5.85%)	0 / 25 (0.00%)	0 / 9 (0.00%)	12 / 194 (6.19%)
occurrences all number	14	0	0	14
Headache
subjects affected / exposed	19 / 188 (10.11%)	0 / 25 (0.00%)	0 / 9 (0.00%)	21 / 194 (10.82%)
occurrences all number	21	0	0	21
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	42 / 188 (22.34%)	2 / 25 (8.00%)	0 / 9 (0.00%)	23 / 194 (11.86%)
occurrences all number	57	2	0	30
Neutropenia
subjects affected / exposed	85 / 188 (45.21%)	5 / 25 (20.00%)	3 / 9 (33.33%)	120 / 194 (61.86%)
occurrences all number	182	13	5	290
Anaemia
subjects affected / exposed	40 / 188 (21.28%)	1 / 25 (4.00%)	1 / 9 (11.11%)	28 / 194 (14.43%)
occurrences all number	68	1	1	48
Febrile neutropenia
subjects affected / exposed	3 / 188 (1.60%)	0 / 25 (0.00%)	1 / 9 (11.11%)	0 / 194 (0.00%)
occurrences all number	3	0	1	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	31 / 188 (16.49%)	3 / 25 (12.00%)	0 / 9 (0.00%)	78 / 194 (40.21%)
occurrences all number	43	4	0	120
Constipation
subjects affected / exposed	39 / 188 (20.74%)	0 / 25 (0.00%)	0 / 9 (0.00%)	27 / 194 (13.92%)
occurrences all number	47	0	0	31
Abdominal pain
subjects affected / exposed	6 / 188 (3.19%)	0 / 25 (0.00%)	0 / 9 (0.00%)	13 / 194 (6.70%)
occurrences all number	7	0	0	14
Vomiting
subjects affected / exposed	22 / 188 (11.70%)	0 / 25 (0.00%)	0 / 9 (0.00%)	15 / 194 (7.73%)
occurrences all number	29	0	0	18
Nausea
subjects affected / exposed	64 / 188 (34.04%)	0 / 25 (0.00%)	0 / 9 (0.00%)	42 / 194 (21.65%)
occurrences all number	82	0	0	58
Skin and subcutaneous tissue disorders
Dermatitis
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	1 / 9 (11.11%)	5 / 194 (2.58%)
occurrences all number	0	0	1	5
Rash
subjects affected / exposed	25 / 188 (13.30%)	0 / 25 (0.00%)	0 / 9 (0.00%)	15 / 194 (7.73%)
occurrences all number	29	0	0	19
Pruritus
subjects affected / exposed	9 / 188 (4.79%)	1 / 25 (4.00%)	0 / 9 (0.00%)	10 / 194 (5.15%)
occurrences all number	9	1	0	11
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	11 / 188 (5.85%)	0 / 25 (0.00%)	0 / 9 (0.00%)	17 / 194 (8.76%)
occurrences all number	15	0	0	22
Back pain
subjects affected / exposed	11 / 188 (5.85%)	0 / 25 (0.00%)	0 / 9 (0.00%)	14 / 194 (7.22%)
occurrences all number	11	0	0	14
Muscle spasms
subjects affected / exposed	11 / 188 (5.85%)	0 / 25 (0.00%)	0 / 9 (0.00%)	4 / 194 (2.06%)
occurrences all number	11	0	0	4
Infections and infestations
Oral herpes
subjects affected / exposed	12 / 188 (6.38%)	0 / 25 (0.00%)	0 / 9 (0.00%)	8 / 194 (4.12%)
occurrences all number	12	0	0	11
Pharyngitis
subjects affected / exposed	1 / 188 (0.53%)	1 / 25 (4.00%)	0 / 9 (0.00%)	14 / 194 (7.22%)
occurrences all number	1	1	0	17
Sinusitis
subjects affected / exposed	5 / 188 (2.66%)	0 / 25 (0.00%)	0 / 9 (0.00%)	19 / 194 (9.79%)
occurrences all number	5	0	0	26
Upper respiratory tract infection
subjects affected / exposed	28 / 188 (14.89%)	1 / 25 (4.00%)	0 / 9 (0.00%)	45 / 194 (23.20%)
occurrences all number	42	1	0	81
Urinary tract infection
subjects affected / exposed	7 / 188 (3.72%)	0 / 25 (0.00%)	0 / 9 (0.00%)	12 / 194 (6.19%)
occurrences all number	9	0	0	22
Nasopharyngitis
subjects affected / exposed	11 / 188 (5.85%)	0 / 25 (0.00%)	0 / 9 (0.00%)	22 / 194 (11.34%)
occurrences all number	15	0	0	29
Lower respiratory tract infection
subjects affected / exposed	4 / 188 (2.13%)	0 / 25 (0.00%)	0 / 9 (0.00%)	11 / 194 (5.67%)
occurrences all number	4	0	0	15
Conjunctivitis
subjects affected / exposed	5 / 188 (2.66%)	0 / 25 (0.00%)	0 / 9 (0.00%)	10 / 194 (5.15%)
occurrences all number	5	0	0	11
Bronchitis
subjects affected / exposed	13 / 188 (6.91%)	1 / 25 (4.00%)	0 / 9 (0.00%)	20 / 194 (10.31%)
occurrences all number	14	1	0	32
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	17 / 188 (9.04%)	0 / 25 (0.00%)	0 / 9 (0.00%)	8 / 194 (4.12%)
occurrences all number	18	0	0	11
Hyperkalaemia
subjects affected / exposed	0 / 188 (0.00%)	0 / 25 (0.00%)	0 / 9 (0.00%)	11 / 194 (5.67%)
occurrences all number	0	0	0	16
Hypokalaemia
subjects affected / exposed	7 / 188 (3.72%)	0 / 25 (0.00%)	1 / 9 (11.11%)	11 / 194 (5.67%)
occurrences all number	7	0	1	12

More information

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Were there any global substantial amendments to the protocol? Yes

26 Nov 2013

An exclusion of participants who had received potent cytochrome (CYP3A4) inhibitors was clarified to make consistent with the rest of the protocol; An exclusion criterion was added for participants with recent major surgery in line with the prescribing information for bendamustine; The pregnancy testing procedure was modified such that testing was required at each cycle of combination therapy and every 3 months thereafter until the end of treatment in order to obtain a more timely diagnosis of pregnancy.

10 Jun 2014

Modifications to the tumor lysis syndrome prophylaxis measures for participants with CLL were implemented following analysis of participants enrolled in different venetoclax trials: All participants randomized to the ‘Venetoclax + Rituximab’ arm were to initiate dosing with 20 mg venetoclax daily for at least 7 days; Outpatient dosing and monitoring for the first venetoclax dose at all dose levels (20 mg, 50 mg, 100 mg, 200 mg, 400 mg) was introduced for low- and medium-risk participants, if there was no indication to hospitalize; Outpatient IV hydration prior to the first venetoclax dose was introduced for medium-risk participants at 20 and 50 mg; Inpatient dosing and monitoring was introduced for high-risk participants prior to the first venetoclax dose only at the 20 mg and 50 mg dose levels; Outpatient dosing and IV hydration prior to the first venetoclax dose was introduced for high-risk participants at dose levels of 100 mg and above, if there was no indication to hospitalize; Reduced frequency of laboratory assessments after dosing; Prophylaxis with rasburicase had to be administered prior to the first dose of venetoclax only for high-risk participants with high uric acid levels and per regional standards/guidelines; Dose Modification for venetoclax + rituximab in case of non-hematologic toxicity was clarified globally.

16 Oct 2014

The recruitment of participants with occult or prior hepatitis B virus (HBV) infection if HBV deoxy-ribonucleic acid (DNA) was undetectable was allowed; In order to collect appropriate MRD information, bone marrow aspiration was added. This was previously only mandated in participants with CR. To synchronize with other venetoclax development studies MRD in peripheral blood was to be monitored for up to 1 year after completion of venetoclax single-agent therapy.

22 Dec 2015

The interim analysis was changed to be information-fraction-based as opposed to time-based (that is, percentage of total PFS) events; A secondary objective of best overall response rate as assessed by the investigator was added; Details regarding multiplicity adjustment and order for testing the key secondary endpoints were added; The secondary outcome measure of MRD response rate was clarified that this assessment was based on the EoCTR visit. MRD response rate at other disease response assessment timepoints were designated as exploratory outcome measures; Additional details were provided on the use of strong, moderate and weak CYP3A4 inhibitors and inducers as well as cautionary medications; Timings for the baseline QoL questionnaires for the ‘Venetoclax + Rituximab’ arm were incorporated; PK outcome measures were further defined to include concentrations of venetoclax.

21 Nov 2016

Allowed for a change in the clinical prioritization of the secondary efficacy endpoints to mirror the evolving relapsed/refractory CLL therapeutic and scientific landscape.

03 Jun 2017

The following updates in the protocol were made in Korea. - The description of the fixed sequence testing of the secondary efficacy endpoints in the statistical section of the protocol was streamlined and the details of the testing of secondary endpoints were set out in the statistical analysis plan, in accordance with the international guideline on Statistical Principles for Clinical Trials (ICH E9). This amendment is implemented to allow for a change in the clinical prioritization of the secondary efficacy endpoints to mirror the evolving R/R CLL therapeutic and scientific landscape. - The sample list of prohibited and cautionary medications was updated, incorporating the FDA’s updated guidelines.

30 Mar 2018

- An exploratory objective was added to evaluate best overall response rate (ORR) to next anti-chronic lymphocytic leukemia (CLL) treatment, as assessed by the investigator. - An optional R/C Substudy was added.At the interim analysis (now primary analysis), the study demonstrated that venetoclax and rituximab (venetoclax + R) is superior to bendamustine and rituximab (BR) in participants with relapsed/refractory CLL. The primary endpoint of investigator assessed progression-free survival (PFS) showed significant improvement with venetoclax. - Secondary endpoints, including overall survival (OS), ORR, and complete response rate, also showed consistent clinically meaningful improvements. The Sponsor included an optional R/C Substudy to allow: -- Eligible participants from Arm A (venetoclax + R) who had clinically progressed after finishing treatment, had not received new anti-CLL therapy, and were in need of treatment have the option to receive treatment with venetoclax + R again (re-treatment). This will allow the Sponsor to study the outcomes of participants who are re-treated with venetoclax + R following prior venetoclax + R treatment. -- Eligible participants from Arm B (BR) who had clinically progressed after finishing treatment, have not received new anti-CLL therapy, and are in need of treatment have the option to cross over and receive venetoclax + R given the results of the primary analysis demonstrating superior outcome for venetoclax + R treatment. - The study duration is extended for an additional 45 months to allow for the collection of long-term data including safety, PFS, and OS. At the primary read out, PFS and OS outcomes for participants in the venetoclax + R arm exceed original protocol expectations, thus requiring longer follow-up to enable estimation of a robust efficacy and median PFS.

30 Mar 2018

- The reporting of secondary malignancies has been extended after the reporting period to capture all events regardless of causality in order to satisfy health authority requirements. The rationale for biomarker assessments has been updated to include next-generation sequencing analysis. These analyses will provide a comprehensive characterization of genomics to enable the understanding of disease pathobiology. - Sample collection for peripheral blood minimal residual disease (MRD) samples has been extended until clinical progression because participants demonstrated persistent MRD negativity and there is a need to better understand the MRD kinetics over longer period of time.

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

Clinical Trial Results: A Multicenter, Phase III, Open-Label, Randomized Study in Relapsed/Refractory Patients With Chronic Lymphocytic Leukemia to Evaluate the Benefit of Venetoclax (GDC-0199/ABT-199) Plus Rituximab Compared With Bendamustine Plus Rituximab

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants With PD as Assessed by the Investigator Using Standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines or Death

Primary: Percentage of Participants With PD as Assessed by the Investigator Using Standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines or Death

Primary: PFS as Assessed by the Investigator Using Standard iwCLL Guidelines

Primary: PFS as Assessed by the Investigator Using Standard iwCLL Guidelines

Secondary: PFS as Assessed by the IRC Using Standard iwCLL Guidelines

Secondary: PFS as Assessed by the IRC Using Standard iwCLL Guidelines

Secondary: Percentage of Participants With PD or Death as Assessed by the Independent Review Committee (IRC) Using Standard iwCLL Guidelines

Secondary: Percentage of Participants With PD or Death as Assessed by the Independent Review Committee (IRC) Using Standard iwCLL Guidelines

Secondary: Percentage of Participants With PD or Death as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

Secondary: Percentage of Participants With PD or Death as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

Secondary: Percentage of Participants With PD or Death as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by Fluorescence in-situ Hybridization (FISH) Test

Secondary: Percentage of Participants With PD or Death as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by Fluorescence in-situ Hybridization (FISH) Test

Secondary: PFS as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

Secondary: PFS as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

Secondary: Percentage of Participants With Best Overall Response of Complete Response (CR), CR with Incomplete Bone Marrow Recovery (CRi), Nodular Partial Response (nPR), or Partial Response (PR) as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Percentage of Participants With Best Overall Response of Complete Response (CR), CR with Incomplete Bone Marrow Recovery (CRi), Nodular Partial Response (nPR), or Partial Response (PR) as Assessed by the Investigator Using iwCLL Guidelines

Secondary: PFS as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

Secondary: PFS as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

Secondary: Percentage of Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the IRC Using iwCLL Guidelines

Secondary: Percentage of Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the IRC Using iwCLL Guidelines

Secondary: Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at end of Combination Treatment Visit as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at end of Combination Treatment Visit as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Percentage of Participants Who Died

Secondary: Percentage of Participants Who Died

Secondary: Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at end of Combination Treatment Visit as Assessed by the IRC Using iwCLL Guidelines

Secondary: Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at end of Combination Treatment Visit as Assessed by the IRC Using iwCLL Guidelines

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Percentage of Participants With PD/Relapse, Start of a new Anti-Chronic Lymphocytic Leukemia (CLL) Therapy, or Death as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Percentage of Participants With PD/Relapse, Start of a new Anti-Chronic Lymphocytic Leukemia (CLL) Therapy, or Death as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Event-Free Survival (EFS) as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Event-Free Survival (EFS) as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Percentage of Participants With Start of New Anti-CLL Treatment or Death as Assessed by the Investigator

Secondary: Percentage of Participants With Start of New Anti-CLL Treatment or Death as Assessed by the Investigator

Secondary: Duration of Responses (DOR) as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Duration of Responses (DOR) as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Percentage of Participants With PD or Death Among Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Percentage of Participants With PD or Death Among Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Percentage of Participants With MRD Negativity in Bone Marrow

Secondary: Percentage of Participants With MRD Negativity in Bone Marrow

Secondary: Time to New Anti-CLL Treatment (TTNT) as Assessed by the Investigator

Secondary: Time to New Anti-CLL Treatment (TTNT) as Assessed by the Investigator

Secondary: Percentage of Participants With Minimal Residual Disease (MRD) Negativity in Peripheral Blood

Secondary: Percentage of Participants With Minimal Residual Disease (MRD) Negativity in Peripheral Blood

Secondary: Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Inventory (MDASI) Core Symptom Severity, Module Symptom Severity, and Interference Scores

Secondary: Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Inventory (MDASI) Core Symptom Severity, Module Symptom Severity, and Interference Scores

Secondary: Plasma Venetoclax Concentrations

Secondary: Plasma Venetoclax Concentrations

Secondary: Change from Baseline in HRQoL as Measured by European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scales Score and Global Health Status/Global Quality-of-Life (QoL) Scale Score

Secondary: Change from Baseline in HRQoL as Measured by European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scales Score and Global Health Status/Global Quality-of-Life (QoL) Scale Score

Secondary: Change From Baseline in HRQoL as Measured by Quality of Life Questionnaire Associated CLL Module (QLQ-CLL16) Multi-Item Scales Score

Secondary: Change From Baseline in HRQoL as Measured by Quality of Life Questionnaire Associated CLL Module (QLQ-CLL16) Multi-Item Scales Score

Secondary: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Number of Participants with Grade 3 or higher Tumor Lysis Syndrome (TLS) and Infusion-related Reactions (IRRs)

Secondary: Number of Participants with Grade 3 or higher Tumor Lysis Syndrome (TLS) and Infusion-related Reactions (IRRs)

Post-hoc: Euro QoL 5 Dimension (EQ-5D) Questionnaire Score

Post-hoc: Euro QoL 5 Dimension (EQ-5D) Questionnaire Score

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Multicenter, Phase III, Open-Label, Randomized Study in Relapsed/Refractory Patients With Chronic Lymphocytic Leukemia to Evaluate the Benefit of Venetoclax (GDC-0199/ABT-199) Plus Rituximab Compared With Bendamustine Plus Rituximab