Trial Outcomes & Findings for CLL11: A Study of Obinutuzumab (RO5072759 [GA101]) With Chlorambucil in Patients With Previously Untreated Chronic Lymphocytic Leukemia (Stage 2) (NCT NCT02053610)

NCT ID: NCT02053610

Last Updated: 2018-09-14

Results Overview

PFS was defined as the time from randomization to the first occurrence of progression, relapse, or death from any cause as assessed by the investigator. Progressive disease 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 x 10\^9/L or by a decrease of neutrophil counts \>50% or \<1.0 x 10\^9/L).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

787 participants

Primary outcome timeframe

Randomization to clinical cutoff (median observation 59.4 months)

Results posted on

2018-09-14

Participant Flow

787 patients were enrolled in the study. Following a 6 patient safety run-in prior to randomization, 781 patients were randomized.

589 patients were randomized to 1 of 3 treatment groups in 2:2:1 ratio: GClb (n=238), RClb (n=233) or Clb (n=118) in Stage 1 and an additional 192 randomized to GClb or RClb in Stage 2. Stage 1 was divided for analysis into: Stage 1a \[NCT01010061\] and Stage 1b \[NCT01998880\]. 663 participants were included in the Stage 2 Analysis reported here.

Participant milestones

Participant milestones
Measure	Rituximab + Chlorambucil (RClb) Participants 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).	Obinutuzumab + Chlorambucil (GClb) Participants received 1000 mg obinutuzumab intravenous (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 in Cycle 1 and Day 1 in 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).
Overall Study STARTED	330	333
Overall Study Received Study Drug	326	331
Overall Study COMPLETED	288	266
Overall Study NOT COMPLETED	42	67

Reasons for withdrawal

Reasons for withdrawal
Measure	Rituximab + Chlorambucil (RClb) Participants 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).	Obinutuzumab + Chlorambucil (GClb) Participants received 1000 mg obinutuzumab intravenous (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 in Cycle 1 and Day 1 in 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).
Overall Study Adverse Event/Intercurrent Illness	25	43
Overall Study Withdrew Consent	2	9
Overall Study Death	5	5
Overall Study Administrative/Other	1	1
Overall Study Disease Progression	2	3
Overall Study Refused treatment/Did not cooperate	1	3
Overall Study Did not Receive Treatment	4	2
Overall Study Insufficient Therapeutic Response	1	1
Overall Study Violation of Selection Criteria	1	0

Baseline Characteristics

CLL11: A Study of Obinutuzumab (RO5072759 [GA101]) With Chlorambucil in Patients With Previously Untreated Chronic Lymphocytic Leukemia (Stage 2)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rituximab + Chlorambucil (RClb) n=330 Participants Participants 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).	Obinutuzumab + Chlorambucil (GClb) n=333 Participants Participants received 1000 mg obinutuzumab intravenous (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 in Cycle 1 and Day 1 in 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).	Total n=663 Participants Total of all reporting groups
Age, Continuous	71.5 years STANDARD_DEVIATION 8.82 • n=5 Participants	71.9 years STANDARD_DEVIATION 8.68 • n=7 Participants	71.7 years STANDARD_DEVIATION 8.75 • n=5 Participants
Sex: Female, Male Female	126 Participants n=5 Participants	130 Participants n=7 Participants	256 Participants n=5 Participants
Sex: Female, Male Male	204 Participants n=5 Participants	203 Participants n=7 Participants	407 Participants n=5 Participants

PRIMARY outcome

Timeframe: Randomization to clinical cutoff (median observation 59.4 months)

Population: Intent--to-treat population (ITT) included all randomized participants. Data for patients without disease progression or death was censored at the time of the last response assessment, or, if no response assessments were performed after the baseline visit, at the time of randomization plus one day.

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=330 Participants Participants 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).	Obinutuzumab + Chlorambucil (GClb) n=333 Participants Participants received 1000 mg obinutuzumab intravenous (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 in Cycle 1 and Day 1 in 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).
Progression-free Survival (PFS)	15.7 months Interval 14.3 to 17.2	28.9 months Interval 26.1 to 32.7

PRIMARY outcome

Timeframe: Randomization to clinical cutoff (median observation 59.4 months)

Population: ITT population included all randomized participants.

Percentage of Participants with Progression Free Survival Events: progression, relapse, or death.

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=330 Participants Participants 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).	Obinutuzumab + Chlorambucil (GClb) n=333 Participants Participants received 1000 mg obinutuzumab intravenous (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 in Cycle 1 and Day 1 in 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).
Percentage of Participants With Progression Free Survival Events	88.5 percentage of participants	73.3 percentage of participants

SECONDARY outcome

Timeframe: Randomization to clinical cutoff of 09 May 2013 (median observation 18.7 months)

Population: Intent-to-treat population (ITT) included all randomized participants. Data for patients without disease progression or death was censored at the time of the last response assessment, or, if no response assessments were performed after the baseline visit, at the time of randomization plus one day.

PFS was defined as the time from randomization to the first occurrence of progression, relapse, or death from any cause as assessed by Independent Review Committee. Progressive disease 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 x 10\^9/L or by a decrease of neutrophil counts \>50% or \<1.0 x 10\^9/L).

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=330 Participants Participants 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).	Obinutuzumab + Chlorambucil (GClb) n=333 Participants Participants received 1000 mg obinutuzumab intravenous (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 in Cycle 1 and Day 1 in 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).
Progression Free Survival Based on Independent Review Committee (IRC) Data	14.9 months Interval 14.2 to 17.2	26.7 months Interval 23.2 to 31.1

SECONDARY outcome

Timeframe: Randomization to clinical cutoff of 09 May 2013 (median observation 18.7 months)

Population: ITT participants included all randomized participants.

Percentage of Participants with Progression Free Survival Events: progression, relapse, or death from any cause as assessed by an Independent Review Committee.

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=330 Participants Participants 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).	Obinutuzumab + Chlorambucil (GClb) n=333 Participants Participants received 1000 mg obinutuzumab intravenous (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 in Cycle 1 and Day 1 in 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).
Percentage of Participants With Progression Free Survival Events Based on Independent Review Committee (IRC) Data	55.5 percentage of participants	30.9 percentage of participants

SECONDARY outcome

Timeframe: Randomization to clinical cutoff (median observation 59.4 months)

Population: Participants from the ITT population, all randomized participants, with data available for analysis. Participants who had not reached the 3-month follow-up visit at the time of the clinical cut-off were excluded from analysis.

EOTR was the first response assessment 56 days from the last dose according to the International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) guidelines. Complete Response (CR) required: Peripheral blood lymphocytes below 4 x 10\^9/L, Absence of significant lymphadenopathy, No hepatomegaly, No splenomegaly, Absence of disease, Blood counts above the following values (Neutrophils \>1.5 x 10\^9/L, Platelets \>100 x 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) required the following for at least 2 months from end of treatment: ≥50% decrease in peripheral blood lymphocyte count from the pre-treatment value AND Either a ≥ 50% reduction in lymphadenopathy OR ≥50% reduction of liver enlargement OR ≥50% reduction of spleen enlargement PLUS at least one of the following: Neutrophils \>1.5 x 10\^9/ or ≥50% increase, Platelets \>100 x 10\^9/L or ≥50% increase, Hemoglobin 11 g/dL or ≥50% increase.

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=330 Participants Participants 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).	Obinutuzumab + Chlorambucil (GClb) n=333 Participants Participants received 1000 mg obinutuzumab intravenous (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 in Cycle 1 and Day 1 in 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).
Percentage of Participants With End of Treatment Response (EOTR) Complete Response (CR)	4.8 percentage of participants Interval 2.8 to 7.8	15.6 percentage of participants Interval 11.9 to 20.0
Percentage of Participants With End of Treatment Response (EOTR) Complete Response incomplete (CRi)	1.5 percentage of participants Interval 0.5 to 3.5	3.6 percentage of participants Interval 1.9 to 6.2
Percentage of Participants With End of Treatment Response (EOTR) Partial Response (PR)	53.9 percentage of participants Interval 48.4 to 59.4	52.0 percentage of participants Interval 46.4 to 57.4
Percentage of Participants With End of Treatment Response (EOTR) Nodular Partial Response (nPR)	5.2 percentage of participants Interval 3.0 to 8.1	7.5 percentage of participants Interval 4.9 to 10.9
Percentage of Participants With End of Treatment Response (EOTR) Stable Disease	15.2 percentage of participants Interval 11.5 to 19.5	4.5 percentage of participants Interval 2.5 to 7.3
Percentage of Participants With End of Treatment Response (EOTR) Progressive Disease	11.2 percentage of participants Interval 8.0 to 15.1	4.5 percentage of participants Interval 2.5 to 7.3
Percentage of Participants With End of Treatment Response (EOTR) No Response Assessment	8.2 percentage of participants 95% CI not estimated for No Response Assessment category.	12.3 percentage of participants 95% CI not estimated for No Response Assessment category.

SECONDARY outcome

Timeframe: Randomization to clinical cutoff (median observation 59.4 months)

Best overall response according to IWCLL guidelines was defined as the percentage of patients with CR, CRi, PR or nodular Partial Response (nPR). CR required all of the following: Peripheral blood lymphocytes below 4 x 10\^9/L, Absence of significant lymphadenopathy, No hepatomegaly, No splenomegaly, Absence of disease, Blood counts above the following values (Neutrophils \>1.5 x 10\^9/L, Platelets \>100 x 10\^9/L, Hemoglobin \>11g/dL) and Bone marrow at least normocellular for age. CRi was CR with incomplete bone marrow recovery. PR required the following for at least 2 months from end of treatment: ≥50% decrease in peripheral blood lymphocyte count from the pre-treatment value AND Either a ≥ 50% reduction in lymphadenopathy OR ≥50% reduction of liver enlargement OR ≥50% reduction of spleen enlargement PLUS at least one of the following: Neutrophils \>1.5 x 10\^9/ or ≥50% increase, Platelets \>100 x 10\^9/L or ≥50% increase, Hemoglobin 11 g/dL or ≥50% increase.

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=330 Participants Participants 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).	Obinutuzumab + Chlorambucil (GClb) n=333 Participants Participants received 1000 mg obinutuzumab intravenous (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 in Cycle 1 and Day 1 in 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).
Percentage of Participants With Best Overall Response Complete Response (CR)	7.0 percentage of participants Interval 4.5 to 10.3	23.7 percentage of participants Interval 19.3 to 28.7
Percentage of Participants With Best Overall Response Complete Response incomplete (CRi)	1.2 percentage of participants Interval 0.3 to 3.1	1.8 percentage of participants Interval 0.7 to 3.9
Percentage of Participants With Best Overall Response Partial Response (PR)	55.5 percentage of participants Interval 49.9 to 60.9	50.8 percentage of participants Interval 45.2 to 56.2
Percentage of Participants With Best Overall Response Nodular Partial Response (nPR)	2.7 percentage of participants Interval 1.3 to 5.1	3.0 percentage of participants Interval 1.4 to 5.5
Percentage of Participants With Best Overall Response Stable Disease	14.5 percentage of participants Interval 10.9 to 18.8	3.9 percentage of participants Interval 2.1 to 6.6
Percentage of Participants With Best Overall Response Progressive Disease	11.5 percentage of participants Interval 8.3 to 15.5	4.5 percentage of participants Interval 2.5 to 7.3
Percentage of Participants With Best Overall Response No Response Assessment	7.6 percentage of participants 95% CI not estimated for No Response Assessment category.	12.3 percentage of participants 95% CI not estimated for No Response Assessment category.

SECONDARY outcome

Timeframe: Randomization to clinical cutoff (median observation 59.4 months)

Population: ITT population included all randomized participants. Participants were censored at the date of last tumor assessment. In cases where no tumor assessment is available, participants were censored at the date of randomization plus one day.

Event-free survival (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 x 10\^9/L or by a decrease of neutrophil counts \>50% or \<1.0 x 10\^9/L).

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=330 Participants Participants 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).	Obinutuzumab + Chlorambucil (GClb) n=333 Participants Participants received 1000 mg obinutuzumab intravenous (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 in Cycle 1 and Day 1 in 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).
Event Free Survival	15 months Interval 14.2 to 17.1	26.5 months Interval 24.8 to 30.1

SECONDARY outcome

Timeframe: Randomization to clinical cutoff (median observation 59.4 months)

Population: ITT population included all randomized participants. Participants 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.

Overall Survival (OS) was defined as the time between the date of randomization and the date of death due to any cause.

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=330 Participants Participants 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).	Obinutuzumab + Chlorambucil (GClb) n=333 Participants Participants received 1000 mg obinutuzumab intravenous (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 in Cycle 1 and Day 1 in 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).
Overall Survival	73.1 months Interval 60.8 to The upper limit of 95% CI could not be estimated due to a low number of deaths.	NA months Interval 74.6 to The median overall survival and the upper limit of 95% CI could not be estimated due to a low number of deaths.

SECONDARY outcome

Timeframe: Randomization to clinical cutoff (median observation 59.4 months)

Population: Participants from the ITT population, all randomized participants, with response.

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.

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=220 Participants Participants 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).	Obinutuzumab + Chlorambucil (GClb) n=271 Participants Participants received 1000 mg obinutuzumab intravenous (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 in Cycle 1 and Day 1 in 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).
Duration of Response	11.8 months Interval 9.5 to 12.6	23.8 months Interval 19.1 to 30.1

SECONDARY outcome

Timeframe: Randomization to clinical cutoff (median observation 59.4 months)

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 patients using a blood sample. Additionally, a bone marrow sample was obtained from patients 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 patient 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).

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=246 Participants Participants 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).	Obinutuzumab + Chlorambucil (GClb) n=237 Participants Participants received 1000 mg obinutuzumab intravenous (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 in Cycle 1 and Day 1 in 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).
Percentage of Participants With Molecular Remission at the End of Treatment	2 percentage of participants Interval 0.9 to 5.2	24 percentage of participants Interval 18.8 to 30.0

SECONDARY outcome

Timeframe: Randomization to clinical cutoff (median observation 59.4 months)

Population: ITT population included all randomized participants. Participants 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.

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.

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=330 Participants Participants 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).	Obinutuzumab + Chlorambucil (GClb) n=333 Participants Participants received 1000 mg obinutuzumab intravenous (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 in Cycle 1 and Day 1 in 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).
Time to Re-Treatment/New Anti-leukemic Therapy	34.9 months Interval 29.1 to 41.6	56.4 months Interval 48.3 to Upper limit of 95% CI was not reached.

SECONDARY outcome

Timeframe: Baseline and Cycle 4 Day 1 (Cy4D1)

Population: ITT population. Here, n signifies the number of participants who were evaluated for specified category.

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 participants. A positive change from Baseline indicated improvement.

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=330 Participants Participants 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).	Obinutuzumab + Chlorambucil (GClb) n=333 Participants Participants received 1000 mg obinutuzumab intravenous (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 in Cycle 1 and Day 1 in 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).
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Appetite Loss Scale: Baseline (n=314, 312)	15.4 unit on a scale Standard Deviation 26.02	19 unit on a scale Standard Deviation 29.37
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Appetite Loss Scale: Cy4D1 (n=277, 258)	12 unit on a scale Standard Deviation 23.22	10.9 unit on a scale Standard Deviation 21.47
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Cognitive Functioning Scale: Baseline(n=312, 315)	83.0 unit on a scale Standard Deviation 20.02	80.4 unit on a scale Standard Deviation 22.52
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Cognitive Functioning Scale: Cy4D1 (n=277, 259)	83.6 unit on a scale Standard Deviation 17.26	83.9 unit on a scale Standard Deviation 20.25
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Constipation Scale: Baseline (n=311, 312)	15.2 unit on a scale Standard Deviation 24.62	14.9 unit on a scale Standard Deviation 23.54
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Constipation Scale: Cy4D1 (n=276,257)	14.3 unit on a scale Standard Deviation 23.05	15.3 unit on a scale Standard Deviation 25.16
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Diarrhoea Scale: Baseline (n=311,313)	8.4 unit on a scale Standard Deviation 18.78	9.5 unit on a scale Standard Deviation 19.58
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Diarrhoea Scale: Cy4D1 (n=276,257)	8.8 unit on a scale Standard Deviation 19.66	9.2 unit on a scale Standard Deviation 20.32
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Dyspnoea Scale: Baseline (n=312,312)	27.5 unit on a scale Standard Deviation 28.62	27.8 unit on a scale Standard Deviation 29.97
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Dyspnoea: Cy4D1 (n=277,257)	20.8 unit on a scale Standard Deviation 26.69	16.5 unit on a scale Standard Deviation 23.75
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Emotional Functioning Scale: Baseline (n=312,314)	77.1 unit on a scale Standard Deviation 21.32	73.9 unit on a scale Standard Deviation 23.14
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Emotional Functioning Scale: Cy4D1 (n=277,259)	82.7 unit on a scale Standard Deviation 18.29	82.5 unit on a scale Standard Deviation 19.18
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Fatigue Scale: Baseline (n=313,312)	36.9 unit on a scale Standard Deviation 25.86	38.5 unit on a scale Standard Deviation 26.05
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Fatigue Scale: Cy4D1 (n=278,258)	30.4 unit on a scale Standard Deviation 22.32	29.8 unit on a scale Standard Deviation 21.43
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Financial Difficulties Scale: Baseline (n=309,312)	10.5 unit on a scale Standard Deviation 21.53	10.5 unit on a scale Standard Deviation 22.14
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Financial Difficulties Scale: Cy4D1(n=273,258)	9.6 unit on a scale Standard Deviation 20.02	8.4 unit on a scale Standard Deviation 19.35
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Nausea, Vomiting Scale: Baseline (n=313,315)	4.5 unit on a scale Standard Deviation 12.66	5.3 unit on a scale Standard Deviation 12.9
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Nausea, Vomiting Scale: Cy4D1 (n=278,258)	4.1 unit on a scale Standard Deviation 10.18	5.2 unit on a scale Standard Deviation 10.96
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Pain scale: Baseline (n=313,316)	22.5 unit on a scale Standard Deviation 27.59	22.9 unit on a scale Standard Deviation 27.73
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Pain scale: Cy4D1 (n=278,259)	15.6 unit on a scale Standard Deviation 22.48	18.1 unit on a scale Standard Deviation 24.60
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Physical Functioning Scale: Baseline (n=313,316)	75.8 unit on a scale Standard Deviation 19.34	73.3 unit on a scale Standard Deviation 20.77
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Physical Functioning Scale: Cy4D1 (n=278,258)	77.8 unit on a scale Standard Deviation 18.5	78.5 unit on a scale Standard Deviation 18.90
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Global Health Status Scale: Baseline (n=310,313)	58.1 unit on a scale Standard Deviation 22.74	58.0 unit on a scale Standard Deviation 23.81
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Global Health Status Scale: Cy4D1 (n=275,256)	65.8 unit on a scale Standard Deviation 20.22	66.7 unit on a scale Standard Deviation 20.27
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Role Functioning Scale: Baseline (n=313,315)	76.4 unit on a scale Standard Deviation 28.68	74.3 unit on a scale Standard Deviation 27.62
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Role Functioning Scale: Cy4D1 (n=277,258)	79.9 unit on a scale Standard Deviation 25.4	78.7 unit on a scale Standard Deviation 24.56
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Social Functioning Scale: Baseline (n=312,314)	82.9 unit on a scale Standard Deviation 23.81	83.7 unit on a scale Standard Deviation 24.96
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Social Functioning Scale: Cy4D1(n=276,259)	85.4 unit on a scale Standard Deviation 21	86.6 unit on a scale Standard Deviation 20.71
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Insomnia: Baseline (n=312,316)	25.6 unit on a scale Standard Deviation 30.91	29.9 unit on a scale Standard Deviation 31.18
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Insomnia: Cy4D1(n=276,258)	20.9 unit on a scale Standard Deviation 26.71	21.6 unit on a scale Standard Deviation 27.97

SECONDARY outcome

Timeframe: Baseline and Cycle 4 Day 1 (Cy4D1)

Population: ITT population. Here, n signifies the number of participants who were evaluated for specified category.

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 participants. A positive change from Baseline indicated improvement.

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=330 Participants Participants 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).	Obinutuzumab + Chlorambucil (GClb) n=333 Participants Participants received 1000 mg obinutuzumab intravenous (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 in Cycle 1 and Day 1 in 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).
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Disease Effects Scale: Baseline (n=276,284)	22.8 unit on a scale Standard Deviation 17.94	22.7 unit on a scale Standard Deviation 18.49
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Disease Effects Scale: Cy4D1 (n=243, 233)	15.4 unit on a scale Standard Deviation 15	14.7 unit on a scale Standard Deviation 15.34
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Fatigue Scale: Baseline (n=276, 284)	27.7 unit on a scale Standard Deviation 23.48	31.1 unit on a scale Standard Deviation 25.32
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Fatigue Scale: Cy4D1 (n=243, 233)	21 unit on a scale Standard Deviation 20.52	20.6 unit on a scale Standard Deviation 20.82
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Future Health: Baseline (n=275, 280)	47.5 unit on a scale Standard Deviation 32.17	49.8 unit on a scale Standard Deviation 32.79
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Future Health: Cy4D1 (n=240, 231)	33.9 unit on a scale Standard Deviation 29.72	30.3 unit on a scale Standard Deviation 31.17
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Infection Scale: Baseline (n=275, 284)	11.8 unit on a scale Standard Deviation 15.83	12.7 unit on a scale Standard Deviation 16.67
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Infection Scale: Cy4D1 (n=243, 233)	9.4 unit on a scale Standard Deviation 13.94	9 unit on a scale Standard Deviation 12.2
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Social Problems: Baseline (n=271, 281)	25.2 unit on a scale Standard Deviation 32.45	23.6 unit on a scale Standard Deviation 31.12
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Social Problems: Cy4D1 (n=242, 232)	19.3 unit on a scale Standard Deviation 26.03	19.5 unit on a scale Standard Deviation 27.94
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Treatment Side Effects Scale: Baseline(n=276, 284)	17.9 unit on a scale Standard Deviation 15.69	19.9 unit on a scale Standard Deviation 17.59
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Treatment Side Effect Scale: Cy4D1(n=243, 233)	14.2 unit on a scale Standard Deviation 13.57	14.6 unit on a scale Standard Deviation 14.89

Adverse Events

Rituximab + Chlorambucil (RClb)

Serious events: 124 serious events

Other events: 279 other events

Deaths: 0 deaths

Obinutuzumab + Chlorambucil (GClb)

Serious events: 150 serious events

Other events: 299 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffman-LaRoche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Rituximab + Chlorambucil (RClb) n=321 participants at risk Participants 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).	Obinutuzumab + Chlorambucil (GClb) n=336 participants at risk Participants received 1000 mg obinutuzumab intravenous (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 in Cycle 1 and Day 1 in 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).
Blood and lymphatic system disorders Neutropenia	32.4% 104/321 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.	38.1% 128/336 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.
Blood and lymphatic system disorders Anaemia	10.6% 34/321 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.	9.8% 33/336 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.
Blood and lymphatic system disorders Thrombocytopenia	6.2% 20/321 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.	13.7% 46/336 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.
Blood and lymphatic system disorders Leukopenia	2.2% 7/321 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.	6.2% 21/336 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.
Injury, poisoning and procedural complications Infusion related reaction	36.8% 118/321 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.	58.6% 197/336 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.
Gastrointestinal disorders Nausea	13.1% 42/321 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.	11.9% 40/336 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.
Gastrointestinal disorders Diarrhoea	7.5% 24/321 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.	9.2% 31/336 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.
Gastrointestinal disorders Constipation	5.0% 16/321 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.	8.0% 27/336 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.
Gastrointestinal disorders Vomiting	6.9% 22/321 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.	5.7% 19/336 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.
General disorders Fatigue	9.3% 30/321 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.	7.7% 26/336 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.
General disorders Pyrexia	6.9% 22/321 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.	8.3% 28/336 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.
General disorders Asthenia	7.8% 25/321 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.	6.8% 23/336 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.
Respiratory, thoracic and mediastinal disorders Cough	5.9% 19/321 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.	7.1% 24/336 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.
Nervous system disorders Headache	5.6% 18/321 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.	6.8% 23/336 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.
Skin and subcutaneous tissue disorders Rash	5.9% 19/321 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.	2.4% 8/336 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.
Infections and infestations Urinary Tract Infection	1.9% 6/321 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.	5.1% 17/336 • 5.5 years Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.