A Study of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib Given in Combination With Bendamustine and Rituximab in Patients With Newly Diagnosed Mantle Cell Lymphoma

• ClinicalTrials.gov Identifier: NCT01776840
• Recruitment Status: Active, not recruiting
• First Posted: January 28, 2013
• Results First Posted: July 26, 2022
• Last Update Posted: April 25, 2024
• Sponsor: Janssen Research & Development, LLC
• 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: Mantle Cell Lymphoma
• Interventions: Drug: Bendamustine; Drug: Rituximab; Drug: Ibrutinib; Drug: Placebo
• Enrollment: 523

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Ibrutinib + BR (Treatment B)	Placebo + BR (Treatment A)
Arm/Group Description	Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.	Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.
Period Title: Overall Study
Started	261	262
Completed	103	107
Not Completed	158	155
Reason Not Completed
Lost to Follow-up	4	4
Withdrawal by Subject	42	22
Ongoing	112	129

Baseline Characteristics

Arm/Group Title		Ibrutinib + BR (Treatment B)	Placebo + BR (Treatment A)	Total
Arm/Group Description		Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.	Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.	Total of all reporting groups
Overall Number of Baseline Participants		261	262	523
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	261 participants	262 participants	523 participants
		71.8 (5.04)	71.7 (5.2)	71.7 (5.12)
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	261 participants	262 participants	523 participants
	70 years and over	162 62.1%	154 58.8%	316 60.4%
	< 70 years	99 37.9%	108 41.2%	207 39.6%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	261 participants	262 participants	523 participants
	Female	83 31.8%	76 29.0%	159 30.4%
	Male	178 68.2%	186 71.0%	364 69.6%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	261 participants	262 participants	523 participants
	Hispanic or Latino	18 6.9%	17 6.5%	35 6.7%
	Not Hispanic or Latino	232 88.9%	234 89.3%	466 89.1%
	Unknown or Not Reported	11 4.2%	11 4.2%	22 4.2%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	261 participants	262 participants	523 participants
American Indian or Alaska Native		0 0.0%	3 1.1%	3 0.6%
Asian		47 18.0%	42 16.0%	89 17.0%
Black or African American		2 0.8%	1 0.4%	3 0.6%
Native Hawaiian or Other Pacific Islander		0 0.0%	0 0.0%	0 0.0%
White		199 76.2%	206 78.6%	405 77.4%
More than one race		1 0.4%	1 0.4%	2 0.4%
Unknown or Not Reported		10 3.8%	9 3.4%	19 3.6%
Other		2 0.8%	0 0.0%	2 0.4%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	261 participants	262 participants	523 participants
ARGENTINA		4 1.5%	0 0.0%	4 0.8%
AUSTRALIA		19 7.3%	12 4.6%	31 5.9%
BELGIUM		5 1.9%	10 3.8%	15 2.9%
BRAZIL		11 4.2%	10 3.8%	21 4.0%
CANADA		4 1.5%	7 2.7%	11 2.1%
CHINA		31 11.9%	26 9.9%	57 10.9%
CZECH REPUBLIC		7 2.7%	8 3.1%	15 2.9%
FRANCE		8 3.1%	13 5.0%	21 4.0%
GERMANY		3 1.1%	5 1.9%	8 1.5%
GREECE		4 1.5%	3 1.1%	7 1.3%
HUNGARY		5 1.9%	5 1.9%	10 1.9%
IRELAND		2 0.8%	0 0.0%	2 0.4%
ISRAEL		5 1.9%	9 3.4%	14 2.7%
ITALY		13 5.0%	13 5.0%	26 5.0%
JAPAN		7 2.7%	4 1.5%	11 2.1%
MEXICO		1 0.4%	2 0.8%	3 0.6%
NETHERLANDS		5 1.9%	3 1.1%	8 1.5%
POLAND		18 6.9%	17 6.5%	35 6.7%
RUSSIAN FEDERATION		15 5.7%	12 4.6%	27 5.2%
SLOVAKIA		1 0.4%	2 0.8%	3 0.6%
SOUTH KOREA		6 2.3%	6 2.3%	12 2.3%
SPAIN		13 5.0%	7 2.7%	20 3.8%
SWEDEN		9 3.4%	9 3.4%	18 3.4%
TAIWAN		2 0.8%	4 1.5%	6 1.1%
TURKEY		8 3.1%	6 2.3%	14 2.7%
UKRAINE		6 2.3%	5 1.9%	11 2.1%
UNITED KINGDOM		14 5.4%	16 6.1%	30 5.7%
UNITED STATES		35 13.4%	48 18.3%	83 15.9%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS)
Description	Progression-free survival (PFS) is defined as the interval between the date of randomization to the date of disease progression (PD) or relapse from complete response (CR) or death, whichever is first reported. Disease assessments were based on the 2007 Revised Response Criteria for Malignant Lymphoma. PD is defined as any new lesion or increase by 50 percent (%) of previously involved sites from nadir (PD criteria: Appearance of new nodal lesion 1.5 centimeters [cm] in any axis, 50% increase in sum of product of diameters [SPD] of greater than [>] 1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis).
Time Frame	Up to 97 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. Here, N (number of participants analyzed) signifies number of participants that were evaluable for this outcome measure.

Arm/Group Title	Ibrutinib + BR (Treatment B)	Placebo + BR (Treatment A)
Arm/Group Description:	Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.	Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.
Overall Number of Participants Analyzed	116	152
Median (95% Confidence Interval); Unit of Measure: months
	80.6 [1]; (61.9 to NA)	52.9; (43.7 to 71.0)

[1]

Here, 'NA' refers that the upper limit of 95% confidence interval was not estimable because of small number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + BR (Treatment B), Placebo + BR (Treatment A)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.011
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.59 to 0.96
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Overall Survival
Description	Overall survival is defined as the time from the date of randomization to the date of the participant's death.
Time Frame	Up to 97 months

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. Here, N (number of participants analyzed) signifies number of participants that were evaluable for this outcome measure.

Arm/Group Title	Ibrutinib + BR (Treatment B)	Placebo + BR (Treatment A)
Arm/Group Description:	Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.	Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.
Overall Number of Participants Analyzed	104	107
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (81.1 to NA)	NA [1]; (86.1 to NA)

[1]

Here, 'NA' refers that the median and upper limit of 95% confidence interval was not estimable because of small number of events.

3. Secondary Outcome

Title	Complete Response Rate
Description	Complete response (CR) rate is defined as the percentage of participants who achieve CR (based on investigator assessment) on or prior to the initiation of subsequent anticancer therapy. Criteria for CR: disappearance of all evidence of disease; mass of any size permitted if positron emission tomography (PET) negative; regression to normal size on computed tomography (CT); spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy.
Time Frame	Up to 97 months

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received.

Arm/Group Title	Ibrutinib + BR (Treatment B)	Placebo + BR (Treatment A)
Arm/Group Description:	Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.	Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.
Overall Number of Participants Analyzed	261	262
Measure Type: Number; Unit of Measure: percentage of participants
	65.5	57.6

4. Secondary Outcome

Title	Time-to-Next Treatment
Description	Time-to-next treatment was measured from the date of randomization to the start date of any anti-mantle cell lymphoma (anti-MCL) treatment subsequent to the study treatment.
Time Frame	Up to 97 months

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. Here, N (number of participants analyzed) signifies number of participants that were evaluable for this outcome measure.

Arm/Group Title	Ibrutinib + BR (Treatment B)	Placebo + BR (Treatment A)
Arm/Group Description:	Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.	Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.
Overall Number of Participants Analyzed	52	106
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	92.0 [2]; (71.5 to NA)

[1]

Here, 'NA' refers that the median and 95% confidence interval were not estimable due to a small number of participants with events.

[2]

Here, 'NA' refers that the upper limit of 95% confidence interval was not estimable due to a small number of participants with events.

5. Secondary Outcome

Title	Percentage of Participants With Overall Response
Description	Percentage of participants with overall response that is participants who achieved CR or PR was reported. Criteria for CR: disappearance of all evidence of disease; 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. Criteria for PR: greater than or equal to (>=) 50% decrease in sum of the diameter of all target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions.
Time Frame	Up to 97 months

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received.

Arm/Group Title	Ibrutinib + BR (Treatment B)	Placebo + BR (Treatment A)
Arm/Group Description:	Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.	Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.
Overall Number of Participants Analyzed	261	262
Measure Type: Number; Unit of Measure: percentage of participants
	89.7	88.5

6. Secondary Outcome

Title	Minimal Residual Disease (MRD)-Negative Response Rate
Description	Minimal residual disease negative rate was defined as the percentage of participants with a best overall response of CR with MRD-negative disease status (that is, <5 mantle cell lymphoma [MCL] cell per 10,000 leukocytes for detection using the MRD assay), as assessed by flow cytometry of a bone marrow and/or peripheral blood sample.
Time Frame	Up to 97 months

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. CR participants with missing MRD data and participants who did not achieve a CR were considered nonresponders.

Arm/Group Title	Ibrutinib + BR (Treatment B)	Placebo + BR (Treatment A)
Arm/Group Description:	Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.	Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.
Overall Number of Participants Analyzed	261	262
Measure Type: Number; Unit of Measure: percentage of participants
	62.1	56.5

7. Secondary Outcome

Title	Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Questionnaire
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, death, or a missing assessment due to being "too ill", whichever occurred first. 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 97 months

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received.

Arm/Group Title	Ibrutinib + BR (Treatment B)	Placebo + BR (Treatment A)
Arm/Group Description:	Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.	Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.
Overall Number of Participants Analyzed	261	262
Median (95% Confidence Interval); Unit of Measure: months
	17.4; (8.3 to 27.6)	22.2; (9.3 to 34.0)

8. Secondary Outcome

Title	Duration of Response (DoR)
Description	Duration of Response (DoR) was defined as the interval between the date of initial documentation of a response including PR and the date of first documented evidence of PD or death.
Time Frame	Up to 97 months

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. Participants who achieved a PR or better were included in the analysis of duration of response.

Arm/Group Title	Ibrutinib + BR (Treatment B)	Placebo + BR (Treatment A)
Arm/Group Description:	Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.	Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.
Overall Number of Participants Analyzed	234	232
Median (95% Confidence Interval); Unit of Measure: months
	81 [1]; (64.2 to NA)	63.5; (47 to 76.9)

[1]

Here, 'NA' refers that the upper limit of 95% confidence interval was not estimable due to a small number of participants with events.

9. Secondary Outcome

Title	Duration of Complete Response (DoCR)
Description	Duration of complete response (DoCR) was defined as the interval between the date of initial documentation of a CR and the date of first documented evidence of PD or death whichever occurs first, for participants who achieved CR.
Time Frame	Up to 97 months

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. Participants who achieved a CR or better were included in the analysis of duration of complete response.

Arm/Group Title	Ibrutinib + BR (Treatment B)	Placebo + BR (Treatment A)
Arm/Group Description:	Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.	Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.
Overall Number of Participants Analyzed	171	151
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (81.7 to NA)	78.1 [2]; (65.6 to NA)

[1]

Here, 'NA' refers that the median and upper limit of 95% confidence interval were not estimable due to a small number of participants with events.

[2]

Here, 'NA' refers that the upper limit of 95% confidence interval were not estimable due to a small number of participants with events.

10. Secondary Outcome

Title	Time to Response
Description	Time to response was defined as the interval between the date of randomization and the date of initial documentation of a response.
Time Frame	Up to 97 months

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. Participants who achieved a PR or better were included in the analysis of time to response.

Arm/Group Title	Ibrutinib + BR (Treatment B)	Placebo + BR (Treatment A)
Arm/Group Description:	Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.	Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.
Overall Number of Participants Analyzed	234	232
Median (Full Range); Unit of Measure: months
	2.79; (2.1 to 10.1)	2.79; (1.9 to 11.2)

11. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Description	Number of participants with TEAEs were reported. Treatment-emergent adverse events are defined as adverse events with onset or worsening on or after date of first dose of study treatment up to and including 30 days after date of last dose of study medication, or the initiation of subsequent anticancer therapy, whichever is earlier.
Time Frame	Up to 97 months

Outcome Measure Data

Analysis Population Description

Safety Analysis Set included all randomized participants who received at least 1 dose of study drug (ibrutinib or placebo).

Arm/Group Title	Ibrutinib + BR (Treatment B)	Placebo + BR (Treatment A)
Arm/Group Description:	Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.	Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.
Overall Number of Participants Analyzed	259	260
Measure Type: Count of Participants; Unit of Measure: Participants
	259 100.0%	257 98.8%

12. Secondary Outcome

Title	Oral Plasma Clearance (CL/F) of Ibrutinib
Description	CL/F of Ibrutinib was determined using population pharmacokinetics (PopPK modeling).
Time Frame	Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic-evaluable population included participants who have received at least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained posttreatment.

Arm/Group Title	Ibrutinib + BR (Treatment B)
Arm/Group Description:	Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.
Overall Number of Participants Analyzed	259
Mean (Standard Error); Unit of Measure: liter per hour (L/h)
	1123 (4.83)

13. Secondary Outcome

Title	Oral Volume of Distribution at Steady State of Ibrutinib
Description	Oral volume of distribution at steady state of ibrutinib was determined using PopPK modeling.
Time Frame	Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic-evaluable population included participants who have received at least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained posttreatment.

Arm/Group Title	Ibrutinib + BR (Treatment B)
Arm/Group Description:	Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.
Overall Number of Participants Analyzed	259
Mean (Standard Error); Unit of Measure: liter
	7286 (7.87)

14. Secondary Outcome

Title	Area Under the Concentration Curve of Ibrutinib During 24 Hours After Dosing at Steady State
Description	Area under the concentration curve of ibrutinib during 24 hours after dosing at steady state was determined using PopPK modeling.
Time Frame	Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic-evaluable population included participants who have received at least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained posttreatment.

Arm/Group Title	Ibrutinib + BR (Treatment B)
Arm/Group Description:	Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.
Overall Number of Participants Analyzed	259
Mean (Standard Deviation); Unit of Measure: nanogram*hour per milliliter (ng*h/mL)
	425 (267)

15. Secondary Outcome

Title	Minimum Observed Plasma Concentration of Ibrutinib
Description	Minimum observed plasma concentration of ibrutinib was determined using PopPK modeling.
Time Frame	Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic-evaluable population included participants who have received at least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained posttreatment.

Arm/Group Title	Ibrutinib + BR (Treatment B)
Arm/Group Description:	Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.
Overall Number of Participants Analyzed	259
Mean (Standard Deviation); Unit of Measure: nanograms per milliliter (ng/mL)
	3.90 (2.64)

16. Secondary Outcome

Title	Maximum Observed Plasma Concentration of Ibrutinib
Description	Maximum observed plasma concentration of ibrutinib was determined using PopPK modeling.
Time Frame	Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic-evaluable population included participants who have received at least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained posttreatment.

Arm/Group Title	Ibrutinib + BR (Treatment B)
Arm/Group Description:	Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.
Overall Number of Participants Analyzed	259
Mean (Standard Deviation); Unit of Measure: ng/mL
	74.5 (48.3)

Adverse Events

Time Frame	Up to 97 months
Adverse Event Reporting Description	Safety analysis set included all randomized participants who received at least 1 dose of study drug (ibrutinib or placebo).
Arm/Group Title	Ibrutinib + BR (Treatment B)	Placebo + BR (Treatment A)
Arm/Group Description	Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.	Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days.
All-Cause Mortality
	Ibrutinib + BR (Treatment B)	Placebo + BR (Treatment A)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	103/259 (39.77%)	107/260 (41.15%)
Serious Adverse Events
	Ibrutinib + BR (Treatment B)	Placebo + BR (Treatment A)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	197/259 (76.06%)	156/260 (60.00%)
Blood and lymphatic system disorders
Anaemia * 1	4/259 (1.54%)	3/260 (1.15%)
Febrile Neutropenia * 1	16/259 (6.18%)	9/260 (3.46%)
Leukocytosis * 1	1/259 (0.39%)	0/260 (0.00%)
Lymphadenitis * 1	3/259 (1.16%)	1/260 (0.38%)
Methaemoglobinaemia * 1	1/259 (0.39%)	0/260 (0.00%)
Neutropenia * 1	3/259 (1.16%)	3/260 (1.15%)
Pancytopenia * 1	0/259 (0.00%)	1/260 (0.38%)
Splenic Infarction * 1	0/259 (0.00%)	1/260 (0.38%)
Thrombocytopenia * 1	2/259 (0.77%)	3/260 (1.15%)
Cardiac disorders
Acute Coronary Syndrome * 1	0/259 (0.00%)	1/260 (0.38%)
Acute Myocardial Infarction * 1	1/259 (0.39%)	4/260 (1.54%)
Angina Pectoris * 1	1/259 (0.39%)	0/260 (0.00%)
Arrhythmia * 1	1/259 (0.39%)	0/260 (0.00%)
Atrial Fibrillation * 1	13/259 (5.02%)	4/260 (1.54%)
Atrial Flutter * 1	3/259 (1.16%)	1/260 (0.38%)
Atrioventricular Block * 1	0/259 (0.00%)	1/260 (0.38%)
Bradycardia * 1	1/259 (0.39%)	1/260 (0.38%)
Cardiac Arrest * 1	3/259 (1.16%)	1/260 (0.38%)
Cardiac Failure * 1	3/259 (1.16%)	0/260 (0.00%)
Cardio-Respiratory Arrest * 1	1/259 (0.39%)	0/260 (0.00%)
Cardiomyopathy * 1	1/259 (0.39%)	0/260 (0.00%)
Cardiopulmonary Failure * 1	0/259 (0.00%)	2/260 (0.77%)
Coronary Artery Disease * 1	0/259 (0.00%)	1/260 (0.38%)
Coronary Artery Stenosis * 1	0/259 (0.00%)	1/260 (0.38%)
Ischaemic Cardiomyopathy * 1	1/259 (0.39%)	0/260 (0.00%)
Left Ventricular Failure * 1	0/259 (0.00%)	1/260 (0.38%)
Mitral Valve Stenosis * 1	1/259 (0.39%)	0/260 (0.00%)
Myocardial Infarction * 1	1/259 (0.39%)	6/260 (2.31%)
Myocardial Ischaemia * 1	2/259 (0.77%)	0/260 (0.00%)
Nodal Rhythm * 1	0/259 (0.00%)	1/260 (0.38%)
Pericardial Effusion * 1	1/259 (0.39%)	0/260 (0.00%)
Silent Myocardial Infarction * 1	1/259 (0.39%)	0/260 (0.00%)
Sinus Node Dysfunction * 1	1/259 (0.39%)	0/260 (0.00%)
Supraventricular Tachycardia * 1	1/259 (0.39%)	0/260 (0.00%)
Ventricular Extrasystoles * 1	0/259 (0.00%)	1/260 (0.38%)
Congenital, familial and genetic disorders
Odontogenic Cyst * 1	0/259 (0.00%)	1/260 (0.38%)
Endocrine disorders
Hyperaldosteronism * 1	1/259 (0.39%)	0/260 (0.00%)
Eye disorders
Cataract * 1	0/259 (0.00%)	1/260 (0.38%)
Exophthalmos * 1	0/259 (0.00%)	1/260 (0.38%)
Retinal Detachment * 1	1/259 (0.39%)	0/260 (0.00%)
Ulcerative Keratitis * 1	0/259 (0.00%)	1/260 (0.38%)
Gastrointestinal disorders
Abdominal Pain * 1	1/259 (0.39%)	1/260 (0.38%)
Abdominal Pain Upper * 1	3/259 (1.16%)	0/260 (0.00%)
Acute Abdomen * 1	1/259 (0.39%)	0/260 (0.00%)
Anal Haemorrhage * 1	2/259 (0.77%)	0/260 (0.00%)
Colitis * 1	1/259 (0.39%)	2/260 (0.77%)
Constipation * 1	0/259 (0.00%)	2/260 (0.77%)
Dental Caries * 1	1/259 (0.39%)	0/260 (0.00%)
Diarrhoea * 1	7/259 (2.70%)	2/260 (0.77%)
Gastric Perforation * 1	1/259 (0.39%)	0/260 (0.00%)
Gastric Ulcer * 1	1/259 (0.39%)	0/260 (0.00%)
Gastric Ulcer Haemorrhage * 1	1/259 (0.39%)	0/260 (0.00%)
Gastritis * 1	3/259 (1.16%)	0/260 (0.00%)
Gastritis Haemorrhagic * 1	1/259 (0.39%)	0/260 (0.00%)
Haematochezia * 1	1/259 (0.39%)	1/260 (0.38%)
Ileus * 1	1/259 (0.39%)	0/260 (0.00%)
Inguinal Hernia * 1	1/259 (0.39%)	2/260 (0.77%)
Intestinal Obstruction * 1	0/259 (0.00%)	1/260 (0.38%)
Intestinal Perforation * 1	0/259 (0.00%)	1/260 (0.38%)
Mouth Haemorrhage * 1	1/259 (0.39%)	0/260 (0.00%)
Mouth Ulceration * 1	1/259 (0.39%)	0/260 (0.00%)
Nausea * 1	4/259 (1.54%)	1/260 (0.38%)
Proctitis * 1	1/259 (0.39%)	0/260 (0.00%)
Small Intestinal Obstruction * 1	1/259 (0.39%)	0/260 (0.00%)
Umbilical Hernia * 1	1/259 (0.39%)	0/260 (0.00%)
Upper Gastrointestinal Haemorrhage * 1	1/259 (0.39%)	0/260 (0.00%)
Vomiting * 1	5/259 (1.93%)	0/260 (0.00%)
General disorders
Asthenia * 1	0/259 (0.00%)	2/260 (0.77%)
Chest Discomfort * 1	0/259 (0.00%)	1/260 (0.38%)
Chest Pain * 1	2/259 (0.77%)	2/260 (0.77%)
Chills * 1	1/259 (0.39%)	1/260 (0.38%)
Death * 1	3/259 (1.16%)	0/260 (0.00%)
Fatigue * 1	1/259 (0.39%)	0/260 (0.00%)
General Physical Health Deterioration * 1	4/259 (1.54%)	0/260 (0.00%)
Localised Oedema * 1	1/259 (0.39%)	0/260 (0.00%)
Malaise * 1	3/259 (1.16%)	0/260 (0.00%)
Mucosal Inflammation * 1	0/259 (0.00%)	1/260 (0.38%)
Multiple Organ Dysfunction Syndrome * 1	3/259 (1.16%)	0/260 (0.00%)
Non-Cardiac Chest Pain * 1	1/259 (0.39%)	0/260 (0.00%)
Oedema Peripheral * 1	2/259 (0.77%)	0/260 (0.00%)
Pyrexia * 1	19/259 (7.34%)	14/260 (5.38%)
Sudden Death * 1	2/259 (0.77%)	0/260 (0.00%)
Hepatobiliary disorders
Cholecystitis * 1	1/259 (0.39%)	0/260 (0.00%)
Cholecystitis Acute * 1	2/259 (0.77%)	1/260 (0.38%)
Cholelithiasis * 1	0/259 (0.00%)	1/260 (0.38%)
Hepatic Function Abnormal * 1	0/259 (0.00%)	1/260 (0.38%)
Immune system disorders
Anaphylactic Reaction * 1	1/259 (0.39%)	1/260 (0.38%)
Drug Hypersensitivity * 1	2/259 (0.77%)	1/260 (0.38%)
Hypersensitivity * 1	2/259 (0.77%)	1/260 (0.38%)
Serum Sickness * 1	1/259 (0.39%)	0/260 (0.00%)
Infections and infestations
Abscess Intestinal * 1	1/259 (0.39%)	0/260 (0.00%)
Abscess Limb * 1	2/259 (0.77%)	0/260 (0.00%)
Appendicitis * 1	1/259 (0.39%)	2/260 (0.77%)
Arthritis Bacterial * 1	0/259 (0.00%)	1/260 (0.38%)
Bacterial Sepsis * 1	0/259 (0.00%)	1/260 (0.38%)
Bronchitis * 1	6/259 (2.32%)	4/260 (1.54%)
Bronchopulmonary Aspergillosis * 1	4/259 (1.54%)	0/260 (0.00%)
Campylobacter Gastroenteritis * 1	1/259 (0.39%)	1/260 (0.38%)
Campylobacter Infection * 1	1/259 (0.39%)	0/260 (0.00%)
Candida Sepsis * 1	1/259 (0.39%)	0/260 (0.00%)
Cellulitis * 1	8/259 (3.09%)	3/260 (1.15%)
Clostridium Colitis * 1	0/259 (0.00%)	1/260 (0.38%)
Clostridium Difficile Colitis * 1	1/259 (0.39%)	0/260 (0.00%)
Clostridium Difficile Infection * 1	3/259 (1.16%)	0/260 (0.00%)
Covid-19 * 1	1/259 (0.39%)	0/260 (0.00%)
Covid-19 Pneumonia * 1	4/259 (1.54%)	2/260 (0.77%)
Cystitis * 1	1/259 (0.39%)	0/260 (0.00%)
Cytomegalovirus Colitis * 1	1/259 (0.39%)	0/260 (0.00%)
Cytomegalovirus Infection * 1	1/259 (0.39%)	0/260 (0.00%)
Device Related Infection * 1	1/259 (0.39%)	2/260 (0.77%)
Disseminated Varicella Zoster Virus Infection * 1	1/259 (0.39%)	0/260 (0.00%)
Diverticulitis * 1	1/259 (0.39%)	1/260 (0.38%)
Epididymitis * 1	1/259 (0.39%)	0/260 (0.00%)
Epiglottitis * 1	1/259 (0.39%)	0/260 (0.00%)
Erysipelas * 1	2/259 (0.77%)	1/260 (0.38%)
Escherichia Bacteraemia * 1	2/259 (0.77%)	0/260 (0.00%)
Escherichia Infection * 1	1/259 (0.39%)	0/260 (0.00%)
Fungal Oesophagitis * 1	1/259 (0.39%)	0/260 (0.00%)
Gastroenteritis * 1	3/259 (1.16%)	1/260 (0.38%)
Gastroenteritis Salmonella * 1	0/259 (0.00%)	1/260 (0.38%)
Gastroenteritis Viral * 1	1/259 (0.39%)	0/260 (0.00%)
Hepatitis B * 1	1/259 (0.39%)	0/260 (0.00%)
Hepatitis B Reactivation * 1	0/259 (0.00%)	1/260 (0.38%)
Herpes Zoster * 1	2/259 (0.77%)	3/260 (1.15%)
Herpes Zoster Oticus * 1	0/259 (0.00%)	1/260 (0.38%)
Histoplasmosis Disseminated * 1	1/259 (0.39%)	0/260 (0.00%)
Infection * 1	1/259 (0.39%)	0/260 (0.00%)
Infective Exacerbation of Chronic Obstructive Airways Disease * 1	1/259 (0.39%)	1/260 (0.38%)
Influenza * 1	1/259 (0.39%)	2/260 (0.77%)
Listeriosis * 1	0/259 (0.00%)	1/260 (0.38%)
Localised Infection * 1	2/259 (0.77%)	0/260 (0.00%)
Lower Respiratory Tract Infection * 1	5/259 (1.93%)	0/260 (0.00%)
Lung Abscess * 1	1/259 (0.39%)	0/260 (0.00%)
Meningococcal Bacteraemia * 1	1/259 (0.39%)	0/260 (0.00%)
Moraxella Infection * 1	0/259 (0.00%)	1/260 (0.38%)
Nosocomial Infection * 1	1/259 (0.39%)	0/260 (0.00%)
Oesophageal Candidiasis * 1	0/259 (0.00%)	1/260 (0.38%)
Oral Candidiasis * 1	1/259 (0.39%)	0/260 (0.00%)
Oropharyngeal Candidiasis * 1	1/259 (0.39%)	0/260 (0.00%)
Osteomyelitis * 1	1/259 (0.39%)	0/260 (0.00%)
Osteomyelitis Chronic * 1	0/259 (0.00%)	1/260 (0.38%)
Otitis Media * 1	1/259 (0.39%)	1/260 (0.38%)
Parasitic Gastroenteritis * 1	1/259 (0.39%)	0/260 (0.00%)
Paronychia * 1	1/259 (0.39%)	0/260 (0.00%)
Periorbital Cellulitis * 1	1/259 (0.39%)	0/260 (0.00%)
Pharyngitis * 1	0/259 (0.00%)	1/260 (0.38%)
Pneumococcal Bacteraemia * 1	0/259 (0.00%)	1/260 (0.38%)
Pneumocystis Jirovecii Pneumonia * 1	2/259 (0.77%)	1/260 (0.38%)
Pneumonia * 1	55/259 (21.24%)	34/260 (13.08%)
Pneumonia Bacterial * 1	1/259 (0.39%)	2/260 (0.77%)
Pneumonia Cytomegaloviral * 1	0/259 (0.00%)	1/260 (0.38%)
Pneumonia Fungal * 1	2/259 (0.77%)	0/260 (0.00%)
Pneumonia Pneumococcal * 1	0/259 (0.00%)	1/260 (0.38%)
Pneumonia Pseudomonal * 1	0/259 (0.00%)	2/260 (0.77%)
Pneumonia Viral * 1	2/259 (0.77%)	1/260 (0.38%)
Postoperative Wound Infection * 1	0/259 (0.00%)	1/260 (0.38%)
Progressive Multifocal Leukoencephalopathy * 1	0/259 (0.00%)	1/260 (0.38%)
Pseudomembranous Colitis * 1	0/259 (0.00%)	2/260 (0.77%)
Pseudomonas Infection * 1	1/259 (0.39%)	0/260 (0.00%)
Pulmonary Sepsis * 1	1/259 (0.39%)	1/260 (0.38%)
Pulmonary Tuberculosis * 1	0/259 (0.00%)	1/260 (0.38%)
Pyelonephritis * 1	1/259 (0.39%)	0/260 (0.00%)
Pyelonephritis Chronic * 1	1/259 (0.39%)	0/260 (0.00%)
Respiratory Syncytial Virus Infection * 1	0/259 (0.00%)	1/260 (0.38%)
Respiratory Tract Infection * 1	5/259 (1.93%)	2/260 (0.77%)
Sepsis * 1	9/259 (3.47%)	6/260 (2.31%)
Septic Shock * 1	3/259 (1.16%)	2/260 (0.77%)
Sialoadenitis * 1	1/259 (0.39%)	0/260 (0.00%)
Sinusitis * 1	4/259 (1.54%)	2/260 (0.77%)
Sinusitis Bacterial * 1	1/259 (0.39%)	0/260 (0.00%)
Sinusitis Fungal * 1	1/259 (0.39%)	0/260 (0.00%)
Skin Infection * 1	2/259 (0.77%)	0/260 (0.00%)
Soft Tissue Infection * 1	2/259 (0.77%)	1/260 (0.38%)
Staphylococcal Bacteraemia * 1	2/259 (0.77%)	0/260 (0.00%)
Staphylococcal Infection * 1	1/259 (0.39%)	0/260 (0.00%)
Staphylococcal Sepsis * 1	1/259 (0.39%)	0/260 (0.00%)
Streptococcal Bacteraemia * 1	1/259 (0.39%)	1/260 (0.38%)
Suspected Covid-19 * 1	1/259 (0.39%)	0/260 (0.00%)
Toxoplasmosis * 1	0/259 (0.00%)	1/260 (0.38%)
Upper Respiratory Tract Infection * 1	4/259 (1.54%)	3/260 (1.15%)
Urinary Tract Infection * 1	7/259 (2.70%)	2/260 (0.77%)
Urosepsis * 1	1/259 (0.39%)	3/260 (1.15%)
Vascular Device Infection * 1	0/259 (0.00%)	1/260 (0.38%)
Injury, poisoning and procedural complications
Facial Bones Fracture * 1	0/259 (0.00%)	1/260 (0.38%)
Fall * 1	0/259 (0.00%)	1/260 (0.38%)
Femur Fracture * 1	2/259 (0.77%)	0/260 (0.00%)
Head Injury * 1	0/259 (0.00%)	1/260 (0.38%)
Hip Fracture * 1	1/259 (0.39%)	0/260 (0.00%)
Humerus Fracture * 1	2/259 (0.77%)	1/260 (0.38%)
Infusion Related Reaction * 1	2/259 (0.77%)	4/260 (1.54%)
Joint Dislocation * 1	1/259 (0.39%)	0/260 (0.00%)
Limb Injury * 1	1/259 (0.39%)	0/260 (0.00%)
Pelvic Fracture * 1	1/259 (0.39%)	0/260 (0.00%)
Skin Laceration * 1	1/259 (0.39%)	1/260 (0.38%)
Spinal Fracture * 1	0/259 (0.00%)	1/260 (0.38%)
Stoma Complication * 1	0/259 (0.00%)	1/260 (0.38%)
Subdural Haematoma * 1	4/259 (1.54%)	4/260 (1.54%)
Toxicity to Various Agents * 1	1/259 (0.39%)	0/260 (0.00%)
Traumatic Intracranial Haemorrhage * 1	1/259 (0.39%)	0/260 (0.00%)
Wound * 1	1/259 (0.39%)	0/260 (0.00%)
Investigations
Alanine Aminotransferase Increased * 1	2/259 (0.77%)	0/260 (0.00%)
Aspartate Aminotransferase Increased * 1	2/259 (0.77%)	0/260 (0.00%)
Blood Creatinine Increased * 1	0/259 (0.00%)	2/260 (0.77%)
Bronchoscopy * 1	1/259 (0.39%)	0/260 (0.00%)
Cytomegalovirus Test Positive * 1	1/259 (0.39%)	1/260 (0.38%)
Gastrointestinal Stoma Output Increased * 1	1/259 (0.39%)	0/260 (0.00%)
Neutrophil Count Decreased * 1	1/259 (0.39%)	1/260 (0.38%)
Platelet Count Decreased * 1	1/259 (0.39%)	3/260 (1.15%)
Scan Abnormal * 1	1/259 (0.39%)	0/260 (0.00%)
Metabolism and nutrition disorders
Decreased Appetite * 1	2/259 (0.77%)	1/260 (0.38%)
Dehydration * 1	4/259 (1.54%)	5/260 (1.92%)
Diabetes Mellitus * 1	0/259 (0.00%)	1/260 (0.38%)
Gout * 1	1/259 (0.39%)	0/260 (0.00%)
Hyperglycaemia * 1	0/259 (0.00%)	2/260 (0.77%)
Hyperkalaemia * 1	0/259 (0.00%)	1/260 (0.38%)
Hypoglycaemia * 1	0/259 (0.00%)	1/260 (0.38%)
Hypokalaemia * 1	0/259 (0.00%)	1/260 (0.38%)
Hyponatraemia * 1	1/259 (0.39%)	2/260 (0.77%)
Metabolic Acidosis * 1	1/259 (0.39%)	0/260 (0.00%)
Tumour Lysis Syndrome * 1	3/259 (1.16%)	3/260 (1.15%)
Musculoskeletal and connective tissue disorders
Arthralgia * 1	1/259 (0.39%)	0/260 (0.00%)
Arthritis * 1	1/259 (0.39%)	0/260 (0.00%)
Back Pain * 1	2/259 (0.77%)	1/260 (0.38%)
Finger Deformity * 1	0/259 (0.00%)	1/260 (0.38%)
Flank Pain * 1	0/259 (0.00%)	2/260 (0.77%)
Jaw Cyst * 1	1/259 (0.39%)	0/260 (0.00%)
Muscular Weakness * 1	1/259 (0.39%)	2/260 (0.77%)
Musculoskeletal Chest Pain * 1	1/259 (0.39%)	0/260 (0.00%)
Myalgia * 1	0/259 (0.00%)	1/260 (0.38%)
Osteoarthritis * 1	1/259 (0.39%)	2/260 (0.77%)
Osteoporosis * 1	0/259 (0.00%)	1/260 (0.38%)
Osteoporotic Fracture * 1	1/259 (0.39%)	0/260 (0.00%)
Pain in Extremity * 1	0/259 (0.00%)	1/260 (0.38%)
Rhabdomyolysis * 1	1/259 (0.39%)	0/260 (0.00%)
Spinal Disorder * 1	0/259 (0.00%)	1/260 (0.38%)
Spinal Osteoarthritis * 1	1/259 (0.39%)	0/260 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute Myeloid Leukaemia * 1	1/259 (0.39%)	2/260 (0.77%)
Adenocarcinoma Gastric * 1	0/259 (0.00%)	1/260 (0.38%)
Adenocarcinoma of Colon * 1	2/259 (0.77%)	2/260 (0.77%)
Appendix Cancer * 1	0/259 (0.00%)	1/260 (0.38%)
Basal Cell Carcinoma * 1	2/259 (0.77%)	4/260 (1.54%)
Benign Anorectal Neoplasm * 1	0/259 (0.00%)	1/260 (0.38%)
Bladder Transitional Cell Carcinoma * 1	2/259 (0.77%)	0/260 (0.00%)
Bowen's Disease * 1	0/259 (0.00%)	1/260 (0.38%)
Brain Neoplasm Malignant * 1	1/259 (0.39%)	0/260 (0.00%)
Cholesteatoma * 1	0/259 (0.00%)	1/260 (0.38%)
Chronic Myelomonocytic Leukaemia * 1	0/259 (0.00%)	1/260 (0.38%)
Gastric Cancer * 1	1/259 (0.39%)	0/260 (0.00%)
Intestinal Adenocarcinoma * 1	1/259 (0.39%)	0/260 (0.00%)
Invasive Ductal Breast Carcinoma * 1	1/259 (0.39%)	0/260 (0.00%)
Langerhans' Cell Histiocytosis * 1	1/259 (0.39%)	0/260 (0.00%)
Laryngeal Squamous Cell Carcinoma * 1	0/259 (0.00%)	1/260 (0.38%)
Lung Adenocarcinoma * 1	1/259 (0.39%)	2/260 (0.77%)
Malignant Melanoma * 1	0/259 (0.00%)	2/260 (0.77%)
Metastatic Malignant Melanoma * 1	1/259 (0.39%)	0/260 (0.00%)
Myelodysplastic Syndrome * 1	0/259 (0.00%)	1/260 (0.38%)
Non-Small Cell Lung Cancer * 1	0/259 (0.00%)	1/260 (0.38%)
Ocular Neoplasm * 1	0/259 (0.00%)	1/260 (0.38%)
Prostate Cancer * 1	2/259 (0.77%)	2/260 (0.77%)
Renal Cell Carcinoma * 1	1/259 (0.39%)	0/260 (0.00%)
Skin Squamous Cell Carcinoma Metastatic * 1	1/259 (0.39%)	0/260 (0.00%)
Small Cell Lung Cancer Metastatic * 1	0/259 (0.00%)	1/260 (0.38%)
Squamous Cell Carcinoma of Lung * 1	2/259 (0.77%)	2/260 (0.77%)
Squamous Cell Carcinoma of Skin * 1	2/259 (0.77%)	4/260 (1.54%)
Thyroid Cancer * 1	1/259 (0.39%)	0/260 (0.00%)
Transitional Cell Carcinoma * 1	0/259 (0.00%)	1/260 (0.38%)
Nervous system disorders
Amnesia * 1	1/259 (0.39%)	0/260 (0.00%)
Amyotrophic Lateral Sclerosis * 1	1/259 (0.39%)	0/260 (0.00%)
Brain Oedema * 1	0/259 (0.00%)	1/260 (0.38%)
Carotid Artery Stenosis * 1	1/259 (0.39%)	0/260 (0.00%)
Central Nervous System Lesion * 1	0/259 (0.00%)	1/260 (0.38%)
Cerebral Ischaemia * 1	0/259 (0.00%)	1/260 (0.38%)
Cerebrovascular Accident * 1	2/259 (0.77%)	1/260 (0.38%)
Dizziness * 1	0/259 (0.00%)	1/260 (0.38%)
Facial Paralysis * 1	0/259 (0.00%)	1/260 (0.38%)
Haemorrhagic Stroke * 1	1/259 (0.39%)	1/260 (0.38%)
Headache * 1	0/259 (0.00%)	1/260 (0.38%)
Ischaemic Stroke * 1	3/259 (1.16%)	0/260 (0.00%)
Lacunar Stroke * 1	1/259 (0.39%)	0/260 (0.00%)
Loss of Consciousness * 1	1/259 (0.39%)	0/260 (0.00%)
Peripheral Motor Neuropathy * 1	0/259 (0.00%)	1/260 (0.38%)
Post Herpetic Neuralgia * 1	0/259 (0.00%)	1/260 (0.38%)
Presyncope * 1	0/259 (0.00%)	1/260 (0.38%)
Quadriplegia * 1	1/259 (0.39%)	0/260 (0.00%)
Seizure * 1	1/259 (0.39%)	1/260 (0.38%)
Spinal Cord Compression * 1	1/259 (0.39%)	0/260 (0.00%)
Subarachnoid Haemorrhage * 1	0/259 (0.00%)	1/260 (0.38%)
Syncope * 1	5/259 (1.93%)	5/260 (1.92%)
Thalamic Infarction * 1	0/259 (0.00%)	1/260 (0.38%)
Transient Global Amnesia * 1	0/259 (0.00%)	1/260 (0.38%)
Transient Ischaemic Attack * 1	1/259 (0.39%)	1/260 (0.38%)
Vascular Encephalopathy * 1	1/259 (0.39%)	0/260 (0.00%)
Product Issues
Device End of Service * 1	1/259 (0.39%)	0/260 (0.00%)
Psychiatric disorders
Anxiety * 1	1/259 (0.39%)	0/260 (0.00%)
Confusional State * 1	0/259 (0.00%)	1/260 (0.38%)
Delirium * 1	1/259 (0.39%)	1/260 (0.38%)
Depression * 1	1/259 (0.39%)	0/260 (0.00%)
Renal and urinary disorders
Acute Kidney Injury * 1	7/259 (2.70%)	2/260 (0.77%)
Calculus Urinary * 1	0/259 (0.00%)	1/260 (0.38%)
Haematuria * 1	1/259 (0.39%)	1/260 (0.38%)
Renal Colic * 1	0/259 (0.00%)	1/260 (0.38%)
Renal Cyst Haemorrhage * 1	1/259 (0.39%)	0/260 (0.00%)
Renal Impairment * 1	3/259 (1.16%)	0/260 (0.00%)
Urinary Retention * 1	0/259 (0.00%)	1/260 (0.38%)
Urinary Tract Obstruction * 1	2/259 (0.77%)	0/260 (0.00%)
Reproductive system and breast disorders
Balanoposthitis * 1	1/259 (0.39%)	0/260 (0.00%)
Benign Prostatic Hyperplasia * 1	2/259 (0.77%)	1/260 (0.38%)
Prostatitis * 1	1/259 (0.39%)	0/260 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute Pulmonary Oedema * 1	1/259 (0.39%)	1/260 (0.38%)
Acute Respiratory Distress Syndrome * 1	1/259 (0.39%)	1/260 (0.38%)
Acute Respiratory Failure * 1	1/259 (0.39%)	2/260 (0.77%)
Asthma * 1	1/259 (0.39%)	1/260 (0.38%)
Atelectasis * 1	0/259 (0.00%)	1/260 (0.38%)
Bronchiectasis * 1	2/259 (0.77%)	0/260 (0.00%)
Bronchopneumopathy * 1	0/259 (0.00%)	1/260 (0.38%)
Bronchospasm * 1	1/259 (0.39%)	0/260 (0.00%)
Chronic Obstructive Pulmonary Disease * 1	1/259 (0.39%)	5/260 (1.92%)
Cough * 1	1/259 (0.39%)	0/260 (0.00%)
Dyspnoea * 1	0/259 (0.00%)	1/260 (0.38%)
Haemoptysis * 1	0/259 (0.00%)	2/260 (0.77%)
Haemothorax * 1	1/259 (0.39%)	0/260 (0.00%)
Hydrothorax * 1	1/259 (0.39%)	0/260 (0.00%)
Hypersensitivity Pneumonitis * 1	1/259 (0.39%)	0/260 (0.00%)
Hypoxia * 1	0/259 (0.00%)	2/260 (0.77%)
Interstitial Lung Disease * 1	1/259 (0.39%)	1/260 (0.38%)
Lung Infiltration * 1	0/259 (0.00%)	1/260 (0.38%)
Organising Pneumonia * 1	1/259 (0.39%)	0/260 (0.00%)
Pleural Effusion * 1	7/259 (2.70%)	2/260 (0.77%)
Pleurisy * 1	1/259 (0.39%)	0/260 (0.00%)
Pneumonia Aspiration * 1	1/259 (0.39%)	0/260 (0.00%)
Pneumonitis * 1	2/259 (0.77%)	2/260 (0.77%)
Pneumothorax * 1	0/259 (0.00%)	1/260 (0.38%)
Productive Cough * 1	1/259 (0.39%)	0/260 (0.00%)
Pulmonary Embolism * 1	1/259 (0.39%)	2/260 (0.77%)
Pulmonary Haemorrhage * 1	0/259 (0.00%)	1/260 (0.38%)
Respiratory Distress * 1	1/259 (0.39%)	0/260 (0.00%)
Respiratory Failure * 1	5/259 (1.93%)	1/260 (0.38%)
Tonsillar Disorder * 1	0/259 (0.00%)	1/260 (0.38%)
Skin and subcutaneous tissue disorders
Actinic Keratosis * 1	0/259 (0.00%)	1/260 (0.38%)
Dermatitis Allergic * 1	1/259 (0.39%)	0/260 (0.00%)
Dermatitis Bullous * 1	1/259 (0.39%)	0/260 (0.00%)
Diabetic Foot * 1	1/259 (0.39%)	0/260 (0.00%)
Drug Eruption * 1	1/259 (0.39%)	0/260 (0.00%)
Drug Reaction with Eosinophilia and Systemic Symptoms * 1	1/259 (0.39%)	0/260 (0.00%)
Rash * 1	5/259 (1.93%)	1/260 (0.38%)
Rash Maculo-Papular * 1	5/259 (1.93%)	0/260 (0.00%)
Urticaria * 1	0/259 (0.00%)	1/260 (0.38%)
Surgical and medical procedures
Coronary Artery Bypass * 1	0/259 (0.00%)	1/260 (0.38%)
Tracheostomy Closure * 1	0/259 (0.00%)	1/260 (0.38%)
Vascular disorders
Aortic Stenosis * 1	0/259 (0.00%)	1/260 (0.38%)
Arterial Thrombosis * 1	0/259 (0.00%)	1/260 (0.38%)
Deep Vein Thrombosis * 1	0/259 (0.00%)	1/260 (0.38%)
Embolism * 1	1/259 (0.39%)	0/260 (0.00%)
Giant Cell Arteritis * 1	1/259 (0.39%)	0/260 (0.00%)
Haematoma * 1	0/259 (0.00%)	1/260 (0.38%)
Hypertension * 1	1/259 (0.39%)	0/260 (0.00%)
Hypertensive Crisis * 1	1/259 (0.39%)	0/260 (0.00%)
Hypertensive Urgency * 1	1/259 (0.39%)	0/260 (0.00%)
Hypotension * 1	2/259 (0.77%)	2/260 (0.77%)
Peripheral Artery Aneurysm * 1	1/259 (0.39%)	0/260 (0.00%)
Raynaud's Phenomenon * 1	1/259 (0.39%)	0/260 (0.00%)
1 Term from vocabulary, MedDRA Version 24.0; * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Ibrutinib + BR (Treatment B)	Placebo + BR (Treatment A)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	256/259 (98.84%)	255/260 (98.08%)
Blood and lymphatic system disorders
Anaemia * 1	83/259 (32.05%)	60/260 (23.08%)
Leukopenia * 1	26/259 (10.04%)	14/260 (5.38%)
Lymphopenia * 1	18/259 (6.95%)	14/260 (5.38%)
Neutropenia * 1	109/259 (42.08%)	104/260 (40.00%)
Thrombocytopenia * 1	61/259 (23.55%)	43/260 (16.54%)
Cardiac disorders
Atrial Fibrillation * 1	30/259 (11.58%)	14/260 (5.38%)
Palpitations * 1	9/259 (3.47%)	13/260 (5.00%)
Ear and labyrinth disorders
Vertigo * 1	11/259 (4.25%)	13/260 (5.00%)
Eye disorders
Cataract * 1	21/259 (8.11%)	16/260 (6.15%)
Dry Eye * 1	16/259 (6.18%)	5/260 (1.92%)
Vision Blurred * 1	14/259 (5.41%)	10/260 (3.85%)
Gastrointestinal disorders
Abdominal Pain * 1	25/259 (9.65%)	29/260 (11.15%)
Abdominal Pain Upper * 1	19/259 (7.34%)	10/260 (3.85%)
Constipation * 1	51/259 (19.69%)	66/260 (25.38%)
Diarrhoea * 1	117/259 (45.17%)	96/260 (36.92%)
Dry Mouth * 1	18/259 (6.95%)	6/260 (2.31%)
Dyspepsia * 1	21/259 (8.11%)	21/260 (8.08%)
Gastrooesophageal Reflux Disease * 1	18/259 (6.95%)	16/260 (6.15%)
Nausea * 1	107/259 (41.31%)	107/260 (41.15%)
Stomatitis * 1	21/259 (8.11%)	6/260 (2.31%)
Vomiting * 1	56/259 (21.62%)	48/260 (18.46%)
General disorders
Asthenia * 1	30/259 (11.58%)	25/260 (9.62%)
Chest Pain * 1	14/259 (5.41%)	12/260 (4.62%)
Chills * 1	17/259 (6.56%)	39/260 (15.00%)
Fatigue * 1	78/259 (30.12%)	77/260 (29.62%)
Influenza Like Illness * 1	14/259 (5.41%)	13/260 (5.00%)
Malaise * 1	12/259 (4.63%)	14/260 (5.38%)
Mucosal Inflammation * 1	14/259 (5.41%)	15/260 (5.77%)
Oedema Peripheral * 1	50/259 (19.31%)	42/260 (16.15%)
Pyrexia * 1	86/259 (33.20%)	76/260 (29.23%)
Immune system disorders
Hypogammaglobulinaemia * 1	8/259 (3.09%)	14/260 (5.38%)
Infections and infestations
Bronchitis * 1	33/259 (12.74%)	36/260 (13.85%)
Cellulitis * 1	15/259 (5.79%)	4/260 (1.54%)
Conjunctivitis * 1	26/259 (10.04%)	6/260 (2.31%)
Herpes Zoster * 1	13/259 (5.02%)	27/260 (10.38%)
Influenza * 1	9/259 (3.47%)	16/260 (6.15%)
Lower Respiratory Tract Infection * 1	13/259 (5.02%)	9/260 (3.46%)
Nasopharyngitis * 1	24/259 (9.27%)	28/260 (10.77%)
Oral Candidiasis * 1	18/259 (6.95%)	7/260 (2.69%)
Pneumonia * 1	53/259 (20.46%)	38/260 (14.62%)
Rhinitis * 1	10/259 (3.86%)	13/260 (5.00%)
Sinusitis * 1	25/259 (9.65%)	34/260 (13.08%)
Skin Infection * 1	18/259 (6.95%)	5/260 (1.92%)
Upper Respiratory Tract Infection * 1	69/259 (26.64%)	68/260 (26.15%)
Urinary Tract Infection * 1	35/259 (13.51%)	32/260 (12.31%)
Injury, poisoning and procedural complications
Contusion * 1	22/259 (8.49%)	12/260 (4.62%)
Fall * 1	15/259 (5.79%)	13/260 (5.00%)
Infusion Related Reaction * 1	19/259 (7.34%)	26/260 (10.00%)
Investigations
Alanine Aminotransferase Increased * 1	23/259 (8.88%)	12/260 (4.62%)
Aspartate Aminotransferase Increased * 1	24/259 (9.27%)	14/260 (5.38%)
Blood Creatinine Increased * 1	23/259 (8.88%)	22/260 (8.46%)
Lymphocyte Count Decreased * 1	32/259 (12.36%)	26/260 (10.00%)
Neutrophil Count Decreased * 1	38/259 (14.67%)	43/260 (16.54%)
Platelet Count Decreased * 1	41/259 (15.83%)	28/260 (10.77%)
Weight Decreased * 1	26/259 (10.04%)	20/260 (7.69%)
White Blood Cell Count Decreased * 1	30/259 (11.58%)	34/260 (13.08%)
Metabolism and nutrition disorders
Decreased Appetite * 1	54/259 (20.85%)	36/260 (13.85%)
Hyperglycaemia * 1	15/259 (5.79%)	10/260 (3.85%)
Hyperuricaemia * 1	22/259 (8.49%)	20/260 (7.69%)
Hypocalcaemia * 1	17/259 (6.56%)	7/260 (2.69%)
Hypokalaemia * 1	39/259 (15.06%)	30/260 (11.54%)
Hypomagnesaemia * 1	24/259 (9.27%)	18/260 (6.92%)
Musculoskeletal and connective tissue disorders
Arthralgia * 1	45/259 (17.37%)	44/260 (16.92%)
Back Pain * 1	35/259 (13.51%)	37/260 (14.23%)
Muscle Spasms * 1	21/259 (8.11%)	13/260 (5.00%)
Muscular Weakness * 1	15/259 (5.79%)	5/260 (1.92%)
Myalgia * 1	31/259 (11.97%)	30/260 (11.54%)
Pain in Extremity * 1	18/259 (6.95%)	24/260 (9.23%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous Cell Carcinoma of Skin * 1	12/259 (4.63%)	13/260 (5.00%)
Nervous system disorders
Dizziness * 1	22/259 (8.49%)	19/260 (7.31%)
Headache * 1	33/259 (12.74%)	40/260 (15.38%)
Paraesthesia * 1	13/259 (5.02%)	13/260 (5.00%)
Psychiatric disorders
Anxiety * 1	14/259 (5.41%)	17/260 (6.54%)
Depression * 1	16/259 (6.18%)	12/260 (4.62%)
Insomnia * 1	29/259 (11.20%)	28/260 (10.77%)
Renal and urinary disorders
Haematuria * 1	15/259 (5.79%)	7/260 (2.69%)
Respiratory, thoracic and mediastinal disorders
Cough * 1	77/259 (29.73%)	85/260 (32.69%)
Dyspnoea * 1	26/259 (10.04%)	45/260 (17.31%)
Epistaxis * 1	31/259 (11.97%)	12/260 (4.62%)
Nasal Congestion * 1	7/259 (2.70%)	14/260 (5.38%)
Oropharyngeal Pain * 1	22/259 (8.49%)	23/260 (8.85%)
Productive Cough * 1	15/259 (5.79%)	18/260 (6.92%)
Skin and subcutaneous tissue disorders
Dry Skin * 1	21/259 (8.11%)	10/260 (3.85%)
Erythema * 1	13/259 (5.02%)	12/260 (4.62%)
Pruritus * 1	46/259 (17.76%)	56/260 (21.54%)
Rash * 1	95/259 (36.68%)	57/260 (21.92%)
Rash Maculo-Papular * 1	22/259 (8.49%)	10/260 (3.85%)
Skin Lesion * 1	16/259 (6.18%)	10/260 (3.85%)
Urticaria * 1	16/259 (6.18%)	7/260 (2.69%)
Vascular disorders
Haematoma * 1	20/259 (7.72%)	3/260 (1.15%)
Hypertension * 1	35/259 (13.51%)	29/260 (11.15%)
Hypotension * 1	21/259 (8.11%)	16/260 (6.15%)
1 Term from vocabulary, MedDRA Version 24.0; * Indicates events were collected by non-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.

If an investigator wishes to publish information from the study, 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 by the sponsor in writing, the investigator will withhold such publication for up to an additional 60 days.

Results Point of Contact

• Name/Title: EXECUTIVE MEDICAL DIRECTOR
• 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):

Wang ML, Jurczak W, Jerkeman M, Trotman J, Zinzani PL, Belada D, Boccomini C, Flinn IW, Giri P, Goy A, Hamlin PA, Hermine O, Hernandez-Rivas JA, Hong X, Kim SJ, Lewis D, Mishima Y, Ozcan M, Perini GF, Pocock C, Song Y, Spurgeon SE, Storring JM, Walewski J, Zhu J, Qin R, Henninger T, Deshpande S, Howes A, Le Gouill S, Dreyling M; SHINE Investigators. Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma. N Engl J Med. 2022 Jun 30;386(26):2482-2494. doi: 10.1056/NEJMoa2201817. Epub 2022 Jun 3.

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT01776840
• Other Study ID Numbers: CR100967; PCI-32765MCL3002 ( Other Identifier: Janssen Research & Development, LLC ); U1111-1137-0389 ( Other Identifier: Universal Trial Number ); 2012-004056-11 ( EudraCT Number )
• First Submitted: January 24, 2013
• First Posted: January 28, 2013
• Results First Submitted: June 30, 2022
• Results First Posted: July 26, 2022
• Last Update Posted: April 25, 2024