Ibrutinib With Rituximab in Adults With Waldenström's Macroglobulinemia

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ClinicalTrials.gov Identifier: NCT02165397

Recruitment Status : Completed

First Posted : June 17, 2014

Results First Posted : November 16, 2020

Last Update Posted : March 3, 2021

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Sponsor:

Collaborator:

Janssen Research & Development, LLC

Information provided by (Responsible Party):

Pharmacyclics LLC.

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
Condition	Waldenström's Macroglobulinemia
Interventions	Drug: Ibrutinib Drug: Placebo Drug: Rituximab
Enrollment	181

Participant Flow

Recruitment Details	This study was conducted in 48 sites (10 in the United States, 30 in Europe, 4 in Canada and 4 in Australia).
Pre-assignment Details	Participants were randomized in a 1:1 ratio to receive ibrutinib + rituximab (Ibr+R) or placebo + rituximab (Pbo+R). Separately, participants refractory to treatment with rituximab were enrolled in an open-label ibrutinib monotherapy substudy to further investigate the safety and efficacy of ibrutinib.


Arm/Group Title	Ibrutinib + Rituximab	Placebo + Rituximab	Open-Label Substudy: Ibrutinib
Arm/Group Description	Ibrutinib: 420 mg (3 capsules) oral...	Placebo: 3 capsules of placebo oral...	Ibrutinib: 420 mg (3 capsules) oral...
Arm/Group Description	Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m^2 intravenous (IV) per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Participants (rituximab refractory) were treated in an open-label substudy independently of the 2 randomized main treatment arms.
Period Title: Overall Study
Started	75	75	31
Completed ^[1]	61	56	21
Not Completed	14	19	10
Reason Not Completed
Death	7	10	8
Lost to Follow-up	1	3	0
Withdrawal by Subject	6	6	1
Other, Not Specified	0	0	1
[1] On-study until study termination by sponsor.

Baseline Characteristics

Arm/Group Title		Ibrutinib + Rituximab	Placebo + Rituximab	Open-Label Substudy: Ibrutinib	Total
Arm/Group Description		Ibrutinib: 420 mg (3 capsules) oral...	Placebo: 3 capsules of placebo oral...	Ibrutinib: 420 mg (3 capsules) oral...	Total of all reporting groups
Arm/Group Description		Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Participants (rituximab refractory) were treated in an open-label substudy independently of the 2 randomized main treatment arms.	Total of all reporting groups
Overall Number of Baseline Participants		75	75	31	181
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Customized Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	75 participants	75 participants	31 participants	181 participants
< 65 years old		28 37.3%	30 40.0%	14 45.2%	72 39.8%
>= 65 years old		47 62.7%	45 60.0%	17 54.8%	109 60.2%
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	75 participants	75 participants	31 participants	181 participants
	Female	30 40.0%	21 28.0%	11 35.5%	62 34.3%
	Male	45 60.0%	54 72.0%	20 64.5%	119 65.7%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	75 participants	75 participants	31 participants	181 participants
	Hispanic or Latino	3 4.0%	1 1.3%	1 3.2%	5 2.8%
	Not Hispanic or Latino	72 96.0%	74 98.7%	30 96.8%	176 97.2%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	75 participants	75 participants	31 participants	181 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	3 4.0%	0 0.0%	2 6.5%	5 2.8%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	1 1.3%	1 1.3%	0 0.0%	2 1.1%
	White	58 77.3%	60 80.0%	26 83.9%	144 79.6%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	13 17.3%	14 18.7%	3 9.7%	30 16.6%

Outcome Measures

1.Primary Outcome


Title	Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 54
Description	PFS was defined as the time from date randomization to date of first I...
Description	PFS was defined as the time from date randomization to date of first IRC-confirmed disease progression (PD) assessed according to the modified VIth International Workshop on Waldenström's Macroglobulinemia (IWWM) criteria (National Comprehensive Cancer Network [NCCN] 2014) or death due to any cause, whichever occurs first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. As the median PFS was not reached in the Ibrutinib + Rituximab arm at the time of the analysis, Kaplan Meier landmark estimate of the PFS rate at 54 months (that is, the estimated percentage of participants with PFS at Month 54) is presented.
Time Frame	Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])

Outcome Measure Data

Analysis Population Description

Intent to Treat population: all randomized/enrolled participants


Arm/Group Title	Ibrutinib + Rituximab	Placebo + Rituximab	Open-Label Substudy: Ibrutinib
Arm/Group Description:	Ibrutinib: 420 mg (3 capsules) oral...	Placebo: 3 capsules of placebo oral...	Ibrutinib: 420 mg (3 capsules) oral...
Arm/Group Description:	Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Participants (rituximab refractory) were treated in an open-label substudy independently of the 2 randomized main treatment arms.
Overall Number of Participants Analyzed	75	75	31
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
	68.0 (54.8 to 78.1)	25.3 (15.3 to 36.6)	39.7 (22.3 to 56.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Rituximab, Placebo + Rituximab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The treatment effect was tested with a stratified log rank test.
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.250
	Confidence Interval	(2-Sided) 95% 0.148 to 0.420
	Estimation Comments	The hazard ratio and its 95% confidence interval were based on a Cox regression model stratified by the randomization stratification factors.

2.Secondary Outcome


Title	Overall Response Rate (ORR) Based on IRC Assessment Up to 3 Years After Last Participant Randomized
Description	ORR, defined as the percentage of participants achieving a best overal...
Description	ORR, defined as the percentage of participants achieving a best overall response of protocol-specified complete response (CR), very good partial response (VGPR), or partial response (PR) per the IRC assessment at or prior to initiation of subsequent antineoplastic therapy and confirmed by 2 consecutive assessments. IRC assessment of response was conducted according to the modified VIth IWWM (NCCN 2014) criteria and incorporated assessments from the central radiology review. CR required complete resolution of lymphadenopathy/splenomegaly if present at baseline. VGPR and PR required reduction in lymphadenopathy/splenomegaly if present at baseline.. Kaplan-Meier estimate.
Time Frame	Median time on study: 49.7 months (Ibr+R and Pbo+R) and 57.9 months (Open-Label Ibr)

Outcome Measure Data

Analysis Population Description

Intent to Treat population: all randomized/enrolled participants


Arm/Group Title	Ibrutinib + Rituximab	Placebo + Rituximab	Open-Label Substudy: Ibrutinib
Arm/Group Description:	Ibrutinib: 420 mg (3 capsules) oral...	Placebo: 3 capsules of placebo oral...	Ibrutinib: 420 mg (3 capsules) oral...
Arm/Group Description:	Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Participants (rituximab refractory) were treated in an open-label substudy independently of the 2 randomized main treatment arms.
Overall Number of Participants Analyzed	75	75	31
Measure Type: Number Unit of Measure: percentage of participants
	76.0	30.7	77.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Rituximab, Placebo + Rituximab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	Response rate was compared using Cochran-Mantel-Haenszel (CMH) chi-square test.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	2.526
	Confidence Interval	(2-Sided) 95% 1.753 to 3.639
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Time to Next Treatment (TnT) Time From the Date of Randomization to the Start Date of Any Subsequent WM Treatment.
Description	TTnT was measured from the date of randomization to the start date of ...
Description	TTnT was measured from the date of randomization to the start date of any subsequent WM treatment. Participants without subsequent treatment were censored at the date of the last study visit. As the median TTnT was not reached in the Ibrutinib + Rituximab arm and the Open-Label Substudy arm at the time of the analysis, Kaplan Meier landmark estimate of the TTnT rate at 54 months (that is, the estimated percentage of participants not receiving subsequent WM treatment at Month 54) are presented.
Time Frame	Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])

Outcome Measure Data

Analysis Population Description

Intent to Treat population: all randomized/enrolled participants


Arm/Group Title	Ibrutinib + Rituximab	Placebo + Rituximab	Open-Label Substudy: Ibrutinib
Arm/Group Description:	Ibrutinib: 420 mg (3 capsules) oral...	Placebo: 3 capsules of placebo oral...	Ibrutinib: 420 mg (3 capsules) oral...
Arm/Group Description:	Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Participants (rituximab refractory) were treated in an open-label substudy independently of the 2 randomized main treatment arms.
Overall Number of Participants Analyzed	75	75	31
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
	87.4 (77.2 to 93.3)	29.4 (18.2 to 41.6)	64.6 (44.1 to 79.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Rituximab, Placebo + Rituximab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	P-value is from a stratified log-rank test.
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.102
	Confidence Interval	(2-Sided) 95% 0.049 to 0.212
	Estimation Comments	Hazard ratio is estimated using a stratified Cox regression model.

4.Secondary Outcome


Title	Percentage of Participants With Sustained Hemoglobin (Hgb) Improvement Up to 3 Years After Last Participant Randomized
Description	Percentage of participants achieving a sustained improvement in Hgb at...
Description	Percentage of participants achieving a sustained improvement in Hgb at or prior to initiation of subsequent antineoplastic therapy. Hgb improvement is defined as an increase of ≥ 2 g/dL over baseline regardless of baseline value, or an increase to >11 g/dL with a ≥0.5 g/dL improvement if baseline is ≤ 11 g/dL. Sustained Hgb improvement is defined as improvement that is sustained continuously for ≥ 56 days (8 weeks) without blood transfusion or growth factors, which includes hemoglobin > 110 g/L with at least a 5 g/L improvement if baseline ≤110 g/L or increase ≥20 g/L over baseline.
Time Frame	Median time on study: 49.7 months (Ibr+R and Pbo+R) and 57.9 months (Open-Label Ibr)

Outcome Measure Data

Analysis Population Description

Intent to Treat population: all randomized/enrolled participants


Arm/Group Title	Ibrutinib + Rituximab	Placebo + Rituximab	Open-Label Substudy: Ibrutinib
Arm/Group Description:	Ibrutinib: 420 mg (3 capsules) oral...	Placebo: 3 capsules of placebo oral...	Ibrutinib: 420 mg (3 capsules) oral...
Arm/Group Description:	Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Participants (rituximab refractory) were treated in an open-label substudy independently of the 2 randomized main treatment arms.
Overall Number of Participants Analyzed	75	75	31
Measure Type: Number Unit of Measure: percentage of participants
	77.3	42.7	71.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Rituximab, Placebo + Rituximab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	1.813
	Confidence Interval	(2-Sided) 95% 1.357 to 2.421
	Estimation Comments	[Not Specified]

5.Secondary Outcome


Title	Percentage of Participants With ≥ 3 Points Increase From Baseline by Week 25 in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Subscale Score
Description	Percentage of participants with ≥ 3 points increase from baselin...
Description	Percentage of participants with ≥ 3 points increase from baseline by Week 25 in the FACIT-Fatigue subscale score.The FACIT-Fatigue is a 13-item questionnaire that assesses participant reported fatigue and its impact upon daily activities and function over the past 7 days. Each of the 13 items of the FACIT-Fatigue Scale ranges from 0-4, with a range of possible total scores from 0 (extreme fatigue) to 52 (no fatigue). Scores below 30 indicate severe fatigue.
Time Frame	Baseline, 25 weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat population: all randomized/enrolled participants


Arm/Group Title	Ibrutinib + Rituximab	Placebo + Rituximab	Open-Label Substudy: Ibrutinib
Arm/Group Description:	Ibrutinib: 420 mg (3 capsules) oral...	Placebo: 3 capsules of placebo oral...	Ibrutinib: 420 mg (3 capsules) oral...
Arm/Group Description:	Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Participants (rituximab refractory) were treated in an open-label substudy independently of the 2 randomized main treatment arms.
Overall Number of Participants Analyzed	75	75	31
Measure Type: Number Unit of Measure: percentage of participants
	68.0	54.7	87.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Rituximab, Placebo + Rituximab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1059
	Comments	CMH chi squared test
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	1.238
	Confidence Interval	(2-Sided) 95% 0.955 to 1.603
	Estimation Comments	[Not Specified]

6.Secondary Outcome


Title	Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 54
Description	OS, defined as the time from the date of randomization to the date of ...
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 any 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 54) are presented.
Time Frame	Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])

Outcome Measure Data

Analysis Population Description

Intent to Treat population: all randomized/enrolled participants


Arm/Group Title	Ibrutinib + Rituximab	Placebo + Rituximab	Open-Label Substudy: Ibrutinib
Arm/Group Description:	Ibrutinib: 420 mg (3 capsules) oral...	Placebo: 3 capsules of placebo oral...	Ibrutinib: 420 mg (3 capsules) oral...
Arm/Group Description:	Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Participants (rituximab refractory) were treated in an open-label substudy independently of the 2 randomized main treatment arms.
Overall Number of Participants Analyzed	75	75	31
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
	86.4 (73.7 to 93.3)	84.2 (71.3 to 91.6)	73.4 (53.7 to 85.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Rituximab, Placebo + Rituximab
	Comments	Data cutoff 18 December 2019
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.643
	Comments	P-value is from unstratified log rank test.
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.808
	Confidence Interval	(2-Sided) 95% 0.328 to 1.99
	Estimation Comments	Hazard ratio is estimated using unstratified Cox regression model with treatment as the only covariate.

Adverse Events

Time Frame	From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Ibrutinib + Rituximab	Placebo + Rituximab	Open-Label Substudy: Ibrutinib
Arm/Group Description	Ibrutinib: 420 mg (3 capsules) oral...	Placebo: 3 capsules of placebo oral...	Ibrutinib: 420 mg (3 capsules) oral...
Arm/Group Description	Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment.
All-Cause Mortality
	Ibrutinib + Rituximab	Placebo + Rituximab	Open-Label Substudy: Ibrutinib
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	9/75 (12.00%)	10/75 (13.33%)	8/31 (25.81%)
Serious Adverse Events Serious Adverse Events
	Ibrutinib + Rituximab	Placebo + Rituximab	Open-Label Substudy: Ibrutinib
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	40/75 (53.33%)	25/75 (33.33%)	16/31 (51.61%)
Blood and lymphatic system disorders
Anaemia ^† 1	2/75 (2.67%)	0/75 (0.00%)	0/31 (0.00%)
Febrile neutropenia ^† 1	0/75 (0.00%)	0/75 (0.00%)	1/31 (3.23%)
Immune thrombocytopenic purpura ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Leukopenia ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Neutropenia ^† 1	0/75 (0.00%)	0/75 (0.00%)	1/31 (3.23%)
Thrombocytopenia ^† 1	0/75 (0.00%)	0/75 (0.00%)	1/31 (3.23%)
Cardiac disorders
Angina pectoris ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Angina unstable ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Atrial fibrillation ^† 1	8/75 (10.67%)	1/75 (1.33%)	0/31 (0.00%)
Cardiac failure ^† 1	2/75 (2.67%)	0/75 (0.00%)	0/31 (0.00%)
Cardiac tamponade ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Coronary artery disease ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Left ventricular failure ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Myocardial infarction ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Myocardial ischaemia ^† 1	2/75 (2.67%)	0/75 (0.00%)	0/31 (0.00%)
Pericarditis ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Prinzmetal angina ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Congenital, familial and genetic disorders
Hypertrophic cardiomyopathy ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Eye disorders
Ulcerative keratitis ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Gastrointestinal disorders
Abdominal pain ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Abdominal pain upper ^† 1	0/75 (0.00%)	0/75 (0.00%)	1/31 (3.23%)
Constipation ^† 1	1/75 (1.33%)	1/75 (1.33%)	1/31 (3.23%)
Diarrhoea ^† 1	0/75 (0.00%)	1/75 (1.33%)	1/31 (3.23%)
Faecalith ^† 1	0/75 (0.00%)	0/75 (0.00%)	1/31 (3.23%)
Gastrointestinal haemorrhage ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Ileus ^† 1	0/75 (0.00%)	0/75 (0.00%)	1/31 (3.23%)
Melaena ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
General disorders
Asthenia ^† 1	0/75 (0.00%)	0/75 (0.00%)	1/31 (3.23%)
Death ^† 1 [1]	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Fatigue ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Gait disturbance ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
General physical health deterioration ^† 1	1/75 (1.33%)	1/75 (1.33%)	0/31 (0.00%)
Oedema peripheral ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Pyrexia ^† 1	2/75 (2.67%)	0/75 (0.00%)	0/31 (0.00%)
Hepatobiliary disorders
Cholecystitis ^† 1	1/75 (1.33%)	1/75 (1.33%)	0/31 (0.00%)
Cholecystitis acute ^† 1	1/75 (1.33%)	0/75 (0.00%)	1/31 (3.23%)
Infections and infestations
Arthritis bacterial ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Atypical pneumonia ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Cellulitis ^† 1	2/75 (2.67%)	0/75 (0.00%)	1/31 (3.23%)
Clostridium difficile colitis ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Enterococcal sepsis ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Erysipelas ^† 1	2/75 (2.67%)	0/75 (0.00%)	0/31 (0.00%)
Escherichia sepsis ^† 1	0/75 (0.00%)	0/75 (0.00%)	1/31 (3.23%)
Gastroenteritis ^† 1	2/75 (2.67%)	0/75 (0.00%)	0/31 (0.00%)
Hemianopia ^† 1	0/75 (0.00%)	0/75 (0.00%)	1/31 (3.23%)
Orchitis ^† 1	0/75 (0.00%)	0/75 (0.00%)	1/31 (3.23%)
Osteomyelitis ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Pneumonia ^† 1	8/75 (10.67%)	2/75 (2.67%)	1/31 (3.23%)
Pneumonia bacterial ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Pneumonia pneumococcal ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Pneumonia viral ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Prostatic abscess ^† 1	0/75 (0.00%)	0/75 (0.00%)	1/31 (3.23%)
Pulmonary sepsis ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Respiratory syncytial virus infection ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Respiratory tract infection ^† 1	4/75 (5.33%)	0/75 (0.00%)	1/31 (3.23%)
Sepsis ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Septic shock ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Staphylococcal bacteraemia ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Staphylococcal sepsis ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Streptococcal bacteraemia ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Subcutaneous abscess ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Upper respiratory tract infection ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Urosepsis ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Injury, poisoning and procedural complications
Fall ^† 1	3/75 (4.00%)	0/75 (0.00%)	0/31 (0.00%)
Femur fracture ^† 1	1/75 (1.33%)	0/75 (0.00%)	1/31 (3.23%)
Infusion related reaction ^† 1	0/75 (0.00%)	5/75 (6.67%)	0/31 (0.00%)
Lower limb fracture ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Pelvic fracture ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Spinal compression fracture ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Spinal fracture ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Subdural haematoma ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Tendon injury ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Investigations
Neutrophil count decreased ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Metabolism and nutrition disorders
Dehydration ^† 1	0/75 (0.00%)	1/75 (1.33%)	1/31 (3.23%)
Fluid overload ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Hyponatraemia ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Lactic acidosis ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	3/75 (4.00%)	0/75 (0.00%)	0/31 (0.00%)
Breast cancer metastatic ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Fracture pain ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Joint swelling ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Mobility decreased ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Musculoskeletal chest pain ^† 1	0/75 (0.00%)	0/75 (0.00%)	1/31 (3.23%)
Psoriatic arthropathy ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Soft tissue necrosis ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Synovial cyst ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Tendonitis ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign pancreatic neoplasm ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Bing-Neel syndrome ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Breast cancer ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Diffuse large B-cell lymphoma ^† 1	0/75 (0.00%)	0/75 (0.00%)	1/31 (3.23%)
Invasive lobular breast carcinoma ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Prostate cancer ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Renal cell carcinoma ^† 1	0/75 (0.00%)	0/75 (0.00%)	1/31 (3.23%)
Small cell lung cancer ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Squamous cell carcinoma ^† 1	1/75 (1.33%)	1/75 (1.33%)	0/31 (0.00%)
Nervous system disorders
Aphasia ^† 1	0/75 (0.00%)	0/75 (0.00%)	1/31 (3.23%)
Haemorrhage intracranial ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Lumbar radiculopathy ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Syncope ^† 1	1/75 (1.33%)	0/75 (0.00%)	2/31 (6.45%)
Transient ischaemic attack ^† 1	0/75 (0.00%)	0/75 (0.00%)	1/31 (3.23%)
Renal and urinary disorders
Acute kidney injury ^† 1	2/75 (2.67%)	0/75 (0.00%)	0/31 (0.00%)
Dysuria ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Haematuria ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Urinary retention ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Reproductive system and breast disorders
Prostatitis ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Respiratory, thoracic and mediastinal disorders
Bronchopneumopathy ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Dyspnoea ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Epistaxis ^† 1	1/75 (1.33%)	1/75 (1.33%)	0/31 (0.00%)
Lung disorder ^† 1	2/75 (2.67%)	0/75 (0.00%)	0/31 (0.00%)
Pleural effusion ^† 1	0/75 (0.00%)	1/75 (1.33%)	1/31 (3.23%)
Pulmonary oedema ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Skin and subcutaneous tissue disorders
Eczema ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Purpura ^† 1	1/75 (1.33%)	0/75 (0.00%)	0/31 (0.00%)
Vascular disorders
Circulatory collapse ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
Hypertension ^† 1	1/75 (1.33%)	1/75 (1.33%)	0/31 (0.00%)
Hypotension ^† 1	0/75 (0.00%)	1/75 (1.33%)	0/31 (0.00%)
1 Term from vocabulary, MedDRA 22.1 † Indicates events were collected by systematic assessment [1] Cause of death unknown
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Ibrutinib + Rituximab	Placebo + Rituximab	Open-Label Substudy: Ibrutinib
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	75/75 (100.00%)	75/75 (100.00%)	30/31 (96.77%)
Blood and lymphatic system disorders
Anaemia ^† 1	17/75 (22.67%)	21/75 (28.00%)	5/31 (16.13%)
Increased tendency to bruise ^† 1	9/75 (12.00%)	2/75 (2.67%)	8/31 (25.81%)
Lymphadenopathy ^† 1	0/75 (0.00%)	0/75 (0.00%)	2/31 (6.45%)
Neutropenia ^† 1	12/75 (16.00%)	7/75 (9.33%)	9/31 (29.03%)
Spontaneous haematoma ^† 1	0/75 (0.00%)	0/75 (0.00%)	2/31 (6.45%)
Thrombocytopenia ^† 1	5/75 (6.67%)	8/75 (10.67%)	6/31 (19.35%)
Cardiac disorders
Atrial fibrillation ^† 1	11/75 (14.67%)	1/75 (1.33%)	0/31 (0.00%)
Palpitations ^† 1	4/75 (5.33%)	0/75 (0.00%)	2/31 (6.45%)
Ear and labyrinth disorders
Tinnitus ^† 1	0/75 (0.00%)	0/75 (0.00%)	4/31 (12.90%)
Eye disorders
Cataract ^† 1	7/75 (9.33%)	1/75 (1.33%)	4/31 (12.90%)
Diplopia ^† 1	0/75 (0.00%)	0/75 (0.00%)	2/31 (6.45%)
Dry eye ^† 1	5/75 (6.67%)	5/75 (6.67%)	3/31 (9.68%)
Eye irritation ^† 1	6/75 (8.00%)	1/75 (1.33%)	0/31 (0.00%)
Lacrimation increased ^† 1	9/75 (12.00%)	3/75 (4.00%)	0/31 (0.00%)
Photophobia ^† 1	6/75 (8.00%)	2/75 (2.67%)	0/31 (0.00%)
Vision blurred ^† 1	7/75 (9.33%)	2/75 (2.67%)	4/31 (12.90%)
Visual acuity reduced ^† 1	9/75 (12.00%)	3/75 (4.00%)	0/31 (0.00%)
Vitreous detachment ^† 1	0/75 (0.00%)	0/75 (0.00%)	2/31 (6.45%)
Vitreous floaters ^† 1	4/75 (5.33%)	2/75 (2.67%)	2/31 (6.45%)
Gastrointestinal disorders
Abdominal discomfort ^† 1	0/75 (0.00%)	0/75 (0.00%)	3/31 (9.68%)
Abdominal distension ^† 1	0/75 (0.00%)	0/75 (0.00%)	2/31 (6.45%)
Abdominal pain ^† 1	4/75 (5.33%)	2/75 (2.67%)	4/31 (12.90%)
Abdominal pain upper ^† 1	4/75 (5.33%)	2/75 (2.67%)	2/31 (6.45%)
Constipation ^† 1	9/75 (12.00%)	9/75 (12.00%)	5/31 (16.13%)
Diarrhoea ^† 1	23/75 (30.67%)	11/75 (14.67%)	14/31 (45.16%)
Dry mouth ^† 1	4/75 (5.33%)	0/75 (0.00%)	0/31 (0.00%)
Dyspepsia ^† 1	13/75 (17.33%)	1/75 (1.33%)	2/31 (6.45%)
Gastritis ^† 1	4/75 (5.33%)	0/75 (0.00%)	0/31 (0.00%)
Gastrooesophageal reflux disease ^† 1	7/75 (9.33%)	1/75 (1.33%)	3/31 (9.68%)
Gingival bleeding ^† 1	0/75 (0.00%)	0/75 (0.00%)	2/31 (6.45%)
Nausea ^† 1	17/75 (22.67%)	9/75 (12.00%)	7/31 (22.58%)
Stomatitis ^† 1	4/75 (5.33%)	1/75 (1.33%)	0/31 (0.00%)
Vomiting ^† 1	5/75 (6.67%)	8/75 (10.67%)	0/31 (0.00%)
General disorders
Asthenia ^† 1	12/75 (16.00%)	19/75 (25.33%)	4/31 (12.90%)
Chest pain ^† 1	4/75 (5.33%)	0/75 (0.00%)	0/31 (0.00%)
Chills ^† 1	0/75 (0.00%)	0/75 (0.00%)	2/31 (6.45%)
Fatigue ^† 1	13/75 (17.33%)	18/75 (24.00%)	5/31 (16.13%)
Influenza like illness ^† 1	4/75 (5.33%)	4/75 (5.33%)	0/31 (0.00%)
Oedema peripheral ^† 1	17/75 (22.67%)	9/75 (12.00%)	5/31 (16.13%)
Pyrexia ^† 1	12/75 (16.00%)	12/75 (16.00%)	11/31 (35.48%)
Infections and infestations
Bronchitis ^† 1	11/75 (14.67%)	5/75 (6.67%)	3/31 (9.68%)
Cellulitis ^† 1	4/75 (5.33%)	1/75 (1.33%)	3/31 (9.68%)
Conjunctivitis ^† 1	4/75 (5.33%)	3/75 (4.00%)	4/31 (12.90%)
Folliculitis ^† 1	4/75 (5.33%)	1/75 (1.33%)	0/31 (0.00%)
Herpes zoster ^† 1	6/75 (8.00%)	1/75 (1.33%)	2/31 (6.45%)
Influenza ^† 1	10/75 (13.33%)	5/75 (6.67%)	2/31 (6.45%)
Localised infection ^† 1	0/75 (0.00%)	0/75 (0.00%)	2/31 (6.45%)
Nasopharyngitis ^† 1	12/75 (16.00%)	7/75 (9.33%)	3/31 (9.68%)
Oral herpes ^† 1	6/75 (8.00%)	0/75 (0.00%)	0/31 (0.00%)
Paronychia ^† 1	0/75 (0.00%)	0/75 (0.00%)	2/31 (6.45%)
Pneumonia ^† 1	5/75 (6.67%)	2/75 (2.67%)	2/31 (6.45%)
Respiratory tract infection ^† 1	6/75 (8.00%)	2/75 (2.67%)	5/31 (16.13%)
Respiratory tract infection viral ^† 1	0/75 (0.00%)	0/75 (0.00%)	2/31 (6.45%)
Rhinitis ^† 1	4/75 (5.33%)	1/75 (1.33%)	2/31 (6.45%)
Sinusitis ^† 1	4/75 (5.33%)	2/75 (2.67%)	4/31 (12.90%)
Upper respiratory tract infection ^† 1	10/75 (13.33%)	3/75 (4.00%)	6/31 (19.35%)
Urinary tract infection ^† 1	11/75 (14.67%)	0/75 (0.00%)	3/31 (9.68%)
Injury, poisoning and procedural complications
Contusion ^† 1	7/75 (9.33%)	1/75 (1.33%)	2/31 (6.45%)
Fall ^† 1	7/75 (9.33%)	3/75 (4.00%)	3/31 (9.68%)
Infusion related reaction ^† 1	32/75 (42.67%)	43/75 (57.33%)	0/31 (0.00%)
Traumatic haematoma ^† 1	5/75 (6.67%)	0/75 (0.00%)	0/31 (0.00%)
Investigations
Blood Creatinine Increased ^† 1	5/75 (6.67%)	0/75 (0.00%)	0/31 (0.00%)
Blood Uric Acid Increased ^† 1	4/75 (5.33%)	0/75 (0.00%)	0/31 (0.00%)
Metabolism and nutrition disorders
Decreased appetite ^† 1	3/75 (4.00%)	7/75 (9.33%)	3/31 (9.68%)
Gout ^† 1	4/75 (5.33%)	1/75 (1.33%)	0/31 (0.00%)
Hyperuricaemia ^† 1	4/75 (5.33%)	4/75 (5.33%)	2/31 (6.45%)
Hypokalaemia ^† 1	9/75 (12.00%)	1/75 (1.33%)	2/31 (6.45%)
Hyponatraemia ^† 1	5/75 (6.67%)	2/75 (2.67%)	0/31 (0.00%)
Iron deficiency ^† 1	4/75 (5.33%)	0/75 (0.00%)	0/31 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	19/75 (25.33%)	9/75 (12.00%)	7/31 (22.58%)
Back pain ^† 1	13/75 (17.33%)	7/75 (9.33%)	9/31 (29.03%)
Muscle spasms ^† 1	16/75 (21.33%)	9/75 (12.00%)	5/31 (16.13%)
Muscular weakness ^† 1	0/75 (0.00%)	0/75 (0.00%)	2/31 (6.45%)
Musculoskeletal chest pain ^† 1	0/75 (0.00%)	0/75 (0.00%)	2/31 (6.45%)
Myalgia ^† 1	5/75 (6.67%)	3/75 (4.00%)	2/31 (6.45%)
Osteoarthritis ^† 1	4/75 (5.33%)	1/75 (1.33%)	0/31 (0.00%)
Pain in extremity ^† 1	10/75 (13.33%)	6/75 (8.00%)	5/31 (16.13%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma ^† 1	4/75 (5.33%)	4/75 (5.33%)	0/31 (0.00%)
Tumour flare ^† 1	6/75 (8.00%)	35/75 (46.67%)	0/31 (0.00%)
Nervous system disorders
Dizziness ^† 1	10/75 (13.33%)	6/75 (8.00%)	4/31 (12.90%)
Headache ^† 1	13/75 (17.33%)	17/75 (22.67%)	7/31 (22.58%)
Paraesthesia ^† 1	4/75 (5.33%)	4/75 (5.33%)	2/31 (6.45%)
Peripheral sensory neuropathy ^† 1	5/75 (6.67%)	4/75 (5.33%)	2/31 (6.45%)
Sciatica ^† 1	6/75 (8.00%)	0/75 (0.00%)	3/31 (9.68%)
Psychiatric disorders
Depression ^† 1	0/75 (0.00%)	0/75 (0.00%)	3/31 (9.68%)
Insomnia ^† 1	12/75 (16.00%)	3/75 (4.00%)	2/31 (6.45%)
Renal and urinary disorders
Haematuria ^† 1	0/75 (0.00%)	0/75 (0.00%)	2/31 (6.45%)
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	16/75 (21.33%)	8/75 (10.67%)	9/31 (29.03%)
Dyspnoea ^† 1	8/75 (10.67%)	10/75 (13.33%)	3/31 (9.68%)
Epistaxis ^† 1	8/75 (10.67%)	7/75 (9.33%)	4/31 (12.90%)
Oropharyngeal pain ^† 1	4/75 (5.33%)	2/75 (2.67%)	3/31 (9.68%)
Productive cough ^† 1	3/75 (4.00%)	4/75 (5.33%)	0/31 (0.00%)
Rhinorrhoea ^† 1	5/75 (6.67%)	5/75 (6.67%)	2/31 (6.45%)
Skin and subcutaneous tissue disorders
Actinic keratosis ^† 1	0/75 (0.00%)	0/75 (0.00%)	2/31 (6.45%)
Dermatitis contact ^† 1	0/75 (0.00%)	0/75 (0.00%)	2/31 (6.45%)
Dry skin ^† 1	0/75 (0.00%)	0/75 (0.00%)	6/31 (19.35%)
Ecchymosis ^† 1	9/75 (12.00%)	0/75 (0.00%)	0/31 (0.00%)
Onychoclasis ^† 1	0/75 (0.00%)	0/75 (0.00%)	4/31 (12.90%)
Onycholysis ^† 1	0/75 (0.00%)	0/75 (0.00%)	2/31 (6.45%)
Petechiae ^† 1	7/75 (9.33%)	0/75 (0.00%)	4/31 (12.90%)
Pruritus ^† 1	6/75 (8.00%)	4/75 (5.33%)	2/31 (6.45%)
Psoriasis ^† 1	0/75 (0.00%)	0/75 (0.00%)	2/31 (6.45%)
Rash erythematous ^† 1	7/75 (9.33%)	2/75 (2.67%)	0/31 (0.00%)
Rash maculo-papular ^† 1	5/75 (6.67%)	3/75 (4.00%)	3/31 (9.68%)
Skin lesion ^† 1	4/75 (5.33%)	0/75 (0.00%)	0/31 (0.00%)
Vascular disorders
Hypertension ^† 1	18/75 (24.00%)	3/75 (4.00%)	8/31 (25.81%)
Hypotension ^† 1	0/75 (0.00%)	0/75 (0.00%)	3/31 (9.68%)
1 Term from vocabulary, MedDRA 22.1 † 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.

Institution/Investigator will not publish without Sponsor prior review and approval
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

Layout table for Results Point of Contact information

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

Publications:

Dimopoulos MA, Tedeschi A, Trotman J, Garcia-Sanz R, Macdonald D, Leblond V, Mahe B, Herbaux C, Tam C, Orsucci L, Palomba ML, Matous JV, Shustik C, Kastritis E, Treon SP, Li J, Salman Z, Graef T, Buske C; iNNOVATE Study Group and the European Consortium for Waldenstrom's Macroglobulinemia. Phase 3 Trial of Ibrutinib plus Rituximab in Waldenstrom's Macroglobulinemia. N Engl J Med. 2018 Jun 21;378(25):2399-2410. doi: 10.1056/NEJMoa1802917. Epub 2018 Jun 1.

Dimopoulos MA, Trotman J, Tedeschi A, Matous JV, Macdonald D, Tam C, Tournilhac O, Ma S, Oriol A, Heffner LT, Shustik C, Garcia-Sanz R, Cornell RF, de Larrea CF, Castillo JJ, Granell M, Kyrtsonis MC, Leblond V, Symeonidis A, Kastritis E, Singh P, Li J, Graef T, Bilotti E, Treon S, Buske C; iNNOVATE Study Group and the European Consortium for Waldenstrom's Macroglobulinemia. Ibrutinib for patients with rituximab-refractory Waldenstrom's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Lancet Oncol. 2017 Feb;18(2):241-250. doi: 10.1016/S1470-2045(16)30632-5. Epub 2016 Dec 10.

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

Buske C, Tedeschi A, Trotman J, Garcia-Sanz R, MacDonald D, Leblond V, Mahe B, Herbaux C, Matous JV, Tam CS, Heffner LT, Varettoni M, Palomba ML, Shustik C, Kastritis E, Treon SP, Ping J, Hauns B, Arango-Hisijara I, Dimopoulos MA. Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenstrom's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study. J Clin Oncol. 2022 Jan 1;40(1):52-62. doi: 10.1200/JCO.21.00838. Epub 2021 Oct 4.

Trotman J, Buske C, Tedeschi A, Matous JV, MacDonald D, Tam CS, Tournilhac O, Ma S, Treon SP, Oriol A, Ping J, Briso EM, Arango-Hisijara I, Dimopoulos MA. Single-Agent Ibrutinib for Rituximab-Refractory Waldenstrom Macroglobulinemia: Final Analysis of the Substudy of the Phase III InnovateTM Trial. Clin Cancer Res. 2021 Nov 1;27(21):5793-5800. doi: 10.1158/1078-0432.CCR-21-1497. Epub 2021 Aug 11.

Layout table for additonal information

Responsible Party:	Pharmacyclics LLC.
ClinicalTrials.gov Identifier:	NCT02165397
Other Study ID Numbers:	PCYC-1127-CA
First Submitted:	June 9, 2014
First Posted:	June 17, 2014
Results First Submitted:	October 20, 2020
Results First Posted:	November 16, 2020
Last Update Posted:	March 3, 2021

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