A Multi-Center Study of Ibrutinib in Combination With Obinutuzumab Versus Chlorambucil in Combination With Obinutuzumab in Patients With Treatment naïve Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

• ClinicalTrials.gov Identifier: NCT02264574
• Recruitment Status: Completed
• First Posted: October 15, 2014
• Results First Posted: April 16, 2019
• Last Update Posted: September 21, 2020
• Sponsor: Pharmacyclics LLC.
• Information provided by (Responsible Party): Pharmacyclics LLC.

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Chronic Lymphocytic Leukemia; Small-Cell Lymphoma
• Interventions: Drug: Ibrutinib; Drug: Obinutuzumab; Drug: Chlorambucil
• Enrollment: 229

Participant Flow

Recruitment Details	This study was conducted in 71 sites: 8 in the US, 36 in the EU, and 27 sites in 6 additional countries (Canada, Australia, New Zealand, Russia, Israel, Turkey). The first participant consented 06 October 2014. The last visit of the last participant was 03 September 2019, with a final database lock of 17 October 2019.
Pre-assignment Details	Eligible participants were required to have had a diagnosis of active CLL/SLL conformant to IWCLL 2008 criteria. All subjects were required to have measurable nodal disease. Key exclusion criteria included any previous CLL/SLL treatment; known lymphoma or leukemia of the central nervous system, history/current evidence of Richter's transformation.

Arm/Group Title	IBR+OB	CLB+OB
Arm/Group Description	Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.	Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
Period Title: Overall Study
Started	113	116
Completed [1]	84	86
Not Completed	29	30
Reason Not Completed
Death	21	21
Withdrawal by Subject	8	6
Other, Not Specified	0	3
[1] On-study until study termination by sponsor.

Baseline Characteristics

Arm/Group Title		IBR+OB	CLB+OB	Total
Arm/Group Description		Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.	Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Number of Baseline Participants		113	116	229
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	113 participants	116 participants	229 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	22 19.5%	24 20.7%	46 20.1%
	>=65 years	91 80.5%	92 79.3%	183 79.9%
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	113 participants	116 participants	229 participants
		70.0; (47 to 87)	72.0; (40 to 86)	71.0; (40 to 87)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	113 participants	116 participants	229 participants
	Female	46 40.7%	37 31.9%	83 36.2%
	Male	67 59.3%	79 68.1%	146 63.8%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	113 participants	116 participants	229 participants
	Hispanic or Latino	4 3.5%	6 5.2%	10 4.4%
	Not Hispanic or Latino	109 96.5%	110 94.8%	219 95.6%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	113 participants	116 participants	229 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	1 0.9%	2 1.7%	3 1.3%
	Native Hawaiian or Other Pacific Islander	1 0.9%	1 0.9%	2 0.9%
	Black or African American	2 1.8%	2 1.7%	4 1.7%
	White	109 96.5%	111 95.7%	220 96.1%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	113 participants	116 participants	229 participants
United States		13	11	24
Czechia		8	6	14
United Kingdom		2	2	4
Spain		17	9	26
Russia		11	9	20
New Zealand		0	9	9
Canada		3	5	8
Austria		5	6	11
Sweden		8	3	11
Turkey		15	13	28
Belgium		2	2	4
Poland		2	2	4
Italy		13	15	28
Israel		5	11	16
France		3	5	8
Australia		6	8	14

Outcome Measures

1. Primary Outcome

Title	Primary Analysis: Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 30
Description	PFS was defined as time from the date randomization to the date of first IRC-confirmed disease progression (PD) or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of disease progression was not considered progressive disease. The primary analysis was performed after observing 94 PFS events as pre-specified in the study protocol. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 30 months (that is, the estimated percentage of participants with progression-free survival at Month 30) are presented.
Time Frame	Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]).

Outcome Measure Data

Analysis Population Description

Intent to Treat population: all randomized participants

Arm/Group Title	IBR+OB	CLB+OB
Arm/Group Description:	Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.	Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	113	116
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	78.5; (69.5 to 85.2)	31.1; (22.5 to 40.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IBR+OB, CLB+OB
	Comments	To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints were tested based on serial gatekeeping testing procedure at the two-sided significance level of 0.05 according to the hierarchical order of the primary analysis outcome measures presented in this record.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	The treatment effect was tested with an unstratified log rank test.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.231
	Confidence Interval	(2-Sided) 95%; 0.145 to 0.367
	Estimation Comments	The hazard ratio and its 95% confidence interval were estimated using a Cox regression model with treatment as the only covariate.

2. Primary Outcome

Title	Final Analysis: PFS Based on Investigator Assessment - Kaplan Meier Landmark Estimates at Month 48
Description	PFS was defined as time from the date randomization to the date of first investigator-confirmed PD or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of disease progression was not considered progressive disease. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 48 months (that is, the estimated percentage of participants with progression-free survival at Month 48) are presented.
Time Frame	Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]).

Outcome Measure Data

Analysis Population Description

Intent to Treat population: all randomized participants

Arm/Group Title	IBR+OB	CLB+OB
Arm/Group Description:	Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.	Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	113	116
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	74.0; (64.3 to 81.4)	22.0; (11.0 to 35.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IBR+OB, CLB+OB
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	The treatment effect was tested with an unstratified log rank test.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.251
	Confidence Interval	(2-Sided) 95%; 0.162 to 0.389
	Estimation Comments	The hazard ratio and its 95% confidence interval were estimated using a Cox regression model with treatment as the only covariate.

3. Secondary Outcome

Title	Primary Analysis: PFS in High-Risk Sub-Population (del17p/TP53 Mutation/Del 11q) Based on IRC Assessment - Kaplan Meier Landmark Estimates at Month 30
Description	PFS was analyzed within the high-risk sub-population of participants with del17p or TP53 mutation or del 11q at baseline per central lab results. PFS was defined as time from the date randomization to the date of first IRC-confirmed PD or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the IWCLL 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of PD was not considered progressive disease. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 30 months (that is, the estimated percentage of participants with progression-free survival at Month 30) are presented.
Time Frame	Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]).

Outcome Measure Data

Analysis Population Description

High-Risk Sub-Population Analysis Set: participants with del17p or TP53 mutation or del 11q at baseline per central lab results.

Arm/Group Title	IBR+OB	CLB+OB
Arm/Group Description:	Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.	Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	30	45
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	82.4; (62.7 to 92.3)	14.1; (5.3 to 26.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IBR+OB, CLB+OB
	Comments	To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints were tested based on serial gatekeeping testing procedure at the two-sided significance level of 0.05 according to the hierarchical order of the primary analysis outcome measures presented in this record.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	The treatment effect was tested with an unstratified log rank test.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.119
	Confidence Interval	(2-Sided) 95%; 0.046 to 0.307
	Estimation Comments	The hazard ratio and its 95% confidence interval were estimated using a Cox regression model with treatment as the only covariate.

4. Secondary Outcome

Title	Primary Analysis: Rate of Sustained Hemoglobin Improvement
Description	Percentage of participants with sustained hemoglobin improvement, defined as hemoglobin increase ≥ 2 g/dL over baseline continuously for ≥ 56 days without blood transfusions or growth factors.
Time Frame	Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).

Outcome Measure Data

Analysis Population Description

Intent to Treat population: all randomized participants

Arm/Group Title	IBR+OB	CLB+OB
Arm/Group Description:	Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.	Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	113	116
Measure Type: Number; Unit of Measure: percentage of participants
	39.8	44.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IBR+OB, CLB+OB
	Comments	To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints were tested based on serial gatekeeping testing procedure at the two-sided significance level of 0.05 according to the hierarchical order of the primary analysis outcome measures presented in this record.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5253
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

5. Secondary Outcome

Title	Primary Analysis: Rate of Minimal Residual Disease (MRD)-Negative Response
Description	Percentage of participants who achieved MRD-negative response, defined as < 1 CLL cell per 10,000 leukocytes as assessed by flow cytometry of a bone marrow aspirate per central laboratory. MRD samples were collected before initiation of subsequent antineoplastic treatment and MRD status was reported by central lab within 5 days after collection date. Participants with missing MRD data were considered non-responders.
Time Frame	Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).

Outcome Measure Data

Analysis Population Description

Intent to Treat population: all randomized participants

Arm/Group Title	IBR+OB	CLB+OB
Arm/Group Description:	Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.	Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	113	116
Measure Type: Number; Unit of Measure: percentage of participants
	20.4	17.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IBR+OB, CLB+OB
	Comments	To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints were tested based on serial gatekeeping testing procedure at the two-sided significance level of 0.05 according to the hierarchical order of the primary analysis outcome measures presented in this record.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5465
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

6. Secondary Outcome

Title	Primary Analysis: Overall Response Rate (ORR) Based on IRC Assessment
Description	ORR, defined as the percentage of participants achieving a best overall response of protocol-specified complete response (CR), CR with incomplete blood count recovery (CRi), nodular partial response (nPR), or partial response (PR) per IRC assessment at or prior to initiation of subsequent antineoplastic therapy. Assessment of response included physical examination, radiographic imaging, and evaluation of blood and marrow (if applicable), evaluated in accordance with the IWCLL 2008 criteria (Halleck et al). CR, CRi, nPR, and PR required confirmation with 2 consecutive assessments that were at least 56 days apart and no use of blood supportive product and/or growth factor during this period. Kaplan-Meier estimate.
Time Frame	Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).

Outcome Measure Data

Analysis Population Description

Intent to Treat population: all randomized participants

Arm/Group Title	IBR+OB	CLB+OB
Arm/Group Description:	Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.	Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	113	116
Measure Type: Number; Unit of Measure: percentage of participants
	88.5	73.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IBR+OB, CLB+OB
	Comments	To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints were tested based on serial gatekeeping testing procedure at the two-sided significance level of 0.05 according to the hierarchical order of the primary analysis outcome measures presented in this record.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0035
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	1.208
	Confidence Interval	(2-Sided) 95%; 1.062 to 1.373
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Primary Analysis: Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 30
Description	OS, defined as the time from the date of randomization to the date of death from any cause. All deaths observed as the time of the analysis were considered as events. For participants who were not known to have died at the time of the analysis, OS data were censored at the date last known alive. As the median OS was not reached in either treatment arm at the time of the analysis, Kaplan Meier landmark estimates of the OS rate (that is, the estimated percentage of participants still surviving at Month 30 [primary analysis]) are presented.
Time Frame	Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]).

Outcome Measure Data

Analysis Population Description

Intent to Treat population: all randomized participants

Arm/Group Title	IBR+OB	CLB+OB
Arm/Group Description:	Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.	Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	113	116
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	85.5; (77.4 to 90.9)	84.9; (76.8 to 90.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IBR+OB, CLB+OB
	Comments	To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints were tested based on serial gatekeeping testing procedure at the two-sided significance level of 0.05 according to the hierarchical order of the primary analysis outcome measures presented in this record.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8057
	Comments	[Not Specified]
	Method	Log Rank
	Comments	The treatment effect was tested with an unstratified log rank test.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.921
	Confidence Interval	(2-Sided) 95%; 0.479 to 1.772
	Estimation Comments	The hazard ratio and its 95% confidence interval were estimated using a Cox regression model with treatment as the only covariate.

8. Secondary Outcome

Title	Primary Analysis: Rate of Grade ≥ 3 or Serious Infusion-Related Reaction (IRR) Adverse Events
Description	Percentage of participants experiencing grade ≥ 3 (severe or life threatening) or serious IRR adverse events that started on the day of an obinutuzumab infusion and were assessed as related or possibly related to obinutuzumab. Categories included those events with the Medical Dictionary for Regulatory Activities (MedDRA) dictionary preferred term of IRR and those events which are among the customized standardized MedDRA query (SMQ) for IRR.
Time Frame	Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).

Outcome Measure Data

Analysis Population Description

Intent to Treat population: all randomized participants

Arm/Group Title	IBR+OB	CLB+OB
Arm/Group Description:	Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.	Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	113	116
Measure Type: Number; Unit of Measure: percentage of participants
IRR (Preferred Term)	2.7	8.6
By Customized SMQ	4.4	9.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IBR+OB, CLB+OB
	Comments	IRR Preferred Term To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints were tested based on serial gatekeeping testing procedure at the two-sided significance level of 0.05 according to the hierarchical order of the primary analysis outcome measures presented in this record.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0835
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	IBR+OB, CLB+OB
	Comments	IRR By Customized SMQ To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints were tested based on serial gatekeeping testing procedure at the two-sided significance level of 0.05 according to the hierarchical order of the primary analysis outcome measures presented in this record.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1944
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

9. Secondary Outcome

Title	Primary Analysis: Rate of Sustained Platelet Improvement
Description	Percentage of participants with platelet counts increase ≥ 50% over baseline continuously for ≥ 56 days without blood transfusion or growth factors.
Time Frame	Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).

Outcome Measure Data

Analysis Population Description

Intent to Treat population: all randomized participants

Arm/Group Title	IBR+OB	CLB+OB
Arm/Group Description:	Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.	Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	113	116
Measure Type: Number; Unit of Measure: percentage of participants
	29.2	13.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IBR+OB, CLB+OB
	Comments	To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints were tested based on serial gatekeeping testing procedure at the two-sided significance level of 0.05 according to the hierarchical order of the primary analysis outcome measures presented in this record.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0045
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

10. Secondary Outcome

Title	Primary Analysis: Rate of Clinically Meaningful Improvement in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire EuroQol Five-Dimension (EQ-5D-5L)
Description	Percentage of participants with EQ-5D-5L utility score increase ≥ 0.08 points over baseline at or prior to initiation of subsequent antineoplastic therapy. The EQ-5D-5L is a standardized non-disease specific instrument for describing and valuing health-related quality of life, comprising 5 dimensions of health (mobility, self -care, usual activities, pain/discomfort, and anxiety/depression) to describe the participant's current health state. Each dimension comprises 5 levels with corresponding numeric scores, where 1 indicates no problems, and 5 indicates extreme problems. A unique EQ-5D-5L health state is defined by combining the numeric level scores for each of the 5 dimensions and the total score is normalized from -0.594 to 1.000, with higher scores representing a better health state. An increase in the EQ-5D-5L total score indicates improvement. Participants with missing EQ-5D-5L data were considered not achieving clinically meaningful improvement.
Time Frame	Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).

Outcome Measure Data

Analysis Population Description

Intent to Treat population: all randomized participants with a baseline and post-baseline assessment.

Arm/Group Title	IBR+OB	CLB+OB
Arm/Group Description:	Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.	Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	109	107
Measure Type: Number; Unit of Measure: percentage of participants
	54.9	56.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IBR+OB, CLB+OB
	Comments	To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints were tested based on serial gatekeeping testing procedure at the two-sided significance level of 0.05 according to the hierarchical order of the primary analysis outcome measures presented in this record.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8590
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

11. Secondary Outcome

Title	Final Analysis: PFS in High-Risk Population (del17p/TP53 Mutation/Del 11q/Unmutated Immunoglobulin Heavy Chain Variable Region [IGHV]) Based on Investigator Assessment - Kaplan Meier Landmark Estimates at Month 48
Description	PFS was analyzed within the high-risk population of participants with del17p or TP53 mutation or del 11q or IGHV unmutated at baseline per central lab results. PFS was defined as time from the date randomization to the date of first investigator-confirmed PD or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the IWCLL 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of PD was not considered progressive disease. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 48 months (that is, the estimated percentage of participants with progression-free survival at Month 48) are presented.
Time Frame	Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]).

Outcome Measure Data

Analysis Population Description

High-Risk Population Analysis Set: participants with del17p or TP53 mutation or del 11q or IGHV unmutated at baseline per central lab results.

Arm/Group Title	IBR+OB	CLB+OB
Arm/Group Description:	Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.	Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	73	75
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	70.3; (57.6 to 79.8)	8.0; (2.3 to 18.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IBR+OB, CLB+OB
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	The treatment effect was tested with an unstratified log rank test.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.169
	Confidence Interval	(2-Sided) 95%; 0.102 to 0.282
	Estimation Comments	The hazard ratio and its 95% confidence interval were estimated using a Cox regression model with treatment as the only covariate.

12. Secondary Outcome

Title	Final Analysis: Rate of Sustained Hemoglobin Improvement
Description	Percentage of participants with sustained hemoglobin improvement, defined as hemoglobin increase ≥ 2 g/dL over baseline continuously for ≥ 56 days without blood transfusions or growth factors.
Time Frame	Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).

Outcome Measure Data

Analysis Population Description

Intent to Treat population: all randomized participants

Arm/Group Title	IBR+OB	CLB+OB
Arm/Group Description:	Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.	Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	113	116
Measure Type: Number; Unit of Measure: percentage of participants
	44.2	44.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IBR+OB, CLB+OB
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9657
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

13. Secondary Outcome

Title	Final Analysis: Rate of Minimal Residual Disease (MRD)-Negative Response
Description	Percentage of participants who achieved MRD-negative response, defined as < 1 CLL cell per 10,000 leukocytes as assessed by flow cytometry of a bone marrow aspirate per central laboratory. MRD samples were collected before initiation of subsequent antineoplastic treatment and MRD status was reported by central lab within 5 days after collection date. Participants with missing MRD data were considered non-responders.
Time Frame	Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).

Outcome Measure Data

Analysis Population Description

Intent to Treat population: all randomized participants

Arm/Group Title	IBR+OB	CLB+OB
Arm/Group Description:	Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.	Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	113	116
Measure Type: Number; Unit of Measure: percentage of participants
	24.8	17.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IBR+OB, CLB+OB
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1612
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

14. Secondary Outcome

Title	Final Analysis: ORR Based on Investigator Assessment
Description	ORR, defined as the percentage of participants achieving a best overall response of protocol-specified CR, CRi, nPR or PR per investigator assessment at or prior to initiation of subsequent antineoplastic therapy. Assessment of response included physical examination, radiographic imaging, and evaluation of blood and marrow (if applicable), evaluated in accordance with the IWCLL 2008 criteria (Halleck et al). CR, CRi, nPR, and PR required confirmation with 2 consecutive assessments that were at least 56 days apart and no use of blood supportive product and/or growth factor during this period. Kaplan-Meier estimate.
Time Frame	Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).

Outcome Measure Data

Analysis Population Description

Intent to Treat population: all randomized participants

Arm/Group Title	IBR+OB	CLB+OB
Arm/Group Description:	Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.	Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	113	116
Measure Type: Number; Unit of Measure: percentage of participants
	91.2	81.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IBR+OB, CLB+OB
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0273
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	1.125
	Confidence Interval	(2-Sided) 95%; 1.013 to 1.250
	Estimation Comments	[Not Specified]

15. Secondary Outcome

Title	Final Analysis: Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 48
Description	OS, defined as the time from the date of randomization to the date of death from any cause. All deaths observed as the time of the analysis were considered as events. For participants who were not known to have died at the time of the analysis, OS data were censored at the date last known alive. As the median OS was not reached in either treatment arm at the time of the analysis, Kaplan Meier point estimates of the OS rate (that is, the estimated percentage of participants still surviving at Month 48 [final analysis]) are presented.
Time Frame	Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]).

Outcome Measure Data

Analysis Population Description

Intent to Treat population: all randomized participants

Arm/Group Title	IBR+OB	CLB+OB
Arm/Group Description:	Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.	Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	113	116
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	80.5; (71.6 to 86.9)	81.3; (72.8 to 87.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IBR+OB, CLB+OB
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7934
	Comments	[Not Specified]
	Method	Log Rank
	Comments	The treatment effect was tested with an unstratified log rank test.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.083
	Confidence Interval	(2-Sided) 95%; 0.595 to 1.973
	Estimation Comments	The hazard ratio and its 95% confidence interval were estimated using a Cox regression model with treatment as the only covariate.

16. Secondary Outcome

Title	Final Analysis: Rate of Sustained Platelet Improvement
Description	Percentage of participants with platelet counts increase ≥ 50% over baseline continuously for ≥ 56 days without blood transfusion or growth factors.
Time Frame	Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).

Outcome Measure Data

Analysis Population Description

Intent to Treat population: all randomized participants

Arm/Group Title	IBR+OB	CLB+OB
Arm/Group Description:	Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.	Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	113	116
Measure Type: Number; Unit of Measure: percentage of participants
	30.1	14.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IBR+OB, CLB+OB
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0050
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

Adverse Events

Time Frame	From first dose of study drug up to 30 days after the last dose of study drug. Median treatment duration for the IBR+OB arm was 42.3 (IBR) and 4.6 (OB) months. Median treatment duration for the CLB+OB arm was 5.1 (CLB) and 4.6 (OB) months. Final analysis data (data cutoff date: 17 October 2019).
Adverse Event Reporting Description	One participant in the CLB+OB arm was randomized but went off study without any treatment. This participant had received baseline assessments and was included in all efficacy analyses but was excluded from safety population, i.e. not at risk for adverse event assessment.
Arm/Group Title	IBR+OB	CLB+OB
Arm/Group Description	Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.	Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
All-Cause Mortality
	IBR+OB	CLB+OB
	Affected / at Risk (%)	Affected / at Risk (%)
Total	22/113 (19.47%)	21/115 (18.26%)
Serious Adverse Events
	IBR+OB	CLB+OB
	Affected / at Risk (%)	Affected / at Risk (%)
Total	69/113 (61.06%)	41/115 (35.65%)
Blood and lymphatic system disorders
Anaemia † 1	1/113 (0.88%)	2/115 (1.74%)
Aplastic anaemia † 1	1/113 (0.88%)	0/115 (0.00%)
Febrile neutropenia † 1	5/113 (4.42%)	7/115 (6.09%)
Leukopenia † 1	1/113 (0.88%)	0/115 (0.00%)
Neutropenia † 1	2/113 (1.77%)	0/115 (0.00%)
Thrombocytopenia † 1	3/113 (2.65%)	1/115 (0.87%)
Cardiac disorders
Acute coronary syndrome † 1	3/113 (2.65%)	0/115 (0.00%)
Acute myocardial infarction † 1	1/113 (0.88%)	1/115 (0.87%)
Angina pectoris † 1	2/113 (1.77%)	0/115 (0.00%)
Atrial fibrillation † 1	6/113 (5.31%)	0/115 (0.00%)
Atrial tachycardia † 1	1/113 (0.88%)	0/115 (0.00%)
Cardiac arrest † 1	2/113 (1.77%)	0/115 (0.00%)
Cardiac failure † 1	1/113 (0.88%)	0/115 (0.00%)
Cardiac failure congestive † 1	1/113 (0.88%)	0/115 (0.00%)
Myocardial infarction † 1	1/113 (0.88%)	0/115 (0.00%)
Myocardial ischaemia † 1	0/113 (0.00%)	1/115 (0.87%)
Pericarditis † 1	1/113 (0.88%)	0/115 (0.00%)
Pericarditis constrictive † 1	0/113 (0.00%)	1/115 (0.87%)
Stress cardiomyopathy † 1	1/113 (0.88%)	0/115 (0.00%)
Endocrine disorders
Goitre † 1	1/113 (0.88%)	0/115 (0.00%)
Eye disorders
Cataract † 1	1/113 (0.88%)	0/115 (0.00%)
Retinal detachment † 1	1/113 (0.88%)	0/115 (0.00%)
Gastrointestinal disorders
Abdominal pain † 1	2/113 (1.77%)	0/115 (0.00%)
Constipation † 1	0/113 (0.00%)	1/115 (0.87%)
Diarrhea † 1	1/113 (0.88%)	0/115 (0.00%)
Dyspepsia † 1	1/113 (0.88%)	0/115 (0.00%)
Gastritis † 1	1/113 (0.88%)	0/115 (0.00%)
Haemorrhoids † 1	1/113 (0.88%)	0/115 (0.00%)
Impaired gastric emptying † 1	1/113 (0.88%)	0/115 (0.00%)
Inguinal hernia † 1	1/113 (0.88%)	0/115 (0.00%)
Large intestine polyp † 1	1/113 (0.88%)	0/115 (0.00%)
Nausea † 1	0/113 (0.00%)	2/115 (1.74%)
Oesophageal rupture † 1	1/113 (0.88%)	0/115 (0.00%)
Proctitis † 1	1/113 (0.88%)	0/115 (0.00%)
Small intestinal obstruction † 1	1/113 (0.88%)	1/115 (0.87%)
Stomatitis † 1	1/113 (0.88%)	0/115 (0.00%)
General disorders
Catheter site haematoma † 1	1/113 (0.88%)	0/115 (0.00%)
Death † 1	2/113 (1.77%)	0/115 (0.00%)
Multi-organ disorder † 1	1/113 (0.88%)	0/115 (0.00%)
Pyrexia † 1	4/113 (3.54%)	4/115 (3.48%)
Sudden Death † 1	1/113 (0.88%)	0/115 (0.00%)
Hepatobiliary disorders
Cholecystitis † 1	0/113 (0.00%)	1/115 (0.87%)
Cholelithiasis † 1	1/113 (0.88%)	0/115 (0.00%)
Infections and infestations
Abscess † 1	1/113 (0.88%)	0/115 (0.00%)
Bacterial sepsis † 1	1/113 (0.88%)	0/115 (0.00%)
Bronchitis † 1	1/113 (0.88%)	0/115 (0.00%)
Bronchopulmonary aspergillosis † 1	1/113 (0.88%)	0/115 (0.00%)
Bursitis infective staphylococcal † 1	1/113 (0.88%)	0/115 (0.00%)
Cellulitis † 1	1/113 (0.88%)	0/115 (0.00%)
Erysipelas † 1	1/113 (0.88%)	0/115 (0.00%)
Escherichia sepsis † 1	1/113 (0.88%)	0/115 (0.00%)
Escherichia urinary tract infection † 1	1/113 (0.88%)	0/115 (0.00%)
Gastroenteritis † 1	3/113 (2.65%)	1/115 (0.87%)
Herpes Zoster † 1	1/113 (0.88%)	0/115 (0.00%)
Infective aneurysm † 1	1/113 (0.88%)	0/115 (0.00%)
Listeria sepsis † 1	1/113 (0.88%)	0/115 (0.00%)
Lower respiratory tract infection † 1	1/113 (0.88%)	0/115 (0.00%)
Pharyngitis † 1	1/113 (0.88%)	1/115 (0.87%)
Pneumocystis jirovecii pneumonia † 1	1/113 (0.88%)	0/115 (0.00%)
Pneumonia † 1	8/113 (7.08%)	5/115 (4.35%)
Pneumonia bacterial † 1	1/113 (0.88%)	0/115 (0.00%)
Pneumonia klebsiella † 1	1/113 (0.88%)	0/115 (0.00%)
Prostate infection † 1	1/113 (0.88%)	0/115 (0.00%)
Respiratory tract infection † 1	2/113 (1.77%)	0/115 (0.00%)
Sepsis † 1	0/113 (0.00%)	2/115 (1.74%)
Septic shock † 1	2/113 (1.77%)	0/115 (0.00%)
Sinusitis fungal † 1	1/113 (0.88%)	0/115 (0.00%)
Soft tissue infection † 1	1/113 (0.88%)	0/115 (0.00%)
Streptococcal bacteraemia † 1	1/113 (0.88%)	0/115 (0.00%)
Upper respiratory tract infection † 1	1/113 (0.88%)	0/115 (0.00%)
Urinary tract infection † 1	3/113 (2.65%)	1/115 (0.87%)
Urosepsis † 1	1/113 (0.88%)	0/115 (0.00%)
Vascular device infection † 1	0/113 (0.00%)	1/115 (0.87%)
Injury, poisoning and procedural complications
Accidental overdose † 1	0/113 (0.00%)	1/115 (0.87%)
Concussion † 1	1/113 (0.88%)	1/115 (0.87%)
Craniocerebral injury † 1	0/113 (0.00%)	1/115 (0.87%)
Femur fracture † 1	2/113 (1.77%)	0/115 (0.00%)
Hip fracture † 1	0/113 (0.00%)	1/115 (0.87%)
Incisional hernia † 1	1/113 (0.88%)	0/115 (0.00%)
Infusion related reaction † 1	2/113 (1.77%)	8/115 (6.96%)
Jaw fracture † 1	1/113 (0.88%)	0/115 (0.00%)
Pubis fracture † 1	1/113 (0.88%)	0/115 (0.00%)
Rib fracture † 1	1/113 (0.88%)	0/115 (0.00%)
Spinal compression fracture † 1	1/113 (0.88%)	0/115 (0.00%)
Thoracic vertebral fracture † 1	1/113 (0.88%)	0/115 (0.00%)
Traumatic haematoma † 1	1/113 (0.88%)	0/115 (0.00%)
Upper limb fracture † 1	1/113 (0.88%)	0/115 (0.00%)
Metabolism and nutrition disorders
Dehydration † 1	0/113 (0.00%)	1/115 (0.87%)
Diabetes mellitus inadequate control † 1	1/113 (0.88%)	0/115 (0.00%)
Hypercalcaemia † 1	1/113 (0.88%)	0/115 (0.00%)
Hypokalaemia † 1	1/113 (0.88%)	0/115 (0.00%)
Hypomagnesaemia † 1	1/113 (0.88%)	0/115 (0.00%)
Hyponatraemia † 1	0/113 (0.00%)	1/115 (0.87%)
Tumour lysis syndrome † 1	0/113 (0.00%)	5/115 (4.35%)
Musculoskeletal and connective tissue disorders
Arthritis † 1	1/113 (0.88%)	0/115 (0.00%)
Compartment syndrome † 1	1/113 (0.88%)	0/115 (0.00%)
Inclusion body myositis † 1	1/113 (0.88%)	0/115 (0.00%)
Osteoarthritis † 1	2/113 (1.77%)	0/115 (0.00%)
Osteolysis † 1	0/113 (0.00%)	1/115 (0.87%)
Osteonecrosis of jaw † 1	0/113 (0.00%)	1/115 (0.87%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma gastric † 1	1/113 (0.88%)	0/115 (0.00%)
Adenocarcinoma of colon † 1	3/113 (2.65%)	0/115 (0.00%)
Basal cell carcinoma † 1	1/113 (0.88%)	0/115 (0.00%)
Benign renal neoplasm † 1	1/113 (0.88%)	0/115 (0.00%)
Chronic lymphocytic leukaemia † 1	0/113 (0.00%)	1/115 (0.87%)
Colorectal cancer † 1	1/113 (0.88%)	0/115 (0.00%)
Colorectal cancer metastatic † 1	1/113 (0.88%)	0/115 (0.00%)
Essential thrombocythaemia † 1	0/113 (0.00%)	1/115 (0.87%)
Invasive ductal breast carcinoma † 1	1/113 (0.88%)	0/115 (0.00%)
Kaposi's sarcoma † 1	0/113 (0.00%)	1/115 (0.87%)
Keratoacanthoma † 1	0/113 (0.00%)	1/115 (0.87%)
Malignant melanoma † 1	1/113 (0.88%)	0/115 (0.00%)
Myelodysplastic syndrome † 1	1/113 (0.88%)	0/115 (0.00%)
Neuroendocrine carcinoma of the skin † 1	0/113 (0.00%)	1/115 (0.87%)
Non-small cell lung cancer † 1	1/113 (0.88%)	0/115 (0.00%)
Osteoma † 1	1/113 (0.88%)	0/115 (0.00%)
Prostate Cancer † 1	0/113 (0.00%)	1/115 (0.87%)
Squamous cell carcinoma † 1	1/113 (0.88%)	0/115 (0.00%)
Nervous system disorders
Cerebral ischaemia † 1	1/113 (0.88%)	0/115 (0.00%)
Cerebrovascular accident † 1	2/113 (1.77%)	0/115 (0.00%)
Depressed level of consciousness † 1	1/113 (0.88%)	0/115 (0.00%)
Headache † 1	0/113 (0.00%)	1/115 (0.87%)
Ischaemic stroke † 1	1/113 (0.88%)	0/115 (0.00%)
Loss of consciousness † 1	0/113 (0.00%)	1/115 (0.87%)
Seizure † 1	0/113 (0.00%)	1/115 (0.87%)
Syncope † 1	1/113 (0.88%)	0/115 (0.00%)
Transient ischaemic attack † 1	2/113 (1.77%)	0/115 (0.00%)
Psychiatric disorders
Acute psychosis † 1	1/113 (0.88%)	0/115 (0.00%)
Complete Suicide † 1	1/113 (0.88%)	0/115 (0.00%)
Confusional state † 1	1/113 (0.88%)	0/115 (0.00%)
Renal and urinary disorders
Acute kidney injury † 1	2/113 (1.77%)	1/115 (0.87%)
Nephrolithiasis † 1	1/113 (0.88%)	0/115 (0.00%)
Renal failure † 1	2/113 (1.77%)	0/115 (0.00%)
Urinary retention † 1	1/113 (0.88%)	1/115 (0.87%)
Reproductive system and breast disorders
Benign prostatic hyperplasia † 1	1/113 (0.88%)	0/115 (0.00%)
Uterine prolapse † 1	1/113 (0.88%)	0/115 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure † 1	0/113 (0.00%)	1/115 (0.87%)
Bronchitis chronic † 1	1/113 (0.88%)	0/115 (0.00%)
Haemoptysis † 1	1/113 (0.88%)	0/115 (0.00%)
Pleural effusion † 1	1/113 (0.88%)	0/115 (0.00%)
Productive cough † 1	1/113 (0.88%)	0/115 (0.00%)
Pulmonary embolism † 1	0/113 (0.00%)	1/115 (0.87%)
Respiratory failure † 1	1/113 (0.88%)	1/115 (0.87%)
Vascular disorders
Hypertension † 1	0/113 (0.00%)	1/115 (0.87%)
Peripheral ischaemia † 1	1/113 (0.88%)	0/115 (0.00%)
Venous thrombosis limb † 1	0/113 (0.00%)	1/115 (0.87%)
1 Term from vocabulary, MedDRA Version 22.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	IBR+OB	CLB+OB
	Affected / at Risk (%)	Affected / at Risk (%)
Total	112/113 (99.12%)	111/115 (96.52%)
Blood and lymphatic system disorders
Anaemia † 1	19/113 (16.81%)	29/115 (25.22%)
Increased tendency to bruise † 1	6/113 (5.31%)	0/115 (0.00%)
Neutropenia † 1	50/113 (44.25%)	73/115 (63.48%)
Spontaneous haematoma † 1	10/113 (8.85%)	1/115 (0.87%)
Thrombocytopenia † 1	39/113 (34.51%)	29/115 (25.22%)
Cardiac disorders
Atrial fibrillation † 1	16/113 (14.16%)	0/115 (0.00%)
Palpitations † 1	7/113 (6.19%)	3/115 (2.61%)
Eye disorders
Cataract † 1	11/113 (9.73%)	1/115 (0.87%)
Dry eye † 1	7/113 (6.19%)	3/115 (2.61%)
Lacrimation increased † 1	8/113 (7.08%)	5/115 (4.35%)
Vision blurred † 1	9/113 (7.96%)	7/115 (6.09%)
Gastrointestinal disorders
Abdominal pain † 1	9/113 (7.96%)	6/115 (5.22%)
Constipation † 1	19/113 (16.81%)	14/115 (12.17%)
Diarrhea † 1	39/113 (34.51%)	12/115 (10.43%)
Dyspepsia † 1	9/113 (7.96%)	2/115 (1.74%)
Gastrooesophageal reflux disease † 1	8/113 (7.08%)	3/115 (2.61%)
Nausea † 1	15/113 (13.27%)	34/115 (29.57%)
Stomatitis † 1	7/113 (6.19%)	1/115 (0.87%)
Vomiting † 1	12/113 (10.62%)	14/115 (12.17%)
General disorders
Asthenia † 1	12/113 (10.62%)	17/115 (14.78%)
Chills † 1	7/113 (6.19%)	10/115 (8.70%)
Fatigue † 1	22/113 (19.47%)	19/115 (16.52%)
Oedema peripheral † 1	14/113 (12.39%)	8/115 (6.96%)
Peripheral swelling † 1	7/113 (6.19%)	2/115 (1.74%)
Pyrexia † 1	19/113 (16.81%)	28/115 (24.35%)
Infections and infestations
Bronchitis † 1	8/113 (7.08%)	2/115 (1.74%)
Cellulitis † 1	6/113 (5.31%)	3/115 (2.61%)
Conjunctivitis † 1	12/113 (10.62%)	2/115 (1.74%)
Herpes zoster † 1	6/113 (5.31%)	3/115 (2.61%)
Nasopharyngitis † 1	15/113 (13.27%)	4/115 (3.48%)
Oral herpes † 1	1/113 (0.88%)	6/115 (5.22%)
Pneumonia † 1	12/113 (10.62%)	5/115 (4.35%)
Respiratory tract infection † 1	8/113 (7.08%)	1/115 (0.87%)
Upper respiratory tract infection † 1	18/113 (15.93%)	7/115 (6.09%)
Urinary tract infection † 1	13/113 (11.50%)	7/115 (6.09%)
Injury, poisoning and procedural complications
Contusion † 1	6/113 (5.31%)	1/115 (0.87%)
Fall † 1	10/113 (8.85%)	3/115 (2.61%)
Infusion related reaction † 1	26/113 (23.01%)	61/115 (53.04%)
Investigations
Blood creatine increased † 1	8/113 (7.08%)	1/115 (0.87%)
Weight decreased † 1	3/113 (2.65%)	6/115 (5.22%)
Metabolism and nutrition disorders
Decreased appetite † 1	11/113 (9.73%)	5/115 (4.35%)
Hyperglycaemia † 1	6/113 (5.31%)	7/115 (6.09%)
Hyperuricaemia † 1	15/113 (13.27%)	0/115 (0.00%)
Hypokalaemia † 1	7/113 (6.19%)	2/115 (1.74%)
Iron deficiency † 1	9/113 (7.96%)	0/115 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	27/113 (23.89%)	12/115 (10.43%)
Back pain † 1	21/113 (18.58%)	12/115 (10.43%)
Muscle spasms † 1	16/113 (14.16%)	7/115 (6.09%)
Musculoskeletal pain † 1	6/113 (5.31%)	3/115 (2.61%)
Myalgia † 1	7/113 (6.19%)	4/115 (3.48%)
Pain in extremity † 1	12/113 (10.62%)	10/115 (8.70%)
Nervous system disorders
Dizziness † 1	12/113 (10.62%)	7/115 (6.09%)
Headache † 1	9/113 (7.96%)	13/115 (11.30%)
Tremor † 1	4/113 (3.54%)	7/115 (6.09%)
Psychiatric disorders
Anxiety † 1	10/113 (8.85%)	8/115 (6.96%)
Depression † 1	7/113 (6.19%)	1/115 (0.87%)
Insomnia † 1	13/113 (11.50%)	5/115 (4.35%)
Renal and urinary disorders
Haematuria † 1	6/113 (5.31%)	0/115 (0.00%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	33/113 (29.20%)	14/115 (12.17%)
Dyspnoea † 1	12/113 (10.62%)	15/115 (13.04%)
Epistaxis † 1	7/113 (6.19%)	9/115 (7.83%)
Oropharyngeal pain † 1	8/113 (7.08%)	4/115 (3.48%)
Productive cough † 1	8/113 (7.08%)	2/115 (1.74%)
Skin and subcutaneous tissue disorders
Dry Skin † 1	7/113 (6.19%)	0/115 (0.00%)
Ecchymosis † 1	7/113 (6.19%)	0/115 (0.00%)
Onychoclasis † 1	7/113 (6.19%)	0/115 (0.00%)
Petechiae † 1	6/113 (5.31%)	0/115 (0.00%)
Pruritus † 1	9/113 (7.96%)	4/115 (3.48%)
Rash † 1	10/113 (8.85%)	1/115 (0.87%)
Rash maculo-papular † 1	17/113 (15.04%)	2/115 (1.74%)
Vascular disorders
Hypertension † 1	22/113 (19.47%)	5/115 (4.35%)
Hypotension † 1	1/113 (0.88%)	6/115 (5.22%)
1 Term from vocabulary, MedDRA Version 22.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

1. Institution/Investigator will not publish without Sponsor prior review and approval
2. Institution/Investigator will not publish until the earlier of (i) results of study are submitted for publication (ii) notification that submission of the multicenter results are no longer planned (iii) 18 months after study termination.

Results Point of Contact

• Name/Title: Lori Styles
• Organization: Pharmacyclics LLC, An AbbVie Company
• Phone: (408) 215-3770
• EMail: lstyles@pcyc.com

Publications of Results:

Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, Simkovic M, Samoilova O, Novak J, Ben-Yehuda D, Strugov V, Gill D, Gribben JG, Hsu E, Lih CJ, Zhou C, Clow F, James DF, Styles L, Flinn IW. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jan;20(1):43-56. doi: 10.1016/S1470-2045(18)30788-5. Epub 2018 Dec 3. Erratum In: Lancet Oncol. 2019 Jan;20(1):e10.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, Simkovic M, Novak J, Strugov V, Gill D, Gribben JG, Kwei K, Dai S, Hsu E, Dean JP, Flinn IW. First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase III iLLUMINATE trial. Haematologica. 2022 Sep 1;107(9):2108-2120. doi: 10.3324/haematol.2021.279012.

Burger JA, Robak T, Demirkan F, Bairey O, Moreno C, Simpson D, Munir T, Stevens DA, Dai S, Cheung LWK, Kwei K, Lal I, Hsu E, Kipps TJ, Tedeschi A. Up to 6.5 years (median 4 years) of follow-up of first-line ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and high-risk genomic features: integrated analysis of two phase 3 studies. Leuk Lymphoma. 2022 Jun;63(6):1375-1386. doi: 10.1080/10428194.2021.2020779. Epub 2022 Jan 11.

Allan JN, Shanafelt T, Wiestner A, Moreno C, O'Brien SM, Li J, Krigsfeld G, Dean JP, Ahn IE. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials. Br J Haematol. 2022 Feb;196(4):947-953. doi: 10.1111/bjh.17984. Epub 2021 Dec 5.

Greil R, Tedeschi A, Moreno C, Anz B, Larratt L, Simkovic M, Gill D, Gribben JG, Flinn IW, Wang Z, Cheung LWK, Nguyen AN, Zhou C, Styles L, Demirkan F. Pretreatment with ibrutinib reduces cytokine secretion and limits the risk of obinutuzumab-induced infusion-related reactions in patients with CLL: analysis from the iLLUMINATE study. Ann Hematol. 2021 Jul;100(7):1733-1742. doi: 10.1007/s00277-021-04536-6. Epub 2021 May 20.

• Responsible Party: Pharmacyclics LLC.
• ClinicalTrials.gov Identifier: NCT02264574
• Other Study ID Numbers: PCYC-1130-CA
• First Submitted: October 1, 2014
• First Posted: October 15, 2014
• Results First Submitted: March 25, 2019
• Results First Posted: April 16, 2019
• Last Update Posted: September 21, 2020