A Study of the Bruton's Tyrosine Kinase Inhibitor, PCI-32765 (Ibrutinib), in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma

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ClinicalTrials.gov Identifier: NCT01855750

Recruitment Status : Completed

First Posted : May 16, 2013

Results First Posted : March 19, 2019

Last Update Posted : April 13, 2020

Sponsor:

Collaborator:

Pharmacyclics LLC.

Information provided by (Responsible Party):

Janssen Research & Development, LLC

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
Condition	Lymphoma
Interventions	Drug: Ibrutinib Drug: Placebo Drug: Rituximab Drug: Cyclophosphamide Drug: Doxorubicin Drug: Vincristine Drug: Prednisone (or equivalent)
Enrollment	838

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Treatment Arm B: Ibrutinib+R-CHOP	Treatment Arm A: Placebo+R-CHOP
Arm/Group Description	Participants received ibrutinib 560...	Participants received matching plac...
Arm/Group Description	Participants received ibrutinib 560 milligram (mg) (4*140 mg) capsules orally once daily (Cycle 1 Day 1 to Day 21 of last cycle; 21-day cycles) along with R-CHOP (Rituximab - Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) as a background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Participants received background chemotherapy plus ibrutinib for 6 or 8 cycles per site preference (21 days per cycle).	Participants received matching placebo (4 capsules) orally once daily (21-day cycles) along with R-CHOP background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Participants received background chemotherapy plus matching placebo for 6 or 8 cycles per site preference (21 days per cycle).
Period Title: Overall Study
Started	419	419
Treated	416 ^[1]	418 ^[2]
Completed	0	0
Not Completed	419	419
Reason Not Completed
Death	78	78
Lost to Follow-up	9	23
Withdrawal by Subject	35	28
Sponsor ends the study	297	290
[1] 3 participants not treated:2 withdrew consent and 1 not treated per Sponsor/investigator's decision. [2] 1 participant not treated: withdrew consent.

Baseline Characteristics

Arm/Group Title		Treatment Arm B: Ibrutinib+R-CHOP	Treatment Arm A: Placebo+R-CHOP	Total
Arm/Group Description		Participants received ibrutinib 560...	Participants received matching plac...	Total of all reporting groups
Arm/Group Description		Participants received ibrutinib 560 milligram (mg) (4*140 mg) capsules orally once daily (Cycle 1 Day 1 to Day 21 of last cycle; 21-day cycles) along with R-CHOP (Rituximab - Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) as a background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Participants received background chemotherapy plus ibrutinib for 6 or 8 cycles per site preference (21 days per cycle).	Participants received matching placebo (4 capsules) orally once daily (21-day cycles) along with R-CHOP background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Participants received background chemotherapy plus matching placebo for 6 or 8 cycles per site preference (21 days per cycle).	Total of all reporting groups
Overall Number of Baseline Participants		419	419	838
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	419 participants	419 participants	838 participants
		61.1 (12.57)	58.8 (13.57)	59.9 (13.12)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	419 participants	419 participants	838 participants
	Female	198 47.3%	193 46.1%	391 46.7%
	Male	221 52.7%	226 53.9%	447 53.3%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	419 participants	419 participants	838 participants
	Hispanic or Latino	17 4.1%	13 3.1%	30 3.6%
	Not Hispanic or Latino	388 92.6%	396 94.5%	784 93.6%
	Unknown or Not Reported	14 3.3%	10 2.4%	24 2.9%
Race/Ethnicity, Customized Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	419 participants	419 participants	838 participants
	White	237 56.6%	250 59.7%	487 58.1%
	Black or African American	4 1.0%	4 1.0%	8 1.0%
	Asian	166 39.6%	160 38.2%	326 38.9%
	American Indian or Alaska Native	2 0.5%	1 0.2%	3 0.4%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Other	1 0.2%	1 0.2%	2 0.2%
	Unknown	0 0.0%	0 0.0%	0 0.0%
	Not reported	7 1.7%	2 0.5%	9 1.1%
	Multiple	2 0.5%	1 0.2%	3 0.4%
Region of Enrollment Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	419 participants	419 participants	838 participants
Argentina		1 0.2%	1 0.2%	2 0.2%
Australia		12 2.9%	8 1.9%	20 2.4%
Belgium		8 1.9%	7 1.7%	15 1.8%
Brazil		8 1.9%	4 1.0%	12 1.4%
Canada		12 2.9%	9 2.1%	21 2.5%
China		104 24.8%	96 22.9%	200 23.9%
Czech Republic		18 4.3%	12 2.9%	30 3.6%
Denmark		5 1.2%	6 1.4%	11 1.3%
Finland		6 1.4%	8 1.9%	14 1.7%
France		7 1.7%	4 1.0%	11 1.3%
Germany		5 1.2%	8 1.9%	13 1.6%
Hungary		5 1.2%	6 1.4%	11 1.3%
Israel		11 2.6%	12 2.9%	23 2.7%
Italy		24 5.7%	18 4.3%	42 5.0%
Japan		33 7.9%	40 9.5%	73 8.7%
Mexico		2 0.5%	1 0.2%	3 0.4%
Netherlands		5 1.2%	1 0.2%	6 0.7%
Norway		1 0.2%	6 1.4%	7 0.8%
Poland		15 3.6%	24 5.7%	39 4.7%
Russia		19 4.5%	34 8.1%	53 6.3%
Korea, Republic Of		14 3.3%	11 2.6%	25 3.0%
Spain		5 1.2%	7 1.7%	12 1.4%
Sweden		0 0.0%	1 0.2%	1 0.1%
Taiwan, Province Of China		8 1.9%	9 2.1%	17 2.0%
Turkey		27 6.4%	24 5.7%	51 6.1%
Ukraine		10 2.4%	9 2.1%	19 2.3%
United Kingdom		14 3.3%	17 4.1%	31 3.7%
United States		40 9.5%	36 8.6%	76 9.1%

Outcome Measures

1.Primary Outcome


Title	Event-Free Survival (EFS) - Intent-to-Treat (ITT) Population
Description	EFS: duration from randomization date to disease progression(PD) date,...
Description	EFS: duration from randomization date to disease progression(PD) date, relapse from complete response(CR) assessed by investigator, initiation of subsequent systemic antilymphoma therapy for either positron emission tomography(PET)-positive/ biopsy-proven residual disease upon completion of >=6 cycles of R-CHOP therapy/death, whichever occurred first. Responses were based on Revised Response Criteria for Malignant Lymphoma. PD: any new lesion or increase by 50% of previously involved sites from nadir; PD criteria: Appearance of new nodal lesion 1.5 cm in any axis, 50% increase in sum of product of diameters(SPD) of >1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis. CR: disappearance of all evidence of disease; CR criteria: nodal masses PET positive prior to therapy; mass of any size permitted if PET negative; regression to normal size on CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy.
Time Frame	Up to 5.5 years

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) population included all randomized participants, enrolled with non-germinal center B-cell (GCB) of diffuse large B-cell lymphoma (DLBCL) subtype by immunohistochemistry (IHC), and were analyzed according to treatment to which they were randomized.


Arm/Group Title	Treatment Arm B: Ibrutinib+R-CHOP	Treatment Arm A: Placebo+R-CHOP
Arm/Group Description:	Participants received ibrutinib 560...	Participants received matching plac...
Arm/Group Description:	Participants received ibrutinib 560 milligram (mg) (4*140 mg) capsules orally once daily (Cycle 1 Day 1 to Day 21 of last cycle; 21-day cycles) along with R-CHOP (Rituximab - Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) as a background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Participants received background chemotherapy plus ibrutinib for 6 or 8 cycles per site preference (21 days per cycle).	Participants received matching placebo (4 capsules) orally once daily (21-day cycles) along with R-CHOP background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Participants received background chemotherapy plus matching placebo for 6 or 8 cycles per site preference (21 days per cycle).
Overall Number of Participants Analyzed	419	419
Median (95% Confidence Interval) Unit of Measure: Months
	49.64 ^[1] (47.47 to NA)	54.77 (48.16 to 54.77)

[1]

Here NA signifies that the upper limit of Confidence Interval (CI) was not estimable due to lesser number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Arm B: Ibrutinib+R-CHOP, Treatment Arm A: Placebo+R-CHOP
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.5167
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.922
	Confidence Interval	(2-Sided) 95% 0.720 to 1.180
	Estimation Comments	[Not Specified]

2.Primary Outcome


Title	Event-Free Survival (EFS) - Activated B-Cell (ABC) Population
Description	EFS: duration from randomization date to PD date, relapse from CR asse...
Description	EFS: duration from randomization date to PD date, relapse from CR assessed by investigator, initiation of subsequent systemic antilymphoma therapy for either PET-positive/ biopsy-proven residual disease upon completion of >=6 cycles of R-CHOP therapy/death, whichever occurred first. Responses were based on Revised Response Criteria for Malignant Lymphoma. PD: any new lesion or increase by 50% of previously involved sites from nadir; PD criteria: Appearance of new nodal lesion 1.5 cm in any axis, 50% increase in SPD of >1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis. CR: disappearance of all evidence of disease; CR criteria: nodal masses PET positive prior to therapy; mass of any size permitted if PET negative; regression to normal size on CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy.
Time Frame	Up to approximately 4.5 years

Outcome Measure Data

Analysis Population Description

ABC population included ITT population (all randomized participants, enrolled with non-GCB of DLBCL subtype by IHC) having ABC subtype determined by gene expression profiling (GEP) (retrospectively determined from available formalin-fixed paraffin-embedded [FFPE] tissue specimens). Participants were analyzed according to randomized treatment.


Arm/Group Title	Treatment Arm B: Ibrutinib+R-CHOP	Treatment Arm A: Placebo+R-CHOP
Arm/Group Description:	Participants received ibrutinib 560...	Participants received matching plac...
Arm/Group Description:	Participants received ibrutinib 560 milligram (mg) (4*140 mg) capsules orally once daily (Cycle 1 Day 1 to Day 21 of last cycle; 21-day cycles) along with R-CHOP (Rituximab - Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) as a background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Participants received background chemotherapy plus ibrutinib for 6 or 8 cycles per site preference (21 days per cycle).	Participants received matching placebo (4 capsules) orally once daily (21-day cycles) along with R-CHOP background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Participants received background chemotherapy plus matching placebo for 6 or 8 cycles per site preference (21 days per cycle).
Overall Number of Participants Analyzed	285	282
Median (95% Confidence Interval) Unit of Measure: Months
	48.56 ^[1] (48.56 to NA)	48.16 ^[1] (48.16 to NA)

[1]

Here NA signifies that the upper limit of CI was not estimable due to lesser number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Arm B: Ibrutinib+R-CHOP, Treatment Arm A: Placebo+R-CHOP
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7311
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.949
	Confidence Interval	(2-Sided) 95% 0.704 to 1.279
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Progression-Free Survival (PFS)
Description	PFS was defined as the duration from the date of randomization to the ...
Description	PFS was defined as the duration from the date of randomization to the date of progression, relapse from CR, or death, whichever occurred first. Responses were based on Revised Response Criteria for Malignant Lymphoma. Progressive Disease (PD): any new lesion or increase by 50% of previously involved sites from nadir; PD criteria: Appearance of new nodal lesion 1.5 centimeter (cm) in any axis, 50% increase in SPD of >1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis. CR: disappearance of all evidence of disease; CR criteria: nodal masses PET positive prior to therapy; mass of any size permitted if PET negative; regression to normal size on CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy.
Time Frame	Up to approximately 4.5 years

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants, enrolled with non-GCB of DLBCL subtype by IHC, and were analyzed according to treatment to which they were randomized.


Arm/Group Title	Treatment Arm B: Ibrutinib+R-CHOP	Treatment Arm A: Placebo+R-CHOP
Arm/Group Description:	Participants received ibrutinib 560...	Participants received matching plac...
Arm/Group Description:	Participants received ibrutinib 560 milligram (mg) (4*140 mg) capsules orally once daily (Cycle 1 Day 1 to Day 21 of last cycle; 21-day cycles) along with R-CHOP (Rituximab - Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) as a background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Participants received background chemotherapy plus ibrutinib for 6 or 8 cycles per site preference (21 days per cycle).	Participants received matching placebo (4 capsules) orally once daily (21-day cycles) along with R-CHOP background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Participants received background chemotherapy plus matching placebo for 6 or 8 cycles per site preference (21 days per cycle).
Overall Number of Participants Analyzed	419	419
Median (95% Confidence Interval) Unit of Measure: Months
	48.56 ^[1] (48.56 to NA)	NA ^[2] (48.16 to NA)

[1]

Here NA signifies that the upper limit of Confidence Interval (CI) was not estimable due to lesser number of events.

[2]

Here NA signifies that median and the upper limit of Confidence Interval (CI) were not estimable due to lesser number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Arm B: Ibrutinib+R-CHOP, Treatment Arm A: Placebo+R-CHOP
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.5027
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.917
	Confidence Interval	(2-Sided) 95% 0.710 to 1.183
	Estimation Comments	[Not Specified]

4.Secondary Outcome


Title	Percentage of Participants Who Achieved Complete Response (CR)
Description	Percentage of participants with measurable disease who achieved CR wer...
Description	Percentage of participants with measurable disease who achieved CR were reported. CR: disappearance of all evidence of disease. CR Criteria: Complete disappearance of all disease-related symptoms; all lymph nodes and nodal masses regressed to normal size (less than or equal to [<=]1.5 cm in greatest transverse diameter [GTD] for nodes greater than [>]1.5 cm before therapy). Previous nodes of 1.1 to 1.5 cm in long axis and greater than (>)1.0 cm in short axis before treatment decreased to <=1.0 cm in short axis after treatment. Disappearance of all splenic and hepatic nodules and other extranodal disease; a negative positron emission tomography (PET) scan. A posttreatment residual mass of any size but PET-negative; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy.
Time Frame	Up to approximately 4.5 years

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants, who were enrolled with the non-GCB of DLBCL subtype by IHC. Participants in this population were analyzed according to the treatment to which they were randomized.


Arm/Group Title	Treatment Arm B: Ibrutinib+R-CHOP	Treatment Arm A: Placebo+R-CHOP
Arm/Group Description:	Participants received ibrutinib 560...	Participants received matching plac...
Arm/Group Description:	Participants received ibrutinib 560 milligram (mg) (4*140 mg) capsules orally once daily (Cycle 1 Day 1 to Day 21 of last cycle; 21-day cycles) along with R-CHOP (Rituximab - Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) as a background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Participants received background chemotherapy plus ibrutinib for 6 or 8 cycles per site preference (21 days per cycle).	Participants received matching placebo (4 capsules) orally once daily (21-day cycles) along with R-CHOP background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Participants received background chemotherapy plus matching placebo for 6 or 8 cycles per site preference (21 days per cycle).
Overall Number of Participants Analyzed	419	419
Measure Type: Number Unit of Measure: Percentage of participants
	67.3	68.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Arm B: Ibrutinib+R-CHOP, Treatment Arm A: Placebo+R-CHOP
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.8229
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel (CMH) Chi-square
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.967
	Confidence Interval	(2-Sided) 95% 0.722 to 1.296
	Estimation Comments	[Not Specified]

5.Secondary Outcome


Title	Overall Survival
Description	Overall survival was defined as the duration from the date of randomiz...
Description	Overall survival was defined as the duration from the date of randomization to the date of the participant's death. Median Overall Survival was estimated by using the Kaplan-Meier method.
Time Frame	Up to 5.5 years

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Treatment Arm B: Ibrutinib+R-CHOP	Treatment Arm A: Placebo+R-CHOP
Arm/Group Description:	Participants received ibrutinib 560...	Participants received matching plac...
Arm/Group Description:	Participants received ibrutinib 560 milligram (mg) (4*140 mg) capsules orally once daily (Cycle 1 Day 1 to Day 21 of last cycle; 21-day cycles) along with R-CHOP (Rituximab - Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) as a background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Participants received background chemotherapy plus ibrutinib for 6 or 8 cycles per site preference (21 days per cycle).	Participants received matching placebo (4 capsules) orally once daily (21-day cycles) along with R-CHOP background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Participants received background chemotherapy plus matching placebo for 6 or 8 cycles per site preference (21 days per cycle).
Overall Number of Participants Analyzed	419	419
Median (95% Confidence Interval) Unit of Measure: Months
	NA ^[1] (NA to NA)	NA ^[1] (NA to NA)

[1]

Here NA signifies that the median, lower and upper limit of CI were not estimable due to lesser number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Arm B: Ibrutinib+R-CHOP, Treatment Arm A: Placebo+R-CHOP
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.8549
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.030
	Confidence Interval	(2-Sided) 95% 0.754 to 1.407
	Estimation Comments	[Not Specified]

6.Secondary Outcome


Title	Time to Worsening in the Lymphoma Subscale of Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym)
Description	Time to worsening in the Lymphoma subscale of the FACT-Lym, defined as...
Description	Time to worsening in the Lymphoma subscale of the FACT-Lym, defined as the interval from the date of randomization to the start date of worsening of participant symptoms. Worsening was defined by a 5-point decrease from baseline. FACT-Lym Lymphoma subscale contains 15 questions, scores from 0 to 4 for each question (higher the worse). Lymphoma subscale score is the total of reverse scores, range 0 to 60. Higher scores indicate a better quality of life.
Time Frame	Up to approximately 4.5 years

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Treatment Arm B: Ibrutinib+R-CHOP	Treatment Arm A: Placebo+R-CHOP
Arm/Group Description:	Participants received ibrutinib 560...	Participants received matching plac...
Arm/Group Description:	Participants received ibrutinib 560 milligram (mg) (4*140 mg) capsules orally once daily (Cycle 1 Day 1 to Day 21 of last cycle; 21-day cycles) along with R-CHOP (Rituximab - Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) as a background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Participants received background chemotherapy plus ibrutinib for 6 or 8 cycles per site preference (21 days per cycle).	Participants received matching placebo (4 capsules) orally once daily (21-day cycles) along with R-CHOP background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Participants received background chemotherapy plus matching placebo for 6 or 8 cycles per site preference (21 days per cycle).
Overall Number of Participants Analyzed	419	419
Median (95% Confidence Interval) Unit of Measure: Months
	11.7 (4.9 to 23.5)	35.0 ^[1] (19.8 to NA)

[1]

Here NA signifies that the upper limit of CI was not estimable due to lesser number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Arm B: Ibrutinib+R-CHOP, Treatment Arm A: Placebo+R-CHOP
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0021
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.358
	Confidence Interval	(2-Sided) 95% 1.115 to 1.654
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	Up to 5.5 years
Adverse Event Reporting Description	Safety population included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Treatment Arm B: Ibrutinib+R-CHOP	Treatment Arm A: Placebo+R-CHOP
Arm/Group Description	Participants received ibrutinib 560...	Participants received matching plac...
Arm/Group Description	Participants received ibrutinib 560 milligram (mg) (4*140 mg) capsules orally once daily (Cycle 1 Day 1 to Day 21 of last cycle; 21-day cycles) along with R-CHOP (Rituximab - Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) as a background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Participants received background chemotherapy plus ibrutinib for 6 or 8 cycles per site preference (21 days per cycle).	Participants received matching placebo (4 capsules) orally once daily (21-day cycles) along with R-CHOP background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Participants received background chemotherapy plus matching placebo for 6 or 8 cycles per site preference (21 days per cycle).
All-Cause Mortality
	Treatment Arm B: Ibrutinib+R-CHOP	Treatment Arm A: Placebo+R-CHOP
	Affected / at Risk (%)	Affected / at Risk (%)
Total	78/416 (18.75%)	78/418 (18.66%)
Serious Adverse Events Serious Adverse Events
	Treatment Arm B: Ibrutinib+R-CHOP	Treatment Arm A: Placebo+R-CHOP
	Affected / at Risk (%)	Affected / at Risk (%)
Total	221/416 (53.13%)	143/418 (34.21%)
Blood and lymphatic system disorders
Anaemia ^* 1	15/416 (3.61%)	5/418 (1.20%)
Febrile Neutropenia ^* 1	78/416 (18.75%)	44/418 (10.53%)
Leukopenia ^* 1	4/416 (0.96%)	2/418 (0.48%)
Lymphopenia ^* 1	1/416 (0.24%)	0/418 (0.00%)
Neutropenia ^* 1	17/416 (4.09%)	13/418 (3.11%)
Pancytopenia ^* 1	0/416 (0.00%)	1/418 (0.24%)
Thrombocytopenia ^* 1	9/416 (2.16%)	1/418 (0.24%)
Cardiac disorders
Acute Coronary Syndrome ^* 1	1/416 (0.24%)	0/418 (0.00%)
Acute Myocardial Infarction ^* 1	1/416 (0.24%)	1/418 (0.24%)
Angina Pectoris ^* 1	2/416 (0.48%)	1/418 (0.24%)
Arteriosclerosis Coronary Artery ^* 1	1/416 (0.24%)	0/418 (0.00%)
Atrial Fibrillation ^* 1	13/416 (3.13%)	2/418 (0.48%)
Atrial Flutter ^* 1	1/416 (0.24%)	0/418 (0.00%)
Cardiac Arrest ^* 1	1/416 (0.24%)	0/418 (0.00%)
Cardiac Failure ^* 1	2/416 (0.48%)	5/418 (1.20%)
Cardiac Failure Acute ^* 1	1/416 (0.24%)	1/418 (0.24%)
Cardiac Failure Congestive ^* 1	2/416 (0.48%)	1/418 (0.24%)
Cardiomyopathy ^* 1	0/416 (0.00%)	1/418 (0.24%)
Cardiopulmonary Failure ^* 1	0/416 (0.00%)	1/418 (0.24%)
Left Ventricular Dysfunction ^* 1	0/416 (0.00%)	1/418 (0.24%)
Myocardial Infarction ^* 1	1/416 (0.24%)	1/418 (0.24%)
Myocardial Ischaemia ^* 1	2/416 (0.48%)	0/418 (0.00%)
Sinus Node Dysfunction ^* 1	1/416 (0.24%)	0/418 (0.00%)
Supraventricular Tachycardia ^* 1	0/416 (0.00%)	1/418 (0.24%)
Tachycardia ^* 1	2/416 (0.48%)	0/418 (0.00%)
Ventricular Tachycardia ^* 1	1/416 (0.24%)	0/418 (0.00%)
Congenital, familial and genetic disorders
Congenital Neuropathy ^* 1	0/416 (0.00%)	1/418 (0.24%)
Pyloric Stenosis ^* 1	1/416 (0.24%)	0/418 (0.00%)
Ear and labyrinth disorders
Vertigo ^* 1	1/416 (0.24%)	0/418 (0.00%)
Eye disorders
Eye Haemorrhage ^* 1	1/416 (0.24%)	0/418 (0.00%)
Glaucoma ^* 1	1/416 (0.24%)	0/418 (0.00%)
Retinal Detachment ^* 1	0/416 (0.00%)	1/418 (0.24%)
Gastrointestinal disorders
Abdominal Pain ^* 1	2/416 (0.48%)	2/418 (0.48%)
Colitis ^* 1	3/416 (0.72%)	0/418 (0.00%)
Constipation ^* 1	1/416 (0.24%)	0/418 (0.00%)
Diarrhoea ^* 1	15/416 (3.61%)	4/418 (0.96%)
Diverticular Perforation ^* 1	1/416 (0.24%)	0/418 (0.00%)
Duodenal Ulcer Haemorrhage ^* 1	1/416 (0.24%)	0/418 (0.00%)
Dyspepsia ^* 1	0/416 (0.00%)	1/418 (0.24%)
Enteritis ^* 1	1/416 (0.24%)	0/418 (0.00%)
Gastric Haemorrhage ^* 1	2/416 (0.48%)	1/418 (0.24%)
Gastric Perforation ^* 1	1/416 (0.24%)	1/418 (0.24%)
Gastrointestinal Haemorrhage ^* 1	1/416 (0.24%)	1/418 (0.24%)
Gastrooesophageal Reflux Disease ^* 1	0/416 (0.00%)	1/418 (0.24%)
Ileus ^* 1	1/416 (0.24%)	2/418 (0.48%)
Intestinal Obstruction ^* 1	2/416 (0.48%)	0/418 (0.00%)
Lower Gastrointestinal Haemorrhage ^* 1	1/416 (0.24%)	0/418 (0.00%)
Mechanical Ileus ^* 1	0/416 (0.00%)	1/418 (0.24%)
Nausea ^* 1	6/416 (1.44%)	3/418 (0.72%)
Neutropenic Colitis ^* 1	1/416 (0.24%)	0/418 (0.00%)
Obstruction Gastric ^* 1	0/416 (0.00%)	1/418 (0.24%)
Oesophagitis ^* 1	1/416 (0.24%)	1/418 (0.24%)
Pancreatitis ^* 1	1/416 (0.24%)	0/418 (0.00%)
Rectal Haemorrhage ^* 1	1/416 (0.24%)	0/418 (0.00%)
Small Intestinal Obstruction ^* 1	0/416 (0.00%)	1/418 (0.24%)
Small Intestinal Perforation ^* 1	1/416 (0.24%)	1/418 (0.24%)
Stomatitis ^* 1	2/416 (0.48%)	0/418 (0.00%)
Vomiting ^* 1	8/416 (1.92%)	2/418 (0.48%)
General disorders
Asthenia ^* 1	2/416 (0.48%)	1/418 (0.24%)
Chest Pain ^* 1	1/416 (0.24%)	0/418 (0.00%)
Device Related Thrombosis ^* 1	0/416 (0.00%)	1/418 (0.24%)
Drowning ^* 1	0/416 (0.00%)	1/418 (0.24%)
Fatigue ^* 1	5/416 (1.20%)	1/418 (0.24%)
General Physical Health Deterioration ^* 1	2/416 (0.48%)	1/418 (0.24%)
Injection Site Extravasation ^* 1	1/416 (0.24%)	0/418 (0.00%)
Malaise ^* 1	1/416 (0.24%)	0/418 (0.00%)
Mucosal Inflammation ^* 1	3/416 (0.72%)	0/418 (0.00%)
Multiple Organ Dysfunction Syndrome ^* 1	1/416 (0.24%)	1/418 (0.24%)
Non-Cardiac Chest Pain ^* 1	0/416 (0.00%)	1/418 (0.24%)
Oedema Peripheral ^* 1	1/416 (0.24%)	1/418 (0.24%)
Pain ^* 1	1/416 (0.24%)	0/418 (0.00%)
Pyrexia ^* 1	12/416 (2.88%)	11/418 (2.63%)
Sudden Death ^* 1	2/416 (0.48%)	2/418 (0.48%)
Hepatobiliary disorders
Cholangitis ^* 1	0/416 (0.00%)	1/418 (0.24%)
Cholecystitis ^* 1	1/416 (0.24%)	0/418 (0.00%)
Hepatic Failure ^* 1	2/416 (0.48%)	0/418 (0.00%)
Hepatic Function Abnormal ^* 1	1/416 (0.24%)	2/418 (0.48%)
Infections and infestations
Arteritis Infective ^* 1	1/416 (0.24%)	0/418 (0.00%)
Aspergillus Infection ^* 1	2/416 (0.48%)	0/418 (0.00%)
Atypical Pneumonia ^* 1	1/416 (0.24%)	0/418 (0.00%)
Bacteraemia ^* 1	1/416 (0.24%)	0/418 (0.00%)
Brain Abscess ^* 1	1/416 (0.24%)	0/418 (0.00%)
Bronchitis ^* 1	1/416 (0.24%)	0/418 (0.00%)
Bronchopulmonary Aspergillosis ^* 1	2/416 (0.48%)	1/418 (0.24%)
Cellulitis ^* 1	1/416 (0.24%)	0/418 (0.00%)
Cerebral Aspergillosis ^* 1	1/416 (0.24%)	0/418 (0.00%)
Clostridial Infection ^* 1	2/416 (0.48%)	0/418 (0.00%)
Cryptococcal Fungaemia ^* 1	1/416 (0.24%)	0/418 (0.00%)
Cytomegalovirus Gastrointestinal Infection ^* 1	0/416 (0.00%)	1/418 (0.24%)
Device Related Infection ^* 1	4/416 (0.96%)	1/418 (0.24%)
Enterococcal Sepsis ^* 1	1/416 (0.24%)	0/418 (0.00%)
Erysipelas ^* 1	0/416 (0.00%)	1/418 (0.24%)
Gastroenteritis ^* 1	1/416 (0.24%)	0/418 (0.00%)
Gastroenteritis Bacterial ^* 1	0/416 (0.00%)	1/418 (0.24%)
Haemophilus Infection ^* 1	0/416 (0.00%)	1/418 (0.24%)
Hepatitis B ^* 1	1/416 (0.24%)	1/418 (0.24%)
Hepatitis B Reactivation ^* 1	0/416 (0.00%)	1/418 (0.24%)
Herpes Zoster ^* 1	2/416 (0.48%)	3/418 (0.72%)
Incision Site Infection ^* 1	0/416 (0.00%)	1/418 (0.24%)
Infection ^* 1	3/416 (0.72%)	2/418 (0.48%)
Klebsiella Sepsis ^* 1	0/416 (0.00%)	1/418 (0.24%)
Lower Respiratory Tract Infection ^* 1	1/416 (0.24%)	0/418 (0.00%)
Lower Respiratory Tract Infection Fungal ^* 1	1/416 (0.24%)	0/418 (0.00%)
Lung Abscess ^* 1	1/416 (0.24%)	0/418 (0.00%)
Lung Infection ^* 1	14/416 (3.37%)	7/418 (1.67%)
Lymph Gland Infection ^* 1	0/416 (0.00%)	1/418 (0.24%)
Mucosal Infection ^* 1	1/416 (0.24%)	0/418 (0.00%)
Neutropenic Infection ^* 1	2/416 (0.48%)	1/418 (0.24%)
Neutropenic Sepsis ^* 1	1/416 (0.24%)	2/418 (0.48%)
Peritonitis ^* 1	1/416 (0.24%)	1/418 (0.24%)
Pharyngitis ^* 1	1/416 (0.24%)	0/418 (0.00%)
Pneumocystis Jirovecii Pneumonia ^* 1	3/416 (0.72%)	0/418 (0.00%)
Pneumonia ^* 1	28/416 (6.73%)	14/418 (3.35%)
Pneumonia Cryptococcal ^* 1	1/416 (0.24%)	0/418 (0.00%)
Pneumonia Cytomegaloviral ^* 1	1/416 (0.24%)	0/418 (0.00%)
Pneumonia Klebsiella ^* 1	2/416 (0.48%)	0/418 (0.00%)
Pneumonia Respiratory Syncytial Viral ^* 1	0/416 (0.00%)	1/418 (0.24%)
Pseudomembranous Colitis ^* 1	1/416 (0.24%)	0/418 (0.00%)
Pulmonary Mycosis ^* 1	1/416 (0.24%)	0/418 (0.00%)
Respiratory Syncytial Virus Infection ^* 1	1/416 (0.24%)	0/418 (0.00%)
Respiratory Tract Infection ^* 1	1/416 (0.24%)	0/418 (0.00%)
Respiratory Tract Infection Bacterial ^* 1	1/416 (0.24%)	0/418 (0.00%)
Respiratory Tract Infection Fungal ^* 1	1/416 (0.24%)	0/418 (0.00%)
Sepsis ^* 1	7/416 (1.68%)	3/418 (0.72%)
Septic Shock ^* 1	5/416 (1.20%)	1/418 (0.24%)
Sialoadenitis ^* 1	0/416 (0.00%)	1/418 (0.24%)
Sinusitis ^* 1	0/416 (0.00%)	2/418 (0.48%)
Upper Respiratory Tract Infection ^* 1	3/416 (0.72%)	1/418 (0.24%)
Urinary Tract Infection ^* 1	5/416 (1.20%)	3/418 (0.72%)
Urosepsis ^* 1	1/416 (0.24%)	1/418 (0.24%)
Viral Infection ^* 1	2/416 (0.48%)	0/418 (0.00%)
Viral Upper Respiratory Tract Infection ^* 1	1/416 (0.24%)	0/418 (0.00%)
Wound Infection ^* 1	0/416 (0.00%)	1/418 (0.24%)
Injury, poisoning and procedural complications
Compression Fracture ^* 1	1/416 (0.24%)	0/418 (0.00%)
Femoral Neck Fracture ^* 1	0/416 (0.00%)	1/418 (0.24%)
Fibula Fracture ^* 1	1/416 (0.24%)	0/418 (0.00%)
Hip Fracture ^* 1	0/416 (0.00%)	2/418 (0.48%)
Humerus Fracture ^* 1	0/416 (0.00%)	1/418 (0.24%)
Infusion Related Reaction ^* 1	1/416 (0.24%)	0/418 (0.00%)
Lumbar Vertebral Fracture ^* 1	1/416 (0.24%)	0/418 (0.00%)
Postoperative Thrombosis ^* 1	1/416 (0.24%)	0/418 (0.00%)
Pubis Fracture ^* 1	1/416 (0.24%)	0/418 (0.00%)
Skull Fractured Base ^* 1	1/416 (0.24%)	0/418 (0.00%)
Spinal Compression Fracture ^* 1	1/416 (0.24%)	0/418 (0.00%)
Subdural Haematoma ^* 1	0/416 (0.00%)	3/418 (0.72%)
Investigations
Alanine Aminotransferase Increased ^* 1	0/416 (0.00%)	1/418 (0.24%)
C-Reactive Protein Increased ^* 1	0/416 (0.00%)	1/418 (0.24%)
Neutrophil Count Decreased ^* 1	5/416 (1.20%)	2/418 (0.48%)
Platelet Count Decreased ^* 1	2/416 (0.48%)	0/418 (0.00%)
Weight Decreased ^* 1	1/416 (0.24%)	0/418 (0.00%)
White Blood Cell Count Decreased ^* 1	3/416 (0.72%)	0/418 (0.00%)
White Blood Cell Count Increased ^* 1	1/416 (0.24%)	0/418 (0.00%)
Metabolism and nutrition disorders
Decreased Appetite ^* 1	0/416 (0.00%)	2/418 (0.48%)
Dehydration ^* 1	8/416 (1.92%)	2/418 (0.48%)
Diabetes Mellitus ^* 1	0/416 (0.00%)	1/418 (0.24%)
Fluid Overload ^* 1	1/416 (0.24%)	0/418 (0.00%)
Hyperglycaemia ^* 1	0/416 (0.00%)	1/418 (0.24%)
Hypokalaemia ^* 1	4/416 (0.96%)	0/418 (0.00%)
Hyponatraemia ^* 1	3/416 (0.72%)	1/418 (0.24%)
Hypophagia ^* 1	1/416 (0.24%)	1/418 (0.24%)
Hypoproteinaemia ^* 1	1/416 (0.24%)	0/418 (0.00%)
Ketoacidosis ^* 1	0/416 (0.00%)	1/418 (0.24%)
Tumour Lysis Syndrome ^* 1	1/416 (0.24%)	0/418 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia ^* 1	1/416 (0.24%)	0/418 (0.00%)
Back Pain ^* 1	1/416 (0.24%)	0/418 (0.00%)
Chondrocalcinosis Pyrophosphate ^* 1	1/416 (0.24%)	0/418 (0.00%)
Flank Pain ^* 1	0/416 (0.00%)	1/418 (0.24%)
Muscular Weakness ^* 1	2/416 (0.48%)	0/418 (0.00%)
Myalgia ^* 1	1/416 (0.24%)	0/418 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Angioimmunoblastic T-Cell Lymphoma ^* 1	0/416 (0.00%)	1/418 (0.24%)
Basal Cell Carcinoma ^* 1	1/416 (0.24%)	0/418 (0.00%)
Colorectal Adenocarcinoma ^* 1	0/416 (0.00%)	1/418 (0.24%)
Laryngeal Cancer Metastatic ^* 1	1/416 (0.24%)	0/418 (0.00%)
Malignant Melanoma ^* 1	1/416 (0.24%)	0/418 (0.00%)
Squamous Cell Carcinoma of Skin ^* 1	1/416 (0.24%)	0/418 (0.00%)
Nervous system disorders
Altered State of Consciousness ^* 1	1/416 (0.24%)	0/418 (0.00%)
Central Nervous System Inflammation ^* 1	0/416 (0.00%)	1/418 (0.24%)
Cerebral Haemorrhage ^* 1	1/416 (0.24%)	0/418 (0.00%)
Cerebral Infarction ^* 1	0/416 (0.00%)	1/418 (0.24%)
Cerebrospinal Fluid Leakage ^* 1	0/416 (0.00%)	1/418 (0.24%)
Cerebrovascular Disorder ^* 1	1/416 (0.24%)	0/418 (0.00%)
Dizziness Postural ^* 1	1/416 (0.24%)	0/418 (0.00%)
Epilepsy ^* 1	0/416 (0.00%)	1/418 (0.24%)
Febrile Convulsion ^* 1	1/416 (0.24%)	0/418 (0.00%)
Haemorrhage Intracranial ^* 1	2/416 (0.48%)	0/418 (0.00%)
Hemiparesis ^* 1	0/416 (0.00%)	1/418 (0.24%)
Intracranial Hypotension ^* 1	0/416 (0.00%)	1/418 (0.24%)
Nerve Compression ^* 1	0/416 (0.00%)	1/418 (0.24%)
Polyneuropathy ^* 1	1/416 (0.24%)	0/418 (0.00%)
Sciatica ^* 1	1/416 (0.24%)	0/418 (0.00%)
Seizure ^* 1	1/416 (0.24%)	0/418 (0.00%)
Syncope ^* 1	5/416 (1.20%)	1/418 (0.24%)
Psychiatric disorders
Bipolar I Disorder ^* 1	0/416 (0.00%)	1/418 (0.24%)
Confusional State ^* 1	0/416 (0.00%)	1/418 (0.24%)
Suicidal Ideation ^* 1	1/416 (0.24%)	0/418 (0.00%)
Renal and urinary disorders
Acute Kidney Injury ^* 1	4/416 (0.96%)	1/418 (0.24%)
Cystitis Haemorrhagic ^* 1	1/416 (0.24%)	0/418 (0.00%)
Dysuria ^* 1	1/416 (0.24%)	0/418 (0.00%)
Pollakiuria ^* 1	1/416 (0.24%)	0/418 (0.00%)
Renal Failure ^* 1	1/416 (0.24%)	2/418 (0.48%)
Urinary Retention ^* 1	1/416 (0.24%)	0/418 (0.00%)
Reproductive system and breast disorders
Vaginal Fistula ^* 1	1/416 (0.24%)	0/418 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure ^* 1	0/416 (0.00%)	1/418 (0.24%)
Alveolitis ^* 1	1/416 (0.24%)	0/418 (0.00%)
Atelectasis ^* 1	0/416 (0.00%)	1/418 (0.24%)
Diffuse Alveolar Damage ^* 1	1/416 (0.24%)	0/418 (0.00%)
Dyspnoea ^* 1	1/416 (0.24%)	1/418 (0.24%)
Hypoxia ^* 1	1/416 (0.24%)	0/418 (0.00%)
Interstitial Lung Disease ^* 1	7/416 (1.68%)	4/418 (0.96%)
Obliterative Bronchiolitis ^* 1	0/416 (0.00%)	1/418 (0.24%)
Pharyngeal Haemorrhage ^* 1	0/416 (0.00%)	1/418 (0.24%)
Pleural Effusion ^* 1	1/416 (0.24%)	1/418 (0.24%)
Pneumonia Aspiration ^* 1	1/416 (0.24%)	0/418 (0.00%)
Pneumonitis ^* 1	6/416 (1.44%)	3/418 (0.72%)
Pulmonary Embolism ^* 1	1/416 (0.24%)	3/418 (0.72%)
Pulmonary Mass ^* 1	1/416 (0.24%)	0/418 (0.00%)
Respiratory Failure ^* 1	2/416 (0.48%)	1/418 (0.24%)
Sinus Polyp ^* 1	1/416 (0.24%)	0/418 (0.00%)
Skin and subcutaneous tissue disorders
Dermatitis Allergic ^* 1	1/416 (0.24%)	0/418 (0.00%)
Vascular disorders
Aortic Aneurysm ^* 1	1/416 (0.24%)	0/418 (0.00%)
Arteriosclerosis ^* 1	1/416 (0.24%)	0/418 (0.00%)
Deep Vein Thrombosis ^* 1	1/416 (0.24%)	2/418 (0.48%)
Embolism ^* 1	0/416 (0.00%)	1/418 (0.24%)
Hypotension ^* 1	6/416 (1.44%)	1/418 (0.24%)
Shock Haemorrhagic ^* 1	1/416 (0.24%)	0/418 (0.00%)
Thrombophlebitis ^* 1	1/416 (0.24%)	0/418 (0.00%)
Vena Cava Thrombosis ^* 1	0/416 (0.00%)	1/418 (0.24%)
1 Term from vocabulary, MedDRA Version 20.0 * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Treatment Arm B: Ibrutinib+R-CHOP	Treatment Arm A: Placebo+R-CHOP
	Affected / at Risk (%)	Affected / at Risk (%)
Total	411/416 (98.80%)	411/418 (98.33%)
Blood and lymphatic system disorders
Anaemia ^* 1	173/416 (41.59%)	116/418 (27.75%)
Febrile Neutropenia ^* 1	41/416 (9.86%)	22/418 (5.26%)
Leukopenia ^* 1	70/416 (16.83%)	74/418 (17.70%)
Lymphopenia ^* 1	23/416 (5.53%)	36/418 (8.61%)
Neutropenia ^* 1	213/416 (51.20%)	248/418 (59.33%)
Thrombocytopenia ^* 1	102/416 (24.52%)	53/418 (12.68%)
Gastrointestinal disorders
Abdominal Pain ^* 1	37/416 (8.89%)	34/418 (8.13%)
Abdominal Pain Upper ^* 1	28/416 (6.73%)	34/418 (8.13%)
Constipation ^* 1	111/416 (26.68%)	110/418 (26.32%)
Diarrhoea ^* 1	149/416 (35.82%)	81/418 (19.38%)
Dry Mouth ^* 1	22/416 (5.29%)	17/418 (4.07%)
Dyspepsia ^* 1	26/416 (6.25%)	22/418 (5.26%)
Mouth Ulceration ^* 1	32/416 (7.69%)	20/418 (4.78%)
Nausea ^* 1	170/416 (40.87%)	135/418 (32.30%)
Stomatitis ^* 1	64/416 (15.38%)	47/418 (11.24%)
Vomiting ^* 1	91/416 (21.88%)	59/418 (14.11%)
General disorders
Asthenia ^* 1	28/416 (6.73%)	16/418 (3.83%)
Fatigue ^* 1	138/416 (33.17%)	102/418 (24.40%)
Malaise ^* 1	25/416 (6.01%)	21/418 (5.02%)
Mucosal Inflammation ^* 1	34/416 (8.17%)	23/418 (5.50%)
Oedema Peripheral ^* 1	46/416 (11.06%)	29/418 (6.94%)
Pyrexia ^* 1	83/416 (19.95%)	68/418 (16.27%)
Infections and infestations
Pneumonia ^* 1	22/416 (5.29%)	9/418 (2.15%)
Upper Respiratory Tract Infection ^* 1	35/416 (8.41%)	29/418 (6.94%)
Urinary Tract Infection ^* 1	24/416 (5.77%)	15/418 (3.59%)
Injury, poisoning and procedural complications
Infusion Related Reaction ^* 1	23/416 (5.53%)	26/418 (6.22%)
Investigations
Alanine Aminotransferase Increased ^* 1	25/416 (6.01%)	24/418 (5.74%)
Lymphocyte Count Decreased ^* 1	44/416 (10.58%)	42/418 (10.05%)
Neutrophil Count Decreased ^* 1	99/416 (23.80%)	81/418 (19.38%)
Platelet Count Decreased ^* 1	83/416 (19.95%)	38/418 (9.09%)
Weight Decreased ^* 1	36/416 (8.65%)	18/418 (4.31%)
White Blood Cell Count Decreased ^* 1	107/416 (25.72%)	104/418 (24.88%)
Metabolism and nutrition disorders
Decreased Appetite ^* 1	64/416 (15.38%)	51/418 (12.20%)
Hypoalbuminaemia ^* 1	24/416 (5.77%)	9/418 (2.15%)
Hypokalaemia ^* 1	75/416 (18.03%)	23/418 (5.50%)
Hypomagnesaemia ^* 1	22/416 (5.29%)	7/418 (1.67%)
Hyponatraemia ^* 1	28/416 (6.73%)	11/418 (2.63%)
Musculoskeletal and connective tissue disorders
Back Pain ^* 1	34/416 (8.17%)	40/418 (9.57%)
Bone Pain ^* 1	17/416 (4.09%)	21/418 (5.02%)
Muscle Spasms ^* 1	30/416 (7.21%)	14/418 (3.35%)
Myalgia ^* 1	18/416 (4.33%)	24/418 (5.74%)
Nervous system disorders
Dysgeusia ^* 1	26/416 (6.25%)	19/418 (4.55%)
Headache ^* 1	29/416 (6.97%)	43/418 (10.29%)
Hypoaesthesia ^* 1	28/416 (6.73%)	22/418 (5.26%)
Neuropathy Peripheral ^* 1	65/416 (15.63%)	35/418 (8.37%)
Paraesthesia ^* 1	28/416 (6.73%)	16/418 (3.83%)
Peripheral Sensory Neuropathy ^* 1	77/416 (18.51%)	63/418 (15.07%)
Psychiatric disorders
Insomnia ^* 1	39/416 (9.38%)	43/418 (10.29%)
Respiratory, thoracic and mediastinal disorders
Cough ^* 1	55/416 (13.22%)	47/418 (11.24%)
Dyspnoea ^* 1	30/416 (7.21%)	25/418 (5.98%)
Oropharyngeal Pain ^* 1	32/416 (7.69%)	25/418 (5.98%)
Skin and subcutaneous tissue disorders
Alopecia ^* 1	69/416 (16.59%)	106/418 (25.36%)
Pruritus ^* 1	11/416 (2.64%)	21/418 (5.02%)
Rash ^* 1	22/416 (5.29%)	21/418 (5.02%)
Vascular disorders
Hypertension ^* 1	23/416 (5.53%)	18/418 (4.31%)
Hypotension ^* 1	23/416 (5.53%)	10/418 (2.39%)
1 Term from vocabulary, MedDRA Version 20.0 * Indicates events were collected by non-systematic assessment

Limitations and Caveats

Sponsor decided to stop the study as all participants had concluded study treatment and outcomes were not expected to change and study was considered as completed.

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.

A copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested in writing, such publication will be withheld for up to an additional 60 days.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Medical Officer
Organization:	Janssen Research & Development, LLC
Phone:	844-434-4210
EMail:	ClinicalTrialDisclosure@its.jnj.com

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

Younes A, Sehn LH, Johnson P, Zinzani PL, Hong X, Zhu J, Patti C, Belada D, Samoilova O, Suh C, Leppä S, Rai S, Turgut M, Jurczak W, Cheung MC, Gurion R, Yeh SP, Lopez-Hernandez A, Dührsen U, Thieblemont C, Chiattone CS, Balasubramanian S, Carey J, Liu G, Shreeve SM, Sun S, Zhuang SH, Vermeulen J, Staudt LM, Wilson W; PHOENIX investigators. Randomized Phase III Trial of Ibrutinib and Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Non-Germinal Center B-Cell Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2019 May 20;37(15):1285-1295. doi: 10.1200/JCO.18.02403. Epub 2019 Mar 22.

Layout table for additonal information

Responsible Party:	Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:	NCT01855750
Other Study ID Numbers:	CR102118 PCI-32765DBL3001 ( Other Identifier: Janssen Research & Development, LLC ) U1111-1139-6222 ( Other Identifier: Universal Trial Number ) 2013-000959-40 ( EudraCT Number )
First Submitted:	May 14, 2013
First Posted:	May 16, 2013
Results First Submitted:	February 22, 2019
Results First Posted:	March 19, 2019
Last Update Posted:	April 13, 2020

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