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Clinical Trial Results:
An open-label, multi-center, three arm randomized, phase III study to compare the efficacy and safety of RO5072759 + chlorambucil (GClb), rituximab + chlorambucil (RClb) or chlorambucil (Clb) alone in previously untreated CLL patients with comorbidities.

Summary
EudraCT number	2009-012476-28
Trial protocol	DE FR GB AT ES CZ NL RO SK DK IT EE BG
Global end of trial date	23 Aug 2017

Results information
Results version number	v1(current)
This version publication date	31 Aug 2018
First version publication date	24 Aug 2016
Other versions

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

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Trial information

Top of page

Sponsor protocol code

BO21004

ISRCTN number

-

US NCT number

NCT02053610

WHO universal trial number (UTN)

-

Other trial identifiers

ClinicalTrials.gov identifier: NCT01998880, ClinicalTrials.gov identifier: NCT01010061

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

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

Scientific contact

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

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

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

23 Aug 2017

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

23 Aug 2017

Was the trial ended prematurely?

No

Main objective of the trial

The main objective of this trial is to demonstrate clinically relevant statistical superiority in progression free survival (PFS) with RO5072759 plus chlorambucil (GClb) compared to rituximab plus chlorambucil (RClb) and chlorambucil (Clb) alone and RClb compared to Clb (GClb vs Clb [Stage 1a]; RClb vs Clb [Stage 1b]; GClb vs RClb [Stage 2]) in previously untreated chronic lymphocytic leukemia (CLL) subjects with comorbidities.

Protection of trial subjects

All study subjects were required to read and sign an informed consent form.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

09 Dec 2009

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Romania: 20

Country: Number of subjects enrolled

Slovakia: 3

Country: Number of subjects enrolled

Spain: 109

Country: Number of subjects enrolled

United Kingdom: 33

Country: Number of subjects enrolled

Austria: 28

Country: Number of subjects enrolled

Bulgaria: 33

Country: Number of subjects enrolled

Czech Republic: 21

Country: Number of subjects enrolled

Denmark: 17

Country: Number of subjects enrolled

Estonia: 5

Country: Number of subjects enrolled

France: 74

Country: Number of subjects enrolled

Germany: 146

Country: Number of subjects enrolled

Italy: 57

Country: Number of subjects enrolled

Australia: 33

Country: Number of subjects enrolled

Croatia: 12

Country: Number of subjects enrolled

Canada: 30

Country: Number of subjects enrolled

Switzerland: 15

Country: Number of subjects enrolled

Argentina: 7

Country: Number of subjects enrolled

Thailand: 16

Country: Number of subjects enrolled

New Zealand: 3

Country: Number of subjects enrolled

Hong Kong: 1

Country: Number of subjects enrolled

Mexico: 11

Country: Number of subjects enrolled

Russian Federation: 93

Country: Number of subjects enrolled

Brazil: 2

Country: Number of subjects enrolled

United States: 3

Country: Number of subjects enrolled

Egypt: 8

Worldwide total number of subjects

781

EEA total number of subjects

559

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

163

From 65 to 84 years

592

85 years and over

26

Subject disposition

Top of page

Recruitment details

A total of 787 subjects were enrolled in the study. Following a 6 subject safety run-in, prior to randomisation, 781 subjects were randomised.

Screening details

589 subjects were randomised to 1 of 3 treatment groups in 2:2:1 ratio: Obinutuzumab + Chlorambucil (GClb) (n=238), Rituximab + Chlorambucil (RClb) (n=233) or Chlorambucil (Clb) (n=118) in Stage 1 and an additional 192 subjects were randomised in 1:1 ratio to GClb or RClb in Stage 2.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

No

Stage 1: Rituximab + Chlorambucil (RClb)

Arm description

Subjects received 375 mg/m^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).

Arm type

Experimental

Investigational medicinal product name

Chlorambucil

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle.

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Rituxan, Mabthera, RO0452294

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab 375 mg/m^2 by IV infusion on Days 1 of Cycle 1 then 500 mg/m^2 IV infusion on Day 1 of Cycles 2-6 (28-day cycles).

Stage 1: Obinutuzumab + Chlorambucil (GClb)

Arm description

Subjects received obinutuzumab 1000 milligram (mg) intravenous (IV) infusion, on Day 1 [First infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 milligram per kilogram of body weight (mg/kg) orally on Day 1 and 15 of each 28-day cycle (6 Cycles).

Arm type

Experimental

Investigational medicinal product name

Obinutuzumab

Investigational medicinal product code

RO5072759

Other name

Gazyvaro, Gazyva

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Obinutuzumab 1000 mg by IV infusion on Days 1 [First infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 of the first treatment cycle (Cycle 1) and Day 1 of Cycles 2-6 (28-day cycles).

Investigational medicinal product name

Chlorambucil

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle.

Stage 1: Chlorambucil (Clb)

Arm description

Subjects received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Subjects with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.

Arm type

Experimental

Investigational medicinal product name

Chlorambucil

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle.

Stage 2: Rituximab + Chlorambucil (RClb)

Arm description

Subjects received rituximab 375 mg/m^2 IV infusion on Day 1 of Cycle 1 then 500 mg/m^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28- day cycle (6 cycles).

Arm type

Experimental

Investigational medicinal product name

Chlorambucil

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle.

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Rituxan, Mabthera, RO0452294

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab 375 mg/m^2 by IV infusion on Days 1 of Cycle 1 then 500 mg/m^2 IV infusion on Day 1 of Cycles 2-6 (28-day cycles).

Stage 2: Obinutuzumab + Chlorambucil (GClb)

Arm description

Subjects received obinutuzumab 1000 mg IV infusion, on Day 1 [First infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles).

Arm type

Experimental

Investigational medicinal product name

Obinutuzumab

Investigational medicinal product code

RO5072759

Other name

Gazyvaro, Gazyva

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Obinutuzumab 1000 mg by IV infusion on Days 1 [First infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 of the first treatment cycle (Cycle 1) and Day 1 of Cycles 2-6 (28-day cycles).

Investigational medicinal product name

Chlorambucil

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle.

Number of subjects in period 1	Stage 1: Rituximab + Chlorambucil (RClb)	Stage 1: Obinutuzumab + Chlorambucil (GClb)	Stage 1: Chlorambucil (Clb)	Stage 2: Rituximab + Chlorambucil (RClb)	Stage 2: Obinutuzumab + Chlorambucil (GClb)
Started	233	238	118	330	333
Received study drug	230	236	116	326	331
Completed	205	190	78	288	266
Not completed	28	48	40	42	67
Withdrew Consent	2	5	1	2	9
Violation of Selection Criteria	-	-	1	1	-
Death	3	3	6	5	5
No Treatment Received	3	2	2	4	2
Adverse Event/Intercurrent Illness	16	33	16	25	43
Administrative/Other	1	-	1	1	1
Insufficient Therapeutic Response	1	1	5	1	1
Refused Treatment/Did Not Cooperate	1	2	-	1	3
Disease Progression	1	2	8	2	3

Baseline characteristics

Top of page

Reporting group title

Stage 1: Rituximab + Chlorambucil (RClb)

Reporting group description

Subjects received 375 mg/m^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).

Reporting group title

Stage 1: Obinutuzumab + Chlorambucil (GClb)

Reporting group description

Subjects received obinutuzumab 1000 milligram (mg) intravenous (IV) infusion, on Day 1 [First infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 milligram per kilogram of body weight (mg/kg) orally on Day 1 and 15 of each 28-day cycle (6 Cycles).

Reporting group title

Stage 1: Chlorambucil (Clb)

Reporting group description

Subjects received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Subjects with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.

Reporting group title

Stage 2: Rituximab + Chlorambucil (RClb)

Reporting group description

Subjects received rituximab 375 mg/m^2 IV infusion on Day 1 of Cycle 1 then 500 mg/m^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28- day cycle (6 cycles).

Reporting group title

Stage 2: Obinutuzumab + Chlorambucil (GClb)

Reporting group description

Subjects received obinutuzumab 1000 mg IV infusion, on Day 1 [First infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles).

Notes
[1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
Justification: A 3 arm, parallel group comparative study of GClb vs RClb vs Clb, study was split into two Stages for analysis: Stage 1 (Stage 1a - GClb vs Clb, and Stage 1b - RClb vs Clb) and Stage 2 (RClb vs GClb). In Stage 2, randomization continued in the GClb and RClb arms only. Stage 1 and Stage 2 are not temporally consecutive, but rather compare different treatment arms. All patients enrolled in GClb and RClb arms in Stage 1 were also part of Stage 2, irrespective of whether they had completed or not.

Reporting group values	Stage 1: Rituximab + Chlorambucil (RClb)	Stage 1: Obinutuzumab + Chlorambucil (GClb)	Stage 1: Chlorambucil (Clb)	Stage 2: Rituximab + Chlorambucil (RClb)	Stage 2: Obinutuzumab + Chlorambucil (GClb)	Total
Number of subjects	233	238	118	330	333	781
Age categorical
Units: Subjects
Less than (<) 65 years	47	42	26	73	64	163
Greater than or equal to (>=) 65 years	186	196	92	257	269	618
Gender categorical
Units: Subjects
Female	84	98	43	126	130	299
Male	149	140	75	204	203	482

End points

Top of page

Reporting group title

Stage 1: Rituximab + Chlorambucil (RClb)

Reporting group description

Subjects received 375 mg/m^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).

Reporting group title

Stage 1: Obinutuzumab + Chlorambucil (GClb)

Reporting group description

Subjects received obinutuzumab 1000 milligram (mg) intravenous (IV) infusion, on Day 1 [First infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 milligram per kilogram of body weight (mg/kg) orally on Day 1 and 15 of each 28-day cycle (6 Cycles).

Reporting group title

Stage 1: Chlorambucil (Clb)

Reporting group description

Subjects received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Subjects with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.

Reporting group title

Stage 2: Rituximab + Chlorambucil (RClb)

Reporting group description

Subjects received rituximab 375 mg/m^2 IV infusion on Day 1 of Cycle 1 then 500 mg/m^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28- day cycle (6 cycles).

Reporting group title

Stage 2: Obinutuzumab + Chlorambucil (GClb)

Reporting group description

Subjects received obinutuzumab 1000 mg IV infusion, on Day 1 [First infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles).

Primary: Progression-Free Survival (PFS) in Stage 1

Top of page

End point title

Progression-Free Survival (PFS) in Stage 1 ^[1]

End point description

PFS was defined as time from randomisation to first occurrence of progression, relapse, or death from any cause as assessed by investigator. Progressive disease (PD) required at least one of the following: ≥50% increase in absolute number of lymphocytes, appearance of new palpable lymph nodes (>15 mm in diameter) or new extra nodal lesion, ≥50% increase in diameter of previous site of clinically significant lymphadenopathy, ≥50% increase in enlargement of liver or spleen, transformation to a more aggressive histology or after treatment, progression of any cytopenia (decrease of hemoglobin levels >20 g/L or <10 g/dL or a decrease of platelet counts >50% or <100*10^9/L or by a decrease of neutrophil counts >50% or <1.0*10^9/L). Intent-to-treat population (ITT) included all randomized subjects. Subjects without PFS events were censored.

End point type

Primary

End point timeframe

Randomisation to clinical cutoff date of 10 Oct 2017 (median observation in Stage 1a: 62.5 months and Stage 1b: 57.7 months)

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure only looked at Stage 1 data.

End point values	Stage 1: Rituximab + Chlorambucil (RClb)	Stage 1: Obinutuzumab + Chlorambucil (GClb)	Stage 1: Chlorambucil (Clb)
Number of subjects analysed	233	238	118
Units: months
median (confidence interval 95%)	16.5 (14.3 to 17.7)	31.1 (26.5 to 35.6)	11.1 (10.7 to 11.3)

PFS Stage 1a

Statistical analysis description

Stratified by Binet stage at Baseline.

Comparison groups

Stage 1: Obinutuzumab + Chlorambucil (GClb) v Stage 1: Chlorambucil (Clb)

Number of subjects included in analysis

356

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[2]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.16

upper limit

0.28

Notes
[2] - Type I error controlled through closed test procedure.

PFS Stage 1b

Statistical analysis description

Stratified by Binet stage at Baseline

Comparison groups

Stage 1: Chlorambucil (Clb) v Stage 1: Rituximab + Chlorambucil (RClb)

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[3]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.46

Confidence interval

level

95%

sides

2-sided

lower limit

0.36

upper limit

0.59

Notes
[3] - Type I error controlled through closed test procedure.

Primary: Progression-Free Survival (PFS) Stage 2

Top of page

End point title

Progression-Free Survival (PFS) Stage 2 ^[4]

End point description

PFS was defined as time from randomisation to first occurrence of progression, relapse, or death from any cause as assessed by investigator. PD required at least one of the following: ≥50% increase in absolute number of lymphocytes, appearance of new palpable lymph nodes (>15 mm in diameter) or new extra nodal lesion, ≥50% increase in diameter of previous site of clinically significant lymphadenopathy, ≥50% increase in enlargement of liver or spleen, transformation to a more aggressive histology or after treatment, progression of any cytopenia (decrease of hemoglobin levels >20 g/L or <10 g/dL or a decrease of platelet counts >50% or <100*10^9/L or by a decrease of neutrophil counts >50% or <1.0*10^9/L). ITT population. Data for subjects without disease progression or death was censored at time of last response assessment, or, if no response assessments were performed after baseline visit, at time of randomisation +1 day.

End point type

Primary

End point timeframe

Randomisation to clinical cutoff date of 10 Oct 2017 (median observation 59.4 months)

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure only looked at Stage 2 data.

End point values	Stage 2: Rituximab + Chlorambucil (RClb)	Stage 2: Obinutuzumab + Chlorambucil (GClb)
Number of subjects analysed	330	333
Units: months
median (confidence interval 95%)	15.7 (14.3 to 17.2)	28.9 (26.1 to 32.7)

PFS Stage 2

Comparison groups

Stage 2: Rituximab + Chlorambucil (RClb) v Stage 2: Obinutuzumab + Chlorambucil (GClb)

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[5]

Method

Log-rank Test, stratified

Parameter type

Hazard ratio (HR)

Point estimate

0.49

Confidence interval

level

95%

sides

2-sided

lower limit

0.41

upper limit

0.58

Notes
[5] - Stratified by Binet stage at Baseline

Primary: Percentage of Subjects With Progression Free Survival Events in Stage 1

Top of page

End point title

Percentage of Subjects With Progression Free Survival Events in Stage 1 ^[6] ^[7]

End point description

Percentage of subjects with progression free survival events: progression, relapse, or death.

End point type

Primary

End point timeframe

Randomisation to clinical cutoff date of 10 Oct 2017 (median observation in Stage 1a: 62.5 months and Stage 1b: 57.7 months)

Notes
[6] - 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: This outcome measure only looked at Stage 1 data.
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure only looked at Stage 1 data.

End point values	Stage 1: Rituximab + Chlorambucil (RClb)	Stage 1: Obinutuzumab + Chlorambucil (GClb)	Stage 1: Chlorambucil (Clb)
Number of subjects analysed	233	238	118
Units: percentage of subjects
number (not applicable)	90.1	72.7	90.7

No statistical analyses for this end point

Primary: Percentage of Subjects With Progression Free Survival Events in Stage 2

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End point title

Percentage of Subjects With Progression Free Survival Events in Stage 2 ^[8] ^[9]

End point description

Percentage of subjects with progression free survival events: disease progression, relapse, or death.

End point type

Primary

End point timeframe

Randomisation to clinical cutoff date of 10 Oct 2017 (median observation 59.4 months)

Notes
[8] - 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: This outcome measure only looked at Stage 2 data.
[9] - 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: This outcome measure only looked at Stage 2 data.

End point values	Stage 2: Rituximab + Chlorambucil (RClb)	Stage 2: Obinutuzumab + Chlorambucil (GClb)
Number of subjects analysed	330	333
Units: percentage of subject
number (not applicable)	88.5	73.3

No statistical analyses for this end point

Secondary: Progression Free Survival Based on Independent Review Committee (IRC) Data in Stage 1

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End point title

Progression Free Survival Based on Independent Review Committee (IRC) Data in Stage 1 ^[10]

End point description

PFS was defined as the time from randomisation to the first occurrence of progression, relapse, or death from any cause as assessed by Independent Review Committee. PD required at least one of the following: ≥50% increase in absolute number of lymphocytes, appearance of new palpable lymph nodes (>15 mm in diameter) or new extra nodal lesion, ≥50% increase in diameter of previous site of clinically significant lymphadenopathy, ≥50% increase in enlargement of liver or spleen, transformation to a more aggressive histology or after treatment, progression of any cytopenia (decrease of hemoglobin levels >20 g/L or <10 g/dL or a decrease of platelet counts >50% or <100*10^9/L or by a decrease of neutrophil counts >50% or <1.0*10^9/L). ITT population. Subjects without PFS events were censored.

End point type

Secondary

End point timeframe

Randomisation to clinical cutoff date of 9 May 2013 (median observation for Stage 1a: 22.8 months and Stage 1b: 22.7 months)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure only looked at Stage 1 data.

End point values	Stage 1: Rituximab + Chlorambucil (RClb)	Stage 1: Obinutuzumab + Chlorambucil (GClb)	Stage 1: Chlorambucil (Clb)
Number of subjects analysed	233	238	118
Units: months
median (confidence interval 95%)	16.1 (14.3 to 17.2)	27.2 (23.5 to 33.0)	11.2 (11.0 to 12.1)

No statistical analyses for this end point

Secondary: Progression Free Survival Based on Independent Review Committee (IRC) Data in Stage 2

Top of page

End point title

Progression Free Survival Based on Independent Review Committee (IRC) Data in Stage 2 ^[11]

End point description

PFS was defined as the time from randomisation to the first occurrence of progression, relapse, or death from any cause as assessed by IRC. PD required at least one of the following: ≥50% increase in absolute number of lymphocytes, appearance of new palpable lymph nodes (>15 mm in diameter) or new extra nodal lesion, ≥50% increase in diameter of previous site of clinically significant lymphadenopathy, ≥50% increase in enlargement of liver or spleen, transformation to a more aggressive histology or after treatment, progression of any cytopenia (decrease of hemoglobin levels >20 g/L or <10 g/dL or a decrease of platelet counts >50% or <100*10^9/L or by a decrease of neutrophil counts >50% or <1.0*10^9/L). ITT population. Data for subjects without disease progression or death was censored at time of last response assessment, or, if no response assessments were performed after baseline visit, at time of randomisation +1 day.

End point type

Secondary

End point timeframe

Randomisation to clinical cutoff date of 09 May 2013 (median observation 18.7 months)

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure only looked at Stage 2 data.

End point values	Stage 2: Rituximab + Chlorambucil (RClb)	Stage 2: Obinutuzumab + Chlorambucil (GClb)
Number of subjects analysed	330	333
Units: months
median (confidence interval 95%)	14.9 (14.2 to 17.2)	26.7 (23.2 to 31.1)

No statistical analyses for this end point

Secondary: Percentage of Subjects With Progression Free Survival Events Based on Independent Review Committee (IRC) Data in Stage 1

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End point title

Percentage of Subjects With Progression Free Survival Events Based on Independent Review Committee (IRC) Data in Stage 1 ^[12]

End point description

Percentage of subjects with progression free survival events: progression, relapse, or death from any cause as assessed by an IRC. ITT population. Subjects without PFS events were censored.

End point type

Secondary

End point timeframe

Randomization to clinical cutoff date of 9 May 2013 (median observation of Stage 1a: 22.8 months and Stage 1b: 22.7 months)

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure only looked at Stage 1 data.

End point values	Stage 1: Rituximab + Chlorambucil (RClb)	Stage 1: Obinutuzumab + Chlorambucil (GClb)	Stage 1: Chlorambucil (Clb)
Number of subjects analysed	233	238	118
Units: percentage of subjects
number (not applicable)	64.8	37.4	76.3

No statistical analyses for this end point

Secondary: Percentage of Subjects With Progression Free Survival Events Based on Independent Review Committee (IRC) Data in Stage 2

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End point title

Percentage of Subjects With Progression Free Survival Events Based on Independent Review Committee (IRC) Data in Stage 2 ^[13]

End point description

Percentage of subjects with progression free survival events: progression, relapse, or death from any cause as assessed by an Independent Review Committee.

End point type

Secondary

End point timeframe

Randomisation to clinical cutoff date of 09 May 2013 (median observation 18.7 months)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure only looked at Stage 2 data.

End point values	Stage 2: Rituximab + Chlorambucil (RClb)	Stage 2: Obinutuzumab + Chlorambucil (GClb)
Number of subjects analysed	330	333
Units: percentage of subject
number (not applicable)	55.5	30.9

No statistical analyses for this end point

Secondary: Percentage of Subjects With End of Treatment Response (EOTR) in Stage 1

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End point title

Percentage of Subjects With End of Treatment Response (EOTR) in Stage 1 ^[14]

End point description

EOTR was first response assessment 56 days from last dose based on International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) guidelines. Complete Response (CR): Peripheral lymphocytes below 4*10^9/L, No lymphadenopathy, No hepatomegaly, No splenomegaly, No disease, Blood counts as Neutrophils >1.5*10^9/L, Platelets >100*10^9/L, Hemoglobin >11g/dL and Bone marrow at least normocellular for age. CRi was CR with incomplete bone marrow recovery. Partial response (PR): ≥50% decrease in peripheral lymphocyte count from pre-treatment value and Either a ≥50% reduction in lymphadenopathy OR ≥50% reduction of liver enlargement OR ≥50% reduction of spleen enlargement, at least one of following: Neutrophils >1.5*10^9/L or ≥50% increase, Platelets >100*10^9/L, Hemoglobin 11 g/dL or ≥50% increase. Subjects from ITT population with data available for analysis. Subjects who did not reach 3 month Follow-up visit at clinical cutoff are excluded. Here, 99999 indicates that 95% CI not estimated.

End point type

Secondary

End point timeframe

Randomisation to clinical cutoff date of 10 Oct 2017 (median observation of Stage 1a: 62.5 months and Stage 1b: 57.7 months)

Notes
[14] - 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: This outcome measure only looked at Stage 1 data.

End point values	Stage 1: Rituximab + Chlorambucil (RClb)	Stage 1: Obinutuzumab + Chlorambucil (GClb)	Stage 1: Chlorambucil (Clb)
Number of subjects analysed	233	238	118
Units: percentage of subject
number (confidence interval 95%)
Complete Response (CR)	4.7 (2.4 to 8.3)	17.2 (12.7 to 22.6)	0 (0 to 3.1)
Complete Response incomplete (CRi)	2.1 (0.7 to 4.9)	4.2 (2 to 7.6)	0 (0 to 3.1)
Partial Response (PR)	55.4 (48.7 to 61.9)	48.3 (41.8 to 54.9)	28.8 (20.8 to 37.9)
Nodular Partial Response (nPR)	3.4 (1.5 to 6.7)	7.6 (4.5 to 11.7)	2.5 (0.5 to 7.3)
Stable Disease	13.7 (9.6 to 18.8)	5 (2.6 to 8.6)	22.9 (15.7 to 31.5)
Progressive Disease	12.4 (8.5 to 17.4)	4.2 (2.0 to 7.6)	28.8 (20.8 to 37.9)
No Response Assessment	8.2 (-99999 to 99999)	13.4 (-99999 to 99999)	16.9 (-99999 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Subjects With End of Treatment Response (EOTR) in Stage 2

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End point title

Percentage of Subjects With End of Treatment Response (EOTR) in Stage 2 ^[15]

End point description

EOTR was first response assessment 56 days from last dose based on International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) guidelines. Complete Response (CR): Peripheral lymphocytes below 4*10^9/L, No lymphadenopathy, No hepatomegaly, No splenomegaly, No disease, Blood counts as Neutrophils >1.5*10^9/L, Platelets >100*10^9/L, Hemoglobin >11g/dL and Bone marrow at least normocellular for age. CRi was CR with incomplete bone marrow recovery. Partial response (PR): ≥50% decrease in peripheral lymphocyte count from pre-treatment value and Either a ≥50% reduction in lymphadenopathy OR ≥50% reduction of liver enlargement OR ≥50% reduction of spleen enlargement, at least one of following: Neutrophils >1.5*10^9/L or ≥50% increase, Platelets >100*10^9/L, Hemoglobin 11 g/dL or ≥50% increase. Subjects from ITT population with data available for analysis. Subjects who did not reach 3 month Follow-up visit at clinical cutoff are excluded. Here, 99999 indicates that 95% CI not estimated.

End point type

Secondary

End point timeframe

Randomisation to clinical cutoff date of 10 Oct 2017 (median observation 59.4 months)

Notes
[15] - 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: This outcome measure only looked at Stage 2 data.

End point values	Stage 2: Rituximab + Chlorambucil (RClb)	Stage 2: Obinutuzumab + Chlorambucil (GClb)
Number of subjects analysed	330	333
Units: percentage of subject
number (confidence interval 95%)
Complete Response (CR)	4.8 (2.8 to 7.8)	15.6 (11.9 to 20)
Complete Response incomplete (CRi)	1.5 (0.5 to 3.5)	3.6 (1.9 to 6.2)
Partial Response (PR)	53.9 (48.4 to 59.4)	52.0 (46.4 to 57.4)
Nodular Partial Response (nPR)	5.2 (3 to 8.1)	7.5 (4.9 to 10.9)
Stable Disease	15.2 (11.5 to 19.5)	4.5 (2.5 to 7.3)
Progressive Disease	11.2 (8 to 15.1)	4.5 (2.5 to 7.3)
No Response Assessment	8.2 (-99999 to 99999)	12.3 (-99999 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Subjects With Best Overall Response in Stage 1

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End point title

Percentage of Subjects With Best Overall Response in Stage 1 ^[16]

End point description

Best overall response according to IWCLL guidelines was defined as the percentage of subjects with CR, CRi, PR or nPR. Complete Response (CR): Peripheral lymphocytes below 4*10^9/L, No lymphadenopathy, No hepatomegaly, No splenomegaly, No disease, Blood counts as Neutrophils >1.5*10^9/L, Platelets >100*10^9/L, Hemoglobin >11g/dL and Bone marrow at least normocellular for age. CRi was CR with incomplete bone marrow recovery. Partial response (PR): ≥50% decrease in peripheral lymphocyte count from pre-treatment value and either a ≥50% reduction in lymphadenopathy OR ≥50% reduction of liver enlargement OR ≥50% reduction of spleen enlargement, at least one of following: Neutrophils >1.5*10^9/L or ≥50% increase, Platelets >100*10^9/L, Hemoglobin 11 g/dL or ≥50% increase. Subjects from ITT population with data available for analysis. Subjects who did not reach 3 month Follow-up visit at clinical cutoff are excluded. Here, 99999 indicates that 95% CI was not estimated.

End point type

Secondary

End point timeframe

Randomisation to clinical cutoff date of 10 Oct 2017 (median observation in Stage 1a: 62.5 months and Stage 1b: 57.7 months)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure only looked at Stage 1 data.

End point values	Stage 1: Rituximab + Chlorambucil (RClb)	Stage 1: Obinutuzumab + Chlorambucil (GClb)	Stage 1: Chlorambucil (Clb)
Number of subjects analysed	233	238	118
Units: percentage of subject
number (confidence interval 95%)
Complete Response (CR)	7.7 (4.6 to 11.9)	26.5 (21.0 to 32.6)	0 (0 to 3.1)
Complete Response incomplete (CRi)	1.7 (0.5 to 4.3)	2.5 (0.9 to 5.4)	1.7 (0.2 to 6)
Partial Response (PR)	54.9 (48.3 to 61.4)	47.1 (40.6 to 53.6)	31.4 (23.1 to 40.5)
Nodular Partial Response (nPR)	1.7 (0.5 to 4.3)	2.1 (0.7 to 4.8)	0 (0 to 3.1)
Stable Disease	13.3 (9.2 to 18.4)	4.2 (2.0 to 7.6)	21.2 (14.2 to 29.7)
Progressive Disease	12.4 (8.5 to 17.4)	4.2 (2.0 to 7.6)	28.8 (20.8 to 37.9)
No Response Assessment	8.2 (-99999 to 99999)	13.4 (-99999 to 99999)	16.9 (-99999 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Subjects With Best Overall Response in Stage 2

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End point title

Percentage of Subjects With Best Overall Response in Stage 2 ^[17]

End point description

Best overall response according to IWCLL guidelines was defined as the percentage of subjects with CR, CRi, PR or nPR. Complete Response (CR): Peripheral lymphocytes below 4*10^9/L, No lymphadenopathy, No hepatomegaly, No splenomegaly, No disease, Blood counts as Neutrophils >1.5*10^9/L, Platelets >100*10^9/L, Hemoglobin >11g/dL and Bone marrow at least normocellular for age. CRi was CR with incomplete bone marrow recovery. Partial response (PR): ≥50% decrease in peripheral lymphocyte count from pre-treatment value and either a ≥50% reduction in lymphadenopathy OR ≥50% reduction of liver enlargement OR ≥50% reduction of spleen enlargement, at least one of following: Neutrophils >1.5*10^9/L or ≥50% increase, Platelets >100*10^9/L, Hemoglobin 11 g/dL or ≥50% increase. Subjects from ITT population with data available for analysis. Subjects who did not reach 3 month Follow-up visit at clinical cutoff are excluded. Here, 99999 indicates that 95% CI not estimated.

End point type

Secondary

End point timeframe

Randomisation to clinical cutoff date of 10 Oct 2017 (median observation 59.4 months)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure only looked at Stage 2 data.

End point values	Stage 2: Rituximab + Chlorambucil (RClb)	Stage 2: Obinutuzumab + Chlorambucil (GClb)
Number of subjects analysed	330	333
Units: percentage of subject
number (confidence interval 95%)
Complete Response (CR)	7.0 (4.5 to 10.3)	23.7 (19.3 to 28.7)
Complete Response incomplete (CRi)	1.2 (0.3 to 3.1)	1.8 (0.7 to 3.9)
Partial Response (PR)	55.5 (49.9 to 60.9)	50.8 (45.2 to 56.2)
Nodular Partial Response (nPR)	2.7 (1.3 to 5.1)	3.0 (1.4 to 5.5)
Stable Disease	14.5 (10.9 to 18.8)	3.9 (2.1 to 6.6)
Progressive Disease	11.5 (8.3 to 15.5)	4.5 (2.5 to 7.3)
No Response Assessment	7.6 (-99999 to 99999)	12.3 (-99999 to 99999)

No statistical analyses for this end point

Secondary: Event Free Survival (EFS) in Stage 1

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End point title

Event Free Survival (EFS) in Stage 1 ^[18]

End point description

EFS was defined as the time between date of randomization and the date of disease progression/relapse, death, or start of a new anti-leukemic therapy. Progressive disease as per IWCLL criteria required at least one of the following: ≥50% increase in the absolute number of lymphocytes, appearance of new palpable lymph nodes (>15 mm in longest diameter) or any new extra nodal lesion, ≥50% increase in the longest diameter of any previous site of clinically significant lymphadenopathy, ≥50% increase in the enlargement of the liver and/or spleen, Transformation to a more aggressive histology or After treatment, the progression of any cytopenia (a decrease of hemoglobin levels >20 g/L or <10 g/dL or a decrease of platelet counts >50% or <100*10^9/L or by a decrease of neutrophil counts >50% or <1.0*10^9/L). ITT population. Subjects without EFS events were censored.

End point type

Secondary

End point timeframe

Randomisation to clinical cutoff date of 10 Oct 2017 (median observation in Stage 1a: 62.5 months and 1b: 57.7 months)

Notes
[18] - 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: This outcome measure only looked at Stage 1 data.

End point values	Stage 1: Rituximab + Chlorambucil (RClb)	Stage 1: Obinutuzumab + Chlorambucil (GClb)	Stage 1: Chlorambucil (Clb)
Number of subjects analysed	233	238	118
Units: months
median (confidence interval 95%)	15.7 (14.2 to 17.2)	28.7 (23.9 to 32.9)	10.8 (8 to 11.1)

No statistical analyses for this end point

Secondary: Event Free Survival (EFS) in Stage 2

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End point title

Event Free Survival (EFS) in Stage 2 ^[19]

End point description

EFS was defined as the time between date of randomisation and the date of disease progression/relapse, death, or start of a new anti-leukemic therapy. Progressive disease as per IWCLL criteria required at least one of the following: ≥50% increase in the absolute number of lymphocytes, appearance of new palpable lymph nodes (>15 mm in longest diameter) or any new extra nodal lesion, ≥50% increase in the longest diameter of any previous site of clinically significant lymphadenopathy, ≥50% increase in the enlargement of the liver and/or spleen, Transformation to a more aggressive histology or After treatment, the progression of any cytopenia (a decrease of hemoglobin levels >20 g/L or <10 g/dL or a decrease of platelet counts >50% or <100*10^9/L or by a decrease of neutrophil counts >50% or <1.0*10^9/L). ITT population. Subjects without EFS events were censored.

End point type

Secondary

End point timeframe

Randomisation to clinical cutoff date of 10 Oct 2017 (median observation 59.4 months)

Notes
[19] - 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: This outcome measure only looked at Stage 2 data.

End point values	Stage 2: Rituximab + Chlorambucil (RClb)	Stage 2: Obinutuzumab + Chlorambucil (GClb)
Number of subjects analysed	330	333
Units: months
median (confidence interval 95%)	15 (14.2 to 17.1)	26.5 (24.8 to 30.1)

No statistical analyses for this end point

Secondary: Overall Survival in Stage 1

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End point title

Overall Survival in Stage 1 ^[20]

End point description

Overall Survival (OS) was defined as the time between the date of randomization and the date of death due to any cause. ITT population. Subjects without OS events were censored. Here, 99999 indicates that median survival time and 95% CI could not be estimated due to a low number of deaths.

End point type

Secondary

End point timeframe

Randomisation to clinical cutoff date of 10 Oct 2017 (median observation in Stage 1a: 62.5 months and Stage 1b: 57.7 months)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure only looked at Stage 1 data.

End point values	Stage 1: Rituximab + Chlorambucil (RClb)	Stage 1: Obinutuzumab + Chlorambucil (GClb)	Stage 1: Chlorambucil (Clb)
Number of subjects analysed	233	238	118
Units: months
median (confidence interval 95%)	74.9 (60.8 to 99999)	99999 (74.2 to 99999)	66.7 (50.9 to 99999)

No statistical analyses for this end point

Secondary: Overall Survival in Stage 2

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End point title

Overall Survival in Stage 2 ^[21]

End point description

Overall Survival (OS) was defined as the time between the date of randomization and the date of death due to any cause. ITT population. Subjects who were not reported as having died at the time of the analysis were censored at the date when they were last known to be alive. Here, the median survival time and upper limit of 95% CI could not be estimated due to a low number of deaths

End point type

Secondary

End point timeframe

Randomisation to clinical cutoff date of 10 Oct 2017 (median observation 59.4 months)

Notes
[21] - 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: This outcome measure only looked at Stage 2 data.

End point values	Stage 2: Rituximab + Chlorambucil (RClb)	Stage 2: Obinutuzumab + Chlorambucil (GClb)
Number of subjects analysed	330	333
Units: months
median (confidence interval 95%)	73.1 (60.8 to 99999)	99999 (74.6 to 99999)

No statistical analyses for this end point

Secondary: Duration of Response in Stage 1

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End point title

Duration of Response in Stage 1 ^[22]

End point description

Duration of Response was defined as the date the response [either Complete Response (CR) or Partial Response (PR)] was first recorded until the date of Disease Progression or death due to any cause. Response was assessed according IWCLL guidelines. Subjects from the ITT population with response. Subjects from the ITT population with CR or PR. Subject without response were censored.

End point type

Secondary

End point timeframe

Randomisation to clinical cutoff date of 10 Oct 2017 (median observation in Stage 1a: 62.5 months and Stage 1b: 57.7 months)

Notes
[22] - 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: This outcome measure only looked at Stage 1 data.

End point values	Stage 1: Rituximab + Chlorambucil (RClb)	Stage 1: Obinutuzumab + Chlorambucil (GClb)	Stage 1: Chlorambucil (Clb)
Number of subjects analysed	155	191	41
Units: months
median (confidence interval 95%)	12.2 (9.5 to 14.5)	24.8 (22.1 to 33.5)	5.1 (3.3 to 6.7)

No statistical analyses for this end point

Secondary: Duration of Response in Stage 2

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End point title

Duration of Response in Stage 2 ^[23]

End point description

Duration of Response was defined as the date the response [either Complete Response (CR) or Partial Response (PR)] was first recorded until the date of Disease Progression or death due to any cause. Response was assessed according IWCLL guidelines. Subjects from the ITT population with CR or PR. Subject without response were censored.

End point type

Secondary

End point timeframe

Randomisation to clinical cutoff date of 10 Oct 2017 (median observation 59.4 months)

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure only looked at Stage 2 data.

End point values	Stage 2: Rituximab + Chlorambucil (RClb)	Stage 2: Obinutuzumab + Chlorambucil (GClb)
Number of subjects analysed	220	271
Units: months
median (confidence interval 95%)	11.8 (9.5 to 12.6)	23.8 (19.1 to 30.1)

No statistical analyses for this end point

Secondary: Percentage of Subjects With Molecular Remission at the End of Treatment in Stage 1

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End point title

Percentage of Subjects With Molecular Remission at the End of Treatment in Stage 1 ^[24]

End point description

Molecular remission was defined as a minimal residual disease (MRD)-negative result at the end of treatment (assessment that occurred between 56 days and 6 months of last treatment). Molecular remission was assessed for all subjects using a blood sample. Additionally, a bone marrow sample was obtained from subjects whom the investigator assumed to have a complete response, consistent with the IWCLL guidelines. A combined analysis of blood and bone marrow results was conducted. A subject was considered MRD negative if result was less than 1 chronic lymphocytic leukemia (CLL) cell in 10000 leukocytes (MRD value < 0.0001) based on the method of allele specific polymerase chain reaction (ASO-PCR). Subjects from ITT population with data available for analysis. Subjects who did not reach 3 month Follow-up visit at clinical cutoff are excluded.

End point type

Secondary

End point timeframe

Randomisation to clinical cutoff date of 10 Oct 2017 (median observation in Stage 1a: 62.5 months and Stage 1b: 57.7 months)

Notes
[24] - 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: This outcome measure only looked at Stage 1 data.

End point values	Stage 1: Rituximab + Chlorambucil (RClb)	Stage 1: Obinutuzumab + Chlorambucil (GClb)	Stage 1: Chlorambucil (Clb)
Number of subjects analysed	170	166	90
Units: percentage of subject
number (confidence interval 95%)	2 (0.6 to 5.9)	25 (18.9 to 32.6)	0 (0.0 to 4.0)

No statistical analyses for this end point

Secondary: Percentage of Subjects With Molecular Remission at the End of Treatment in Stage 2

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End point title

Percentage of Subjects With Molecular Remission at the End of Treatment in Stage 2 ^[25]

End point description

Molecular remission was defined as a minimal residual disease (MRD)-negative result at the end of treatment (assessment that occurred between 56 days and 6 months of last treatment). Molecular remission was assessed for all subjects using a blood sample. Additionally, a bone marrow sample was obtained from subjects whom the investigator assumed to have a complete response, consistent with the IWCLL guidelines. A combined analysis of blood and bone marrow results was conducted. A subject was considered MRD negative if result was less than 1 chronic lymphocytic leukemia (CLL) cell in 10000 leukocytes (MRD value < 0.0001) based on the method of allele specific polymerase chain reaction (ASO-PCR). Subjects from ITT population with data available for analysis. Subjects who did not reach 3 month Follow-up visit at clinical cutoff are excluded.

End point type

Secondary

End point timeframe

Randomisation to clinical cutoff date of 10 Oct 2017 (median observation 59.4 months)

Notes
[25] - 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: This outcome measure only looked at Stage 2 data.

End point values	Stage 2: Rituximab + Chlorambucil (RClb)	Stage 2: Obinutuzumab + Chlorambucil (GClb)
Number of subjects analysed	246	237
Units: percentage of subjects
number (confidence interval 95%)	2 (0.9 to 5.2)	24 (18.8 to 30.0)

No statistical analyses for this end point

Secondary: Time to Re-Treatment/New-antileukemic Therapy in Stage 1

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End point title

Time to Re-Treatment/New-antileukemic Therapy in Stage 1 ^[26]

End point description

Time to re-treatment/new anti-leukemic therapy was defined as time between the date of randomization and the date of first intake of re-treatment or new anti-leukemic therapy. ITT population. Subjects without events (re-treatment or new anti-leukemic therapy) were censored. Here, 99999 indicates that the upper limit 95% CI was not reached.

End point type

Secondary

End point timeframe

Randomisation to clinical cutoff date of 10 Oct 2017 (median observation in Stage 1a: 62.5 months and Stage 1b: 57.7 months)

Notes
[26] - 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: This outcome measure only looked at Stage 1 data.

End point values	Stage 1: Rituximab + Chlorambucil (RClb)	Stage 1: Obinutuzumab + Chlorambucil (GClb)	Stage 1: Chlorambucil (Clb)
Number of subjects analysed	233	238	118
Units: months
median (confidence interval 95%)	33.2 (27.8 to 44.4)	55.7 (47.4 to 99999)	15.1 (11.7 to 18.0)

No statistical analyses for this end point

Secondary: Time to Re-Treatment/New-antileukemic Therapy in Stage 2

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End point title

Time to Re-Treatment/New-antileukemic Therapy in Stage 2 ^[27]

End point description

Time to re-treatment/new anti-leukemic therapy was defined as time between the date of randomization and the date of first intake of re-treatment or new anti-leukemic therapy. ITT population. Subjects who were reported as not having started re-treatment or new anti−leukemic therapy were censored at the last visit date they were assessed with regard to start of new treatment or the date of death. Here, 99999 indicates that the upper limit of 95% CI was not reached.

End point type

Secondary

End point timeframe

Randomisation to clinical cutoff date of 10 Oct 2017 (median observation 59.4 months)

Notes
[27] - 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: This outcome measure only looked at Stage 2 data.

End point values	Stage 2: Rituximab + Chlorambucil (RClb)	Stage 2: Obinutuzumab + Chlorambucil (GClb)
Number of subjects analysed	330	333
Units: months
median (confidence interval 95%)	34.9 (29.1 to 41.6)	56.4 (48.3 to 99999)

No statistical analyses for this end point

Secondary: Pharmacokinetics (PK) of Obinutuzumab (RO5072759) in Combination With Chlorambucil (Clb)

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End point title

Pharmacokinetics (PK) of Obinutuzumab (RO5072759) in Combination With Chlorambucil (Clb) ^[28]

End point description

Blood samples were collected from all subjects allocated to the GClb treatment arm pre- and post-dose Day 1 of Cycles 1 to 6 and were sent to a laboratory. The concentration of obinutzumab in serum was determined using a validated enzyme-linked immunosorbent assay (ELISA) and was reported in micrograms/milliliter (μg/mL). PK population includes all subjects with PK data available at the given time-point.

End point type

Secondary

End point timeframe

Pre- and post-dose sampling on day 1 of cycles 1-6 (Up to 26.8 months)

Notes
[28] - 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: This outcome measure only looked at the PK data of obinutuzumab and chlorambucil arm.

End point values	Stage 1: Obinutuzumab + Chlorambucil (GClb)
Number of subjects analysed	220
Units: μg/mL
geometric mean (geometric coefficient of variation)
Post-dose Cycle 1 (n=201)	247 ( 41.6 )
Pre-dose Cycle 2 (n=198)	227 ( 57.9 )
Post-dose Cycle 2 (n=197)	587 ( 36.5 )
Pre-dose Cycle 3 (n=193)	165 ( 68.7 )
Post-dose Cycle 3 (n=192)	527 ( 39.7 )
Pre-dose Cycle 4 (n=191)	156 ( 74.3 )
Post-dose Cycle 4 (n=189)	535 ( 41 )
Pre-dose Cycle 5 (n=185)	163 ( 72.4 )
Post-dose Cycle 5 (n=181)	534 ( 39.1 )
Pre-dose Cycle 6 (n=185)	181 ( 69 )
Post-dose Cycle 6 (n=183)	525 ( 39.6 )

No statistical analyses for this end point

Secondary: European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire in Stage 1

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End point title

European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire in Stage 1 ^[29]

End point description

The EORTC Quality of Life Questionnaire (QLQ-C30) was used to assess patient-reported outcomes (PRO) and symptom burden. The QLQ-C30 contains 30 items including the functional scales of physical functioning (5 items), role functioning (2 items), emotional functioning (4 items), cognitive functioning (2 items), social functioning (2 items) and symptom scales including fatigue (3 items), nausea and vomiting (2 items), and pain (4 items) and six single item scales on dyspnea, sleep disturbance, appetite loss, constipation, diarrhea and financial impact. Final scores are transformed such that they range from 0 − 100, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 − 10 points considered to be of minimally important difference to subjects. A positive change from Baseline indicated improvement.

End point type

Secondary

End point timeframe

Baseline and Cycle 4 Day 1 (Cy4D1)

Notes
[29] - 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: This outcome measure only looked at Stage 1 data.

End point values	Stage 1: Rituximab + Chlorambucil (RClb)	Stage 1: Obinutuzumab + Chlorambucil (GClb)	Stage 1: Chlorambucil (Clb)
Number of subjects analysed	233	238	118
Units: unit on a scale
arithmetic mean (standard deviation)
Appetite Loss: Baseline (n=226, 111, 220)	15.8 ( 27.11 )	18.1 ( 28.46 )	19.8 ( 29.26 )
Appetite Loss: Cy4D1(n=189,92,196)	10.9 ( 21.50 )	10.2 ( 21.77 )	14.5 ( 24.36 )
Cognitive Functioning: Baseline (n=227, 111, 221)	82.7 ( 20.77 )	80.6 ( 21.35 )	81.8 ( 22.76 )
Cognitive Functioning: Cy4D1 (n=190,93,196)	83.0 ( 17.86 )	83.9 ( 20.31 )	85.8 ( 18.54 )
Constipation: Baseline (n=225, 111, 219)	15.1 ( 25.37 )	14.8 ( 23.94 )	16.8 ( 26.92 )
Constipation: Cy4D1 (n=188, 93, 195)	13.3 ( 22.04 )	15.1 ( 25.16 )	12.5 ( 23.53 )
Diarrhoea: Baseline (n=226, 110, 220)	7.6 ( 18.66 )	9.3 ( 20.05 )	8.8 ( 18.98 )
Diarrhoea: Cy4D1 (n=189, 93, 195)	9.2 ( 20.45 )	9.3 ( 19.47 )	6.5 ( 14.95 )
Dyspnoea: Baseline (n=225, 109, 220)	26.1 ( 28.09 )	27.1 ( 29.89 )	23.9 ( 27.63 )
Dyspnoea: Cy4D1 (n=189, 91, 196)	19.7 ( 25.19 )	15.9 ( 23.71 )	22.3 ( 26.78 )
Emotional Functioning: Baseline (n=226, 111, 221)	77.3 ( 21.23 )	73.8 ( 23.45 )	72.9 ( 25.7 )
Emotional Functioning: Cy4D1(n=190,93,196)	82.8 ( 17.52 )	82.5 ( 18.62 )	80.6 ( 18.48 )
Fatigue: Baseline (n=226, 111, 221)	35.8 ( 24.60 )	38 ( 25.72 )	36.9 ( 27.01 )
Fatigue: Cy4D1(n=189, 93, 197)	29.6 ( 22.24 )	29.2 ( 20.39 )	30.8 ( 23.00 )
Financial Difficulties: Baseline (n=224,110, 220)	10.9 ( 22.12 )	8.9 ( 20.69 )	13.6 ( 25.26 )
Financial Difficulty: Cy4D1(n=189,93, 193)	10.2 ( 20.26 )	7.4 ( 17.64 )	9.3 ( 19.88 )
Nausea, Vomiting: Baseline (n=227, 111, 221)	4.4 ( 12.04 )	5 ( 11.18 )	7.4 ( 18.49 )
Nausea, Vomiting: Cy4D1 (n=189,93, 197)	3.6 ( 8.99 )	5.5 ( 11.51 )	7.5 ( 17.81 )
Pain: Baseline (n=228, 111, 221)	21.5 ( 27.37 )	22.9 ( 27.57 )	21.5 ( 25.66 )
Pain: Cy4D1 (n=190, 93, 197)	15.1 ( 22.41 )	17.9 ( 24.09 )	17.7 ( 25.98 )
Physical Functioning: Baseline (n=228, 111, 221)	76.1 ( 18.95 )	73.7 ( 19.86 )	77.3 ( 18.87 )
Physical Functioning: Cy4D1(n=189,93,197)	77.6 ( 18.27 )	78.6 ( 18.71 )	80.9 ( 16.24 )
Global Health Status: Baseline (n=226, 111, 219)	58.7 ( 22.28 )	58.4 ( 22.8 )	57.4 ( 22.9 )
Global Health Status: Cy4D1(n=189,93, 195)	65.7 ( 20.13 )	66.7 ( 20.03 )	63.4 ( 20.56 )
Role Functioning: Baseline(n=227,110, 221)	76.9 ( 28.70 )	76.1 ( 26.18 )	74.7 ( 28.35 )
Role Functioning: Cy4D1(n=189,93,197)	79.4 ( 25.97 )	79.7 ( 23.64 )	81.5 ( 21.35 )
Social Functioning:Baseline(n=226,110, 221)	82.1 ( 24.49 )	86.3 ( 22.52 )	83.3 ( 25.34 )
Social Functioning: Cy4D1(n=190,93,195)	85.5 ( 20.79 )	87.8 ( 19.97 )	85.5 ( 19.38 )
Insomina: Baseline (n=228,111,220)	24.8 ( 30.03 )	29.4 ( 31.12 )	31.5 ( 32.98 )
Insomina: Cy4D1(n=189,93,195)	18.8 ( 25.77 )	20.6 ( 27.13 )	24.4 ( 29.13 )

No statistical analyses for this end point

Secondary: European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire in Stage 2

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End point title

European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire in Stage 2 ^[30]

End point description

The EORTC quality of life questionnaire (QLQ-C30) was used to assess patient-reported outcomes (PRO) and symptom burden. The QLQ-C30 contains 30 items including the functional scales of physical functioning (5 items), role functioning (2 items), emotional functioning (4 items), cognitive functioning (2 items), social functioning (2 items) and symptom scales including fatigue (3 items), nausea and vomiting (2 items), and pain (4 items) and six single item scales on dyspnea, sleep disturbance, appetite loss, constipation, diarrhea and financial impact. Final scores are transformed such that they range from 0 − 100, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 − 10 points considered to be of minimally important difference to subjects.

End point type

Secondary

End point timeframe

Baseline and Cycle 4 Day 1 (Cy4D1)

Notes
[30] - 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: This outcome measure only looked at Stage 2 data.

End point values	Stage 2: Rituximab + Chlorambucil (RClb)	Stage 2: Obinutuzumab + Chlorambucil (GClb)
Number of subjects analysed	330	333
Units: unit on a scale
arithmetic mean (standard deviation)
Appetite Loss Scale: Baseline (n=314, 312)	15.4 ( 26.02 )	19 ( 29.37 )
Appetite Loss Scale: Cy4D1 (n=277, 258)	12 ( 23.22 )	10.9 ( 21.47 )
Cognitive Functioning Scale: Baseline(n=312, 315)	83 ( 20.02 )	80.4 ( 22.52 )
Cognitive Functioning Scale: Cy4D1 (n=277, 259)	83.6 ( 17.26 )	83.9 ( 20.25 )
Constipation Scale: Baseline (n=311, 312)	15.2 ( 24.62 )	14.9 ( 23.54 )
Constipation Scale: Cy4D1 (n=276,256)	14.3 ( 23.05 )	15.3 ( 25.16 )
Diarrhoea Scale: Baseline (n=311,313)	8.4 ( 18.78 )	9.5 ( 19.58 )
Diarrhoea Scale: Cy4D1 (n=276,257)	8.8 ( 19.66 )	9.2 ( 20.32 )
Dyspnoea Scale: Baseline (n=312,312)	27.5 ( 28.62 )	27.8 ( 29.97 )
Dyspnoea: Cy4D1 (n=277,258)	20.8 ( 26.69 )	16.5 ( 23.75 )
Emotional Functioning Scale: Baseline (n=312,314)	77.1 ( 21.32 )	73.9 ( 23.14 )
Emotional Functioning Scale: Cy4D1 (n=277,259)	82.7 ( 18.29 )	82.5 ( 19.18 )
Fatigue Scale: Baseline (n=313,312)	36.9 ( 25.86 )	38.5 ( 26.05 )
Fatigue Scale: Cy4D1 (n=278,258)	30.4 ( 22.32 )	29.8 ( 21.43 )
Financial Difficulties Scale: Baseline (n=309,312)	10.5 ( 21.53 )	10.5 ( 22.14 )
Financial Difficulties Scale Cy4D1(n=273,258)	9.6 ( 20.02 )	8.4 ( 19.35 )
Nausea, Vomiting Scale: Baseline (n=313,315)	4.5 ( 12.66 )	5.3 ( 12.9 )
Nausea, Vomiting Scale: Cy4D1 (n=278,258)	4.1 ( 10.18 )	5.2 ( 10.96 )
Pain scale: Baseline (n=313,316)	22.5 ( 27.59 )	22.9 ( 27.73 )
Pain scale: Cy4D1 (n=278,259)	15.6 ( 22.48 )	18.1 ( 24.60 )
Physical Functioning Scale: Baseline (n=313,316)	75.8 ( 19.34 )	73.3 ( 20.77 )
Physical Functioning Scale: Cy4D1 (n=278,258)	77.8 ( 18.5 )	78.5 ( 18.90 )
Global Health Status Scale: Baseline (n=310,313)	58.1 ( 22.74 )	58 ( 23.81 )
Global Health Status Scale: Cy4D1 (n=257,256)	65.8 ( 20.22 )	66.7 ( 20.27 )
Role Functioning Scale: Baseline (n=313,315)	76.4 ( 28.68 )	74.3 ( 27.62 )
Role Functioning Scale: Cy4D1 (n=277,258)	79.9 ( 25.4 )	78.7 ( 24.56 )
Social Functioning Scale: Baseline (n=312,314)	82.9 ( 23.81 )	83.7 ( 24.96 )
Social Functioning Scale: Cy4D1(n=276,259)	85.4 ( 21 )	86.6 ( 20.71 )
Insomnia: Baseline (n=312,316)	25.6 ( 30.91 )	29.9 ( 31.18 )
Insomnia: Cy4D1(n=276,258)	20.9 ( 26.71 )	21.6 ( 27.97 )

No statistical analyses for this end point

Secondary: European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Score in Stage 1

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End point title

European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Score in Stage 1 ^[31]

End point description

EORTC Quality of Life Questionnaire (QLQ-CLL16) module was used to assess patient-reported outcomes and symptom burden. The QLQ-CLL16 module includes three multi-item scales assessing fatigue (2 items), treatment side effects and disease symptoms (8 items), infection (4 items) and two single item scales on social activities and future health worries. Final scores are transformed such that they range from 0 − 100, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 − 10 points considered to be of minimally important difference to subjects. A positive change from Baseline indicated improvement.

End point type

Secondary

End point timeframe

Baseline and Cycle 4 Day 1 (Cy4D1)

Notes
[31] - 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: This outcome measure only looked at Stage 1 data.

End point values	Stage 1: Rituximab + Chlorambucil (RClb)	Stage 1: Obinutuzumab + Chlorambucil (GClb)	Stage 1: Chlorambucil (Clb)
Number of subjects analysed	233	238	118
Units: unit on a scale
arithmetic mean (standard deviation)
Disease Effects: Baseline (n=209, 102, 198)	22.7 ( 18.21 )	23 ( 18.89 )	23.7 ( 20.18 )
Disease Effects: Cy4D1 (n=176, 86, 173)	14.1 ( 13.71 )	15.0 ( 15.12 )	15.9 ( 14.16 )
Fatigue: Baseline (n=209, 102, 198)	27.8 ( 23.39 )	31.2 ( 25.83 )	27.6 ( 24.65 )
Fatigue: Cy4D1 (n=176, 86, 173)	20.0 ( 20.25 )	20.9 ( 21.51 )	23.4 ( 22.20 )
Future Health: Baseline (n=206, 101, 197)	45.9 ( 31.24 )	47.7 ( 32.14 )	50.8 ( 33.53 )
Future Health: Cy4D1 (n=175, 86, 171)	33.1 ( 28.12 )	29.5 ( 31.74 )	39.1 ( 30.33 )
Infection: Baseline (n=209, 102, 197)	9.7 ( 14.45 )	12 ( 15.91 )	14.6 ( 17.97 )
Infection: Cy4D1 (n=176, 86, 173)	8.9 ( 13.08 )	8.9 ( 11.65 )	8.5 ( 10.70 )
Social Problems: Baseline (n=206, 100, 195)	25.1 ( 31.40 )	24.3 ( 31.99 )	26.3 ( 33.26 )
Social Problems: Cy4D1 (n=175, 85, 173)	19.3 ( 25.94 )	19.4 ( 27.75 )	22.0 ( 27.00 )
Treatment Side Effects: Baseline (n=209,102, 198)	17.5 ( 14.98 )	19.8 ( 17.7 )	17.2 ( 15.27 )
Treatment Side Effect: Cy4D1(n=176, 86, 173)	13.9 ( 12.42 )	14.7 ( 14.68 )	15.6 ( 16.11 )

No statistical analyses for this end point

Secondary: European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire in Stage 2

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End point title

European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire in Stage 2 ^[32]

End point description

EORTC Quality of Life Questionnaire (QLQ-CLL16) module was used to assess patient-reported outcomes and symptom burden. The QLQ-CLL16 module includes three multi-item scales assessing fatigue (2 items), treatment side effects and disease symptoms (8 items), infection (4 items) and two single item scales on social activities and future health worries. Final scores are transformed such that they range from 0 − 100, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 − 10 points considered to be of minimally important difference to subjects.

End point type

Secondary

End point timeframe

Baseline and Cycle 4 Day 1 (Cy4D1)

Notes
[32] - 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: This outcome measure only looked at Stage 2 data.

End point values	Stage 2: Rituximab + Chlorambucil (RClb)	Stage 2: Obinutuzumab + Chlorambucil (GClb)
Number of subjects analysed	330	333
Units: unit on a scale
arithmetic mean (standard deviation)
Disease Effects Scale: Baseline (n=276,284)	22.8 ( 17.94 )	22.7 ( 18.49 )
Disease Effects Scale: Cy4D1 (n=243, 233)	15.4 ( 15 )	14.7 ( 15.34 )
Fatigue Scale: Baseline (n=276, 284)	27.7 ( 23.48 )	31.1 ( 25.32 )
Fatigue Scale: Cy4D1 (n=243, 233)	21 ( 20.52 )	20.6 ( 20.82 )
Future Health: Baseline (n=275, 280)	47.5 ( 32.17 )	49.8 ( 32.79 )
Future Health: Cy4D1 (n=240, 231)	33.9 ( 29.72 )	30.3 ( 31.17 )
Infection Scale: Baseline (n=275, 284)	11.8 ( 15.83 )	12.7 ( 16.67 )
Infection Scale: Cy4D1 (n=243, 233)	9.4 ( 13.94 )	9 ( 12.2 )
Social Problems: Baseline (n=271, 281)	25.2 ( 32.45 )	23.6 ( 31.12 )
Social Problems: Cy4D1 (n=242, 232)	19.3 ( 26.03 )	19.5 ( 27.94 )
Treatment Side Effects Scale: Baseline(n=276, 284)	17.9 ( 15.69 )	19.9 ( 17.59 )
Treatment Side Effect Scale: Cy4D1(n=243, 243)	14.2 ( 13.57 )	14.6 ( 14.89 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From randomisation up to 5.5 years

Adverse event reporting additional description

Adverse events were reported as per the treatment received by the subjects, not as per the stages (i.e. Stage 1a [GClb vs Clb], Stage 1b [RClb vs Clb] and Stage 2 [GClb vs RClb]) of analysis.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Rituximab + Chlorambucil (RClb)

Reporting group description

Subject received 375 mg/m^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28- day cycle (6 cycles).

Reporting group title

Obinutuzumab + Chlorambucil (GClb)

Reporting group description

Subjects received 1000 mg obinutuzumab IV infusion, on Day 1 [First infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 milligram per kilogram of body weight (mg/kg) orally on Day 1 and 15 of each 28-day cycle (6 Cycles).

Reporting group title

Crossover subjects: Obinutuzumab + Chlorambucil (GClb)

Reporting group description

Subjects in Clb arm who progressed during/within 6 months after end of Clb treatment had opportunity to cross over to GClb arm at discretion of investigator. Subjects received 1000 mg obinutuzumab IV infusion, on Day 1 [First infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 milligram per kilogram of body weight (mg/kg) orally on Day 1 and 15 of each 28-day cycle (6 Cycles).

Reporting group title

Chlorambucil (Clb)

Reporting group description

Subjects received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Subjects with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.

Serious adverse events	Rituximab + Chlorambucil (RClb)	Obinutuzumab + Chlorambucil (GClb)	Crossover subjects: Obinutuzumab + Chlorambucil (GClb)	Chlorambucil (Clb)
Total subjects affected by serious adverse events
subjects affected / exposed	124 / 321 (38.63%)	150 / 336 (44.64%)	8 / 30 (26.67%)	45 / 116 (38.79%)
number of deaths (all causes)	144	123	2	57
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of skin
subjects affected / exposed	6 / 321 (1.87%)	6 / 336 (1.79%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 8	0 / 7	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung adenocarcinoma
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	2 / 321 (0.62%)	2 / 336 (0.60%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Plasma cell myeloma
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 1
Prostate cancer
subjects affected / exposed	3 / 321 (0.93%)	1 / 336 (0.30%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Squamous cell carcinoma
subjects affected / exposed	7 / 321 (2.18%)	4 / 336 (1.19%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	2 / 7	0 / 4	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adenocarcinoma gastric
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Choroid melanoma
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Colon cancer
subjects affected / exposed	1 / 321 (0.31%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Gastrointestinal stromal tumour
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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
Hepatocellular carcinoma
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Intraocular melanoma
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Keratoacanthoma
subjects affected / exposed	1 / 321 (0.31%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myelodysplastic syndrome
subjects affected / exposed	3 / 321 (0.93%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 3	0 / 1	0 / 0	0 / 0
Non-small cell lung cancer
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Rectal adenocarcinoma
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Rectal cancer
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Renal cell carcinoma
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Schwannoma
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Squamous cell carcinoma of lung
subjects affected / exposed	1 / 321 (0.31%)	2 / 336 (0.60%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
Superficial spreading melanoma stage unspecified
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Transitional cell carcinoma
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Oropharyngeal cancer
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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	2 / 321 (0.62%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Intracranial tumour haemorrhage
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Diffuse large B-cell lymphoma
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Bronchial carcinoma
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Bowen's disease
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	1 / 30 (3.33%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adenocarcinoma
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Acute myeloid leukaemia
subjects affected / exposed	2 / 321 (0.62%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
Skin cancer
subjects affected / exposed	2 / 321 (0.62%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Metastatic squamous cell carcinoma
subjects affected / exposed	2 / 321 (0.62%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Colon adenoma
subjects affected / exposed	1 / 321 (0.31%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Basal cell carcinoma
subjects affected / exposed	4 / 321 (1.25%)	8 / 336 (2.38%)	1 / 30 (3.33%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 8	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	1 / 321 (0.31%)	2 / 336 (0.60%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Malignant melanoma in situ
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal cancer
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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 neoplasm
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	1 / 30 (3.33%)	0 / 116 (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 / 1	0 / 0
Lung neoplasm
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	1 / 30 (3.33%)	0 / 116 (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 / 1	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aortic stenosis
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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
Capillary leak syndrome
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Diabetic macroangiopathy
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Dry gangrene
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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
Orthostatic hypotension
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral artery thrombosis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Thrombophlebitis superficial
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Circulatory collapse
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Hypertension
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Hypertensive crisis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Malignant hypertension
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Peripheral ischaemia
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Venous thrombosis
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Surgical and medical procedures
Fracture treatment
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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
General disorders and administration site conditions
Chest pain
subjects affected / exposed	2 / 321 (0.62%)	1 / 336 (0.30%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	1 / 321 (0.31%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Death
subjects affected / exposed	3 / 321 (0.93%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
General physical health deterioration
subjects affected / exposed	3 / 321 (0.93%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Malaise
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Pyrexia
subjects affected / exposed	2 / 321 (0.62%)	2 / 336 (0.60%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 2	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	2 / 321 (0.62%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Adhesion
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Chills
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Reproductive system and breast disorders
Prostatic obstruction
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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
Testicular hypertrophy
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Respiratory, thoracic and mediastinal disorders
Pleural effusion
subjects affected / exposed	0 / 321 (0.00%)	2 / 336 (0.60%)	0 / 30 (0.00%)	0 / 116 (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
Pulmonary embolism
subjects affected / exposed	1 / 321 (0.31%)	2 / 336 (0.60%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	2 / 321 (0.62%)	2 / 336 (0.60%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Pulmonary oedema
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Respiratory failure
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 1
Pulmonary alveolar haemorrhage
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Dyspnoea
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Asthma
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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 pulmonary oedema
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Psychiatric disorders
Delirium
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Disorientation
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Mania
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Major depression
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	1 / 30 (3.33%)	0 / 116 (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
Investigations
Platelet count decreased
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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
General physical condition abnormal
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Haemoglobin decreased
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	5 / 321 (1.56%)	34 / 336 (10.12%)	2 / 30 (6.67%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	6 / 6	36 / 36	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 321 (0.31%)	3 / 336 (0.89%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	3 / 321 (0.93%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 321 (0.00%)	2 / 336 (0.60%)	0 / 30 (0.00%)	0 / 116 (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
Femoral neck fracture
subjects affected / exposed	1 / 321 (0.31%)	1 / 336 (0.30%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fracture displacement
subjects affected / exposed	0 / 321 (0.00%)	2 / 336 (0.60%)	0 / 30 (0.00%)	0 / 116 (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
Spinal fracture
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Subdural haematoma
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Subdural haemorrhage
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Tendon rupture
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Spinal compression fracture
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Shunt thrombosis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Pubis fracture
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Lower limb fracture
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Laceration
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Hip fracture
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Post procedural haemorrhage
subjects affected / exposed	2 / 321 (0.62%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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
Congenital, familial and genetic disorders
Hereditary non-polyposis colorectal cancer syndrome
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Phimosis
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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
Myocardial infarction
subjects affected / exposed	0 / 321 (0.00%)	4 / 336 (1.19%)	0 / 30 (0.00%)	2 / 116 (1.72%)
occurrences causally related to treatment / all	0 / 0	1 / 4	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	2 / 321 (0.62%)	4 / 336 (1.19%)	0 / 30 (0.00%)	2 / 116 (1.72%)
occurrences causally related to treatment / all	0 / 3	1 / 4	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 321 (0.31%)	2 / 336 (0.60%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	1 / 321 (0.31%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial thrombosis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Nodal rhythm
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Tachyarrhythmia
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	3 / 321 (0.93%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	2 / 321 (0.62%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Angina pectoris
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Aortic valve stenosis
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Arrhythmia
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Cardiac failure chronic
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Myocardial ischaemia
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Supraventricular tachycardia
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Ventricular extrasystoles
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	2 / 321 (0.62%)	3 / 336 (0.89%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Central nervous system haemorrhage
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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
Haemorrhage intracranial
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
Metabolic encephalopathy
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Cerebral haematoma
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Depressed level of consciousness
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Hypoaesthesia
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Partial seizures
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Presyncope
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Encephalopathy
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Febrile neutropenia
subjects affected / exposed	3 / 321 (0.93%)	6 / 336 (1.79%)	1 / 30 (3.33%)	5 / 116 (4.31%)
occurrences causally related to treatment / all	3 / 3	6 / 6	3 / 3	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	2 / 321 (0.62%)	3 / 336 (0.89%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	2 / 5	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Autoimmune haemolytic anaemia
subjects affected / exposed	1 / 321 (0.31%)	2 / 336 (0.60%)	0 / 30 (0.00%)	2 / 116 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	2 / 321 (0.62%)	4 / 336 (1.19%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	2 / 2	5 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	1 / 321 (0.31%)	4 / 336 (1.19%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	1 / 1	2 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemolysis
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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
Haemolytic anaemia
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Immune thrombocytopenic purpura
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Pancytopenia
subjects affected / exposed	2 / 321 (0.62%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	2 / 2	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cytopenia
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Leukopenia
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 321 (0.00%)	3 / 336 (0.89%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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
Ascites
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Colitis
subjects affected / exposed	1 / 321 (0.31%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Enterocolitis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Inguinal hernia
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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
Pancreatitis acute
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Thrombosis mesenteric vessel
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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
Food poisoning
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Gastric ulcer
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Intestinal obstruction
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Proctitis
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Varices oesophageal
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Dysphagia
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Constipation
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Anal fistula
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Ileus
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	1 / 30 (3.33%)	0 / 116 (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
Hepatobiliary disorders
Biliary colic
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Cholelithiasis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Liver disorder
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Hepatitis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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 atopic
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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
Rash maculo-papular
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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 disorder
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Renal and urinary disorders
Cystitis haemorrhagic
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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
Haematuria
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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
Renal failure
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	3 / 321 (0.93%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute prerenal failure
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Nephritic syndrome
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Nephrolithiasis
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 321 (0.31%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Musculoskeletal chest pain
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Spinal column stenosis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Gouty arthritis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Infections and infestations
Pneumonia
subjects affected / exposed	19 / 321 (5.92%)	14 / 336 (4.17%)	2 / 30 (6.67%)	4 / 116 (3.45%)
occurrences causally related to treatment / all	9 / 25	9 / 17	0 / 2	1 / 4
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2
Respiratory tract infection
subjects affected / exposed	2 / 321 (0.62%)	3 / 336 (0.89%)	0 / 30 (0.00%)	3 / 116 (2.59%)
occurrences causally related to treatment / all	0 / 2	3 / 5	0 / 0	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
Bronchitis
subjects affected / exposed	3 / 321 (0.93%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	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 / 321 (0.31%)	3 / 336 (0.89%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	1 / 1	0 / 4	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	1 / 321 (0.31%)	3 / 336 (0.89%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	1 / 1	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	3 / 321 (0.93%)	1 / 336 (0.30%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	1 / 3	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 321 (0.31%)	3 / 336 (0.89%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	1 / 1	1 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	3 / 321 (0.93%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	3 / 321 (0.93%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	2 / 321 (0.62%)	1 / 336 (0.30%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	2 / 2	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 321 (0.31%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Endocarditis
subjects affected / exposed	1 / 321 (0.31%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 321 (0.00%)	2 / 336 (0.60%)	0 / 30 (0.00%)	2 / 116 (1.72%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia infection
subjects affected / exposed	1 / 321 (0.31%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis B
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	2 / 321 (0.62%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Sepsis
subjects affected / exposed	1 / 321 (0.31%)	1 / 336 (0.30%)	1 / 30 (3.33%)	4 / 116 (3.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 1	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
Septic shock
subjects affected / exposed	0 / 321 (0.00%)	2 / 336 (0.60%)	0 / 30 (0.00%)	2 / 116 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2
Streptococcal sepsis
subjects affected / exposed	1 / 321 (0.31%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Varicella
subjects affected / exposed	2 / 321 (0.62%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	1 / 321 (0.31%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Dacryocystitis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Device related sepsis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Epididymitis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Furuncle
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Gangrene
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	1 / 30 (3.33%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis clostridial
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Infected skin ulcer
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Infectious colitis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Infective exacerbation of bronchiectasis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Intervertebral discitis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Laryngitis
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Liver abscess
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ophthalmic herpes zoster
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Peritonitis
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Pneumocystis jirovecii pneumonia
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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 influenzal
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Septic arthritis staphylococcal
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Staphylococcal infection
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Subcutaneous abscess
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Superinfection bacterial
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Tooth abscess
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Urosepsis
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (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
Neutropenic infection
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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
Oral candidiasis
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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
Staphylococcal sepsis
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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
Stenotrophomonas sepsis
subjects affected / exposed	0 / 321 (0.00%)	0 / 336 (0.00%)	0 / 30 (0.00%)	1 / 116 (0.86%)
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 reactivation
subjects affected / exposed	1 / 321 (0.31%)	0 / 336 (0.00%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Tumour lysis syndrome
subjects affected / exposed	0 / 321 (0.00%)	5 / 336 (1.49%)	0 / 30 (0.00%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 0	5 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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
Hyperglycaemia
subjects affected / exposed	0 / 321 (0.00%)	1 / 336 (0.30%)	0 / 30 (0.00%)	0 / 116 (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

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

Non-serious adverse events	Rituximab + Chlorambucil (RClb)	Obinutuzumab + Chlorambucil (GClb)	Crossover subjects: Obinutuzumab + Chlorambucil (GClb)	Chlorambucil (Clb)
Total subjects affected by non serious adverse events
subjects affected / exposed	279 / 321 (86.92%)	299 / 336 (88.99%)	23 / 30 (76.67%)	89 / 116 (76.72%)
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	118 / 321 (36.76%)	197 / 336 (58.63%)	15 / 30 (50.00%)	0 / 116 (0.00%)
occurrences all number	168	288	21	0
Nervous system disorders
Headache
subjects affected / exposed	18 / 321 (5.61%)	23 / 336 (6.85%)	0 / 30 (0.00%)	8 / 116 (6.90%)
occurrences all number	20	28	0	10
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	104 / 321 (32.40%)	128 / 336 (38.10%)	12 / 30 (40.00%)	21 / 116 (18.10%)
occurrences all number	164	250	28	35
Anaemia
subjects affected / exposed	34 / 321 (10.59%)	33 / 336 (9.82%)	3 / 30 (10.00%)	12 / 116 (10.34%)
occurrences all number	43	34	3	14
Thrombocytopenia
subjects affected / exposed	20 / 321 (6.23%)	46 / 336 (13.69%)	7 / 30 (23.33%)	9 / 116 (7.76%)
occurrences all number	25	61	10	10
Leukopenia
subjects affected / exposed	7 / 321 (2.18%)	21 / 336 (6.25%)	5 / 30 (16.67%)	0 / 116 (0.00%)
occurrences all number	7	28	5	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	30 / 321 (9.35%)	26 / 336 (7.74%)	1 / 30 (3.33%)	12 / 116 (10.34%)
occurrences all number	32	30	1	16
Pyrexia
subjects affected / exposed	22 / 321 (6.85%)	28 / 336 (8.33%)	2 / 30 (6.67%)	8 / 116 (6.90%)
occurrences all number	24	35	2	14
Asthenia
subjects affected / exposed	25 / 321 (7.79%)	23 / 336 (6.85%)	1 / 30 (3.33%)	8 / 116 (6.90%)
occurrences all number	27	24	1	12
Gastrointestinal disorders
Nausea
subjects affected / exposed	42 / 321 (13.08%)	40 / 336 (11.90%)	3 / 30 (10.00%)	29 / 116 (25.00%)
occurrences all number	52	48	4	47
Diarrhoea
subjects affected / exposed	24 / 321 (7.48%)	31 / 336 (9.23%)	3 / 30 (10.00%)	13 / 116 (11.21%)
occurrences all number	25	43	3	16
Constipation
subjects affected / exposed	16 / 321 (4.98%)	27 / 336 (8.04%)	2 / 30 (6.67%)	12 / 116 (10.34%)
occurrences all number	16	28	2	14
Vomiting
subjects affected / exposed	22 / 321 (6.85%)	19 / 336 (5.65%)	0 / 30 (0.00%)	14 / 116 (12.07%)
occurrences all number	25	21	0	15
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	19 / 321 (5.92%)	24 / 336 (7.14%)	4 / 30 (13.33%)	8 / 116 (6.90%)
occurrences all number	22	31	4	10
Dyspnoea
subjects affected / exposed	13 / 321 (4.05%)	9 / 336 (2.68%)	2 / 30 (6.67%)	8 / 116 (6.90%)
occurrences all number	13	11	2	10
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	19 / 321 (5.92%)	8 / 336 (2.38%)	0 / 30 (0.00%)	3 / 116 (2.59%)
occurrences all number	20	9	0	3
Infections and infestations
Bronchitis
subjects affected / exposed	13 / 321 (4.05%)	12 / 336 (3.57%)	2 / 30 (6.67%)	8 / 116 (6.90%)
occurrences all number	16	19	2	8
Urinary tract infection
subjects affected / exposed	6 / 321 (1.87%)	17 / 336 (5.06%)	0 / 30 (0.00%)	2 / 116 (1.72%)
occurrences all number	12	19	0	2
Viral upper respiratory tract infection
subjects affected / exposed	8 / 321 (2.49%)	16 / 336 (4.76%)	0 / 30 (0.00%)	6 / 116 (5.17%)
occurrences all number	9	20	0	7
Herpes zoster
subjects affected / exposed	5 / 321 (1.56%)	5 / 336 (1.49%)	2 / 30 (6.67%)	1 / 116 (0.86%)
occurrences all number	5	5	2	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	9 / 321 (2.80%)	10 / 336 (2.98%)	2 / 30 (6.67%)	9 / 116 (7.76%)
occurrences all number	10	10	2	9

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Were there any global substantial amendments to the protocol? Yes

23 Aug 2009

• A wet signature page has been included.

03 Nov 2009

• 6 subject safety run-in to three cycles was extended while allowing the randomised part of the study to initiate after cycle one provided these patients do not meet the stopping criteria as currently defined in the protocol. An additional safety review after the 6 run-in subjects had completed three (3 cycles) of treatment was introduced as specified below.

14 Jan 2010

• Modification of the exclusion criteria to prevent subjects who were recently vaccinated with live virus from entering the study • Entry criteria were modified so that subjects with the following could participate in the study 1. Positive HCV serology but RNA negative 2. Certain malignancies with good prognosis 3. Autoimmune hemolytic anemia • Inconsistencies in the definition of partial response were amended • Small clarifications to laboratory processes • Updated information to warnings and precautions section because of new safety information providing recommendations for the monitoring of HBV reactivation • The frequency of the DSMB review of safety data was changed from every three months to monthly (until 50 subjects had been randomised) • In response to feedback from investigators, various changes to study drug administration were made including the dose of chlorambucil was capped at a maximum dose associated with a body mass index of 35, antibiotic prophylaxis was strongly recommended; clarified that for subjects with a high circulating lymphocyte count (as opposed to subjects with a WBC ≥100*10^9/L) the infusion (of obinutuzumab or rituximab) could be given more slowly over a longer period of time, or the dose could be split over 2 consecutive days. • Second malignancies were to be reported irrespective of time elapsed since study completion

26 Nov 2010

• The DSMB recommendation to define a clear and consistent cutoff for high circulating lymphocyte count (>25*10^9/L) was implemented and it was recommended that all subjects above this level received corticosteroids as premedication • HBsAg negative/anti-HBc positive subjects with undetectable serum HBV DNA were to be followed at monthly intervals for 12 months for HBV DNA (instead of 3-monthly intervals for 6 months) • Events that required permanent discontinuation of study therapy were clarified • Clarifications were made to the response section to avoid ambiguity and also the IRC section was aligned with the IRC charter • Refinement of the CIRS eligibility criteria (subjects with CIRS grade 4 for Eyes, Ears, Nose, Throat and Larynx organ system became eligible for the study) • Clarification of lab procedures and study assessments

12 Jun 2011

• Premedication requirements were modified to include corticosteroids (100 mg prednisolone or 20 mg dexamethasone or 80 mg methylprednisolone) for all subjects during the first infusion in an effort to reduce the risk of IRRs. Consideration to withholding of antihypertensives on day of infusion was included in the dosing schedule. • Duration of follow-up for B-cell recovery and monitoring of infection was extended to 2 years after the end of treatment • Clarified that not all NCI CTC Grade 4 laboratory parameters are considered serious adverse events since they are not always considered ‘life−threatening-at immediate risk of death” • Dose modification criteria were clarified

09 Dec 2011

• To further reduce the risk and severity of IRRs and on the recommendation of the DSMB, the first infusion of obinutuzumab was to be given over two days (100 mg on Day 1 and 900 mg on Day 2) with a reduced rate of infusion during the first day, and hypertensive drugs were not to be given on the morning of and throughout all infusions • Two additional urinalysis samples were added to obtain long term information on proteinuria

04 Sep 2012

• Clarification of Stage 1a and Stage 1b data release • Documentation of the implemented process for assigning response at Cycle 4 Day 1 and follow-up Day 28 when imaging and bone marrow are not available. Specifically, at 2 visits the eCRF captures response data CR, nCR, PR, SD and PD but according to IWCLL guidelines, imaging and bone marrow examination data are required for a full assessment of response (CR/PR). The problem arose how to complete the eCRF response assessment fields in the absence of the information. The team agreed to follow a standard approach that at these visits, response would be assessed according to the assessments planned; laboratory values, and physical examination. As a result of those changes the definition of disease free survival and duration of response was clarified to exclude those early responses. • Use of the stored plasma sample obtained at baseline for the obinutuzumab PK analysis to determine HAHA at baseline

07 Jun 2013

• Schedule of assessments was updated to include additional HAHA and pharmacokinetic assessments, and additional lymphocyte immunophenotyping and immunoglobulin assessment as well as provision of information on the diagnosis, evaluation and guidance should any subject be diagnosed with progressive mulitifocal leukoencephalopathy.

01 Dec 2016

• End of Study/Study Closure was revised to the date of LPLV, which occurred on 23 August 2017 • Duration of the 6-month follow-up visit period was changed to 5 years from date of last patient randomization, or end of study, whichever occurred first. • Duration of the annual follow-up visit period was changed to a maximum of 5 years from last patient enrollment, or end of study, whichever occurred first • Overview of study design was revised for the end-of-study period • Schedule of assessments was revised

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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