A Study of Ibrutinib in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

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ClinicalTrials.gov Identifier: NCT01611090

Recruitment Status : Completed

First Posted : June 4, 2012

Results First Posted : March 3, 2020

Last Update Posted : March 3, 2020

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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
Conditions	Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma
Interventions	Drug: Ibrutinib Drug: Bendamustine hydrochloride Drug: Rituximab Drug: Placebo
Enrollment	578

Participant Flow

Recruitment Details
Pre-assignment Details	A total of 578 participants were enrolled in the study. Among these, 289 participants were randomized in each ibrutinib + bendamustine/rituximab (BR) treatment group and placebo+BR treatment group.


Arm/Group Title	Ibrutinib+BR	Placebo+BR	Crossover to Ibrutinib
Arm/Group Description	Participants received ibrutinib 420...	Participants received placebo (3 ca...	Participants in the placebo+BR trea...
Arm/Group Description	Participants received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.	Participants received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.	Participants in the placebo+BR treatment group could cross over to receive next-line ibrutinib treatment (420 mg [3 * 140 mg capsules] orally once daily on a 28-day cycle) at the discretion of the investigator at the time of disease progression or if International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria for treatment were met.
Period Title: Randomized Period
Started	289	289	0
Treated	287	287	0
Completed	259	260	0
Not Completed	30	29	0
Reason Not Completed
Lost to Follow-up	8	3	0
Withdrawal by Subject	22	26	0
Period Title: Cross Over (Placebo to Ibrutinib)
Started	0	0	183
Treated	0	0	183
Completed	0	0	178
Not Completed	0	0	5
Reason Not Completed
Lost to Follow-up	0	0	4
Withdrawal by Subject	0	0	1

Baseline Characteristics

Arm/Group Title		Ibrutinib+BR	Placebo+BR	Total
Arm/Group Description		Participants received ibrutinib 420...	Participants received placebo (3 ca...	Total of all reporting groups
Arm/Group Description		Participants received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.	Participants received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Number of Baseline Participants		289	289	578
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	289 participants	289 participants	578 participants
		63.7 (9.82)	63.3 (9.3)	63.5 (9.56)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	289 participants	289 participants	578 participants
	Female	96 33.2%	100 34.6%	196 33.9%
	Male	193 66.8%	189 65.4%	382 66.1%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	289 participants	289 participants	578 participants
	Hispanic or Latino	13 4.5%	21 7.3%	34 5.9%
	Not Hispanic or Latino	256 88.6%	253 87.5%	509 88.1%
	Unknown or Not Reported	20 6.9%	15 5.2%	35 6.1%
Race/Ethnicity, Customized Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	289 participants	289 participants	578 participants
White		264 91.3%	264 91.3%	528 91.3%
Black		8 2.8%	6 2.1%	14 2.4%
Asian		1 0.3%	2 0.7%	3 0.5%
American Indian or Alaska Native		1 0.3%	1 0.3%	2 0.3%
Native Hawaiian or other Pacific Islander		0 0.0%	0 0.0%	0 0.0%
Other		3 1.0%	7 2.4%	10 1.7%
Unknown or not reported		12 4.2%	9 3.1%	21 3.6%
Region of Enrollment Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	289 participants	289 participants	578 participants
ARGENTINA		3 1.0%	3 1.0%	6 1.0%
BELGIUM		14 4.8%	14 4.8%	28 4.8%
BRAZIL		10 3.5%	12 4.2%	22 3.8%
CANADA		27 9.3%	35 12.1%	62 10.7%
COLOMBIA		0 0.0%	1 0.3%	1 0.2%
CZECH REPUBLIC		12 4.2%	11 3.8%	23 4.0%
FRANCE		16 5.5%	11 3.8%	27 4.7%
GERMANY		10 3.5%	11 3.8%	21 3.6%
GREECE		12 4.2%	5 1.7%	17 2.9%
ISRAEL		14 4.8%	12 4.2%	26 4.5%
MEXICO		1 0.3%	2 0.7%	3 0.5%
POLAND		19 6.6%	20 6.9%	39 6.7%
PORTUGAL		7 2.4%	12 4.2%	19 3.3%
RUSSIAN FEDERATION		50 17.3%	50 17.3%	100 17.3%
SOUTH KOREA		0 0.0%	1 0.3%	1 0.2%
SPAIN		9 3.1%	9 3.1%	18 3.1%
SWEDEN		2 0.7%	4 1.4%	6 1.0%
TURKEY		24 8.3%	27 9.3%	51 8.8%
UKRAINE		16 5.5%	14 4.8%	30 5.2%
UNITED KINGDOM		5 1.7%	9 3.1%	14 2.4%
UNITED STATES		38 13.1%	26 9.0%	64 11.1%

Outcome Measures

1.Primary Outcome


Title	Progression-free Survival (PFS)
Description	PFS was defined as the interval between the date of randomization and ...
Description	PFS was defined as the interval between the date of randomization and the date of disease progression or death, whichever was first reported. IWCLL 2008 criteria for PD: New enlarged nodes >1.5 cm, new hepatomegaly or splenomegaly, or other new organ infiltrates, bone lesion, ascites, or pleural effusion confirmed due to chronic lymphocytic leukemia (CLL); >=50% increase in existing lymph nodes; >=50% increase in enlargement of liver or spleen; >=50% increase from baseline in lymphocyte count (and to >=5*10^9/L) or >=50% increase from nadir count confirmed on >=2 serial assessments if absolute lymphocyte count (ALC) >=30,000 per microliter and lymphocyte doubling time is rapid, unless considered treatment-related lymphocytosis; new cytopenia (Hemoglobin b [Hgb] or platelets) attributable to CLL; and transformation to a more aggressive histology.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Intent to treat (ITT) population included all participants randomized into the study regardless of treatment actually received.


Arm/Group Title	Ibrutinib+BR	Placebo+BR
Arm/Group Description:	Participants received ibrutinib 420...	Participants received placebo (3 ca...
Arm/Group Description:	Participants received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.	Participants received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	289	289
Median (95% Confidence Interval) Unit of Measure: Months
	65.12 ^[1] (55.43 to NA)	14.32 (13.86 to 16.62)

[1]

Here, NA indicates upper limit of confidence interval (CI) was not estimable due to insufficient number of events.

Statistical Analysis 1

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

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.229
	Confidence Interval	(2-Sided) 95% 0.183 to 0.286
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Overall Response Rate (ORR)
Description	ORR defined as number of participants achieving a complete response (C...
Description	ORR defined as number of participants achieving a complete response (CR), complete response with incomplete marrow recovery (CRi), nodular partial response (nPR) or partial response (PR). IWCLL 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils >1.510^9/liter (L), platelets >10010^9/L, Hgb >11 gram per deciliter (g/dL) and absolute lymphocyte count <4000/microliter (mcL); CRi- CR with incomplete recovery of bone marrow; nPR- participants meet criteria for CR, but the bone marrow biopsy shows B-lymphoid nodules, may represent a clonal infiltrate; PR-2 of the following when abnormal at baseline: >=50% decrease in ALC, >=50% decrease in sum products of up to 6 lymph nodes, >=50% decrease in enlargement of spleen or liver; and 1 of the following: neutrophils >1.510^9/L, Platelets >10010^9/L and Hgb>11 g/dL or >=50% improvement over baseline in any of these; no new enlarged nodes or new hepatosplenomegaly.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Intent to treat (ITT) population included all participants randomized into the study regardless of treatment actually received.


Arm/Group Title	Ibrutinib+BR	Placebo+BR
Arm/Group Description:	Participants received ibrutinib 420...	Participants received placebo (3 ca...
Arm/Group Description:	Participants received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.	Participants received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	289	289
Measure Type: Number Unit of Measure: Percentage of participants
	87.2	66.1

3.Secondary Outcome


Title	Overall Survival (OS)
Description	OS was defined as the interval between the date of randomization and t...
Description	OS was defined as the interval between the date of randomization and the date of death from any cause.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Intent to treat (ITT) population included all participants randomized into the study regardless of treatment actually received.


Arm/Group Title	Ibrutinib+BR	Placebo+BR
Arm/Group Description:	Participants received ibrutinib 420...	Participants received placebo (3 ca...
Arm/Group Description:	Participants received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.	Participants received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	289	289
Median (95% Confidence Interval) Unit of Measure: Months
	NA ^[1] (70.93 to NA)	NA ^[2] (NA to NA)

[1]

Here, NA indicates median and upper limit of CI was not estimable due to insufficient number of events.

[2]

Here, NA indicates median and CI was not estimable due to insufficient number of events.

4.Secondary Outcome


Title	Percentage of Participants With Minimal Residual Disease (MRD)-Negative Response
Description	MRD-negative response was defined as the percentage of participants wh...
Description	MRD-negative response was defined as the percentage of participants who reach MRD negative disease status (less than 1 chronic lymphocytic leukemia [CLL] cell per 10,000 leukocytes) in either bone marrow or peripheral blood. All randomized participants were included in this analysis. Participants with missing MRD data were considered non-responders.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Intent to treat (ITT) population included all participants randomized into the study regardless of treatment actually received.


Arm/Group Title	Ibrutinib+BR	Placebo+BR
Arm/Group Description:	Participants received ibrutinib 420...	Participants received placebo (3 ca...
Arm/Group Description:	Participants received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.	Participants received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	289	289
Measure Type: Number Unit of Measure: Percentage of participants
	28.7	5.9

5.Secondary Outcome


Title	Percentage of Participants With Sustained Hematologic Improvement
Description	Sustained hematologic improvement was defined as hematological improve...
Description	Sustained hematologic improvement was defined as hematological improvement that was sustained continuously for greater than or equal to (>=) 56 days without blood transfusion or growth factors: 1) Platelet counts greater than (>)100* 109/liter (L) if baseline less than or equal to (<=) 100*109/L or increase >= 50 percent (%) over baseline; 2) Hemoglobin >11 gram per deciliters (g/dL) if baseline <= 11 g/dL or increase >= 2 g/dL over baseline.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population included all participants randomized into the study regardless of treatment actually received.


Arm/Group Title	Ibrutinib+BR	Placebo+BR
Arm/Group Description:	Participants received ibrutinib 420...	Participants received placebo (3 ca...
Arm/Group Description:	Participants received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.	Participants received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	289	289
Measure Type: Number Unit of Measure: Percentage of Participants
Hemoglobin	36.7	29.1
Platelets	30.8	21.8

6.Secondary Outcome


Title	Median Time to Clinically Meaningful Improvement in FACIT-Fatigue Scale
Description	Time to improvement is defined as the time interval (months) from rand...
Description	Time to improvement is defined as the time interval (months) from randomization to the first observation of improvement. FACIT-Fatigue is an instrument for use as a measure of the effect of fatigue in patients with cancer and other chronic diseases. Responses to the 13-item FACIT Fatigue Scale are reported on a 5-point categorical response scale ranging from 0 (not at all) to 4 (very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worst score) to 52 (best score).
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

ITT population included all participants randomized into the study regardless of treatment actually received.


Arm/Group Title	Ibrutinib+BR	Placebo+BR
Arm/Group Description:	Participants received ibrutinib 420...	Participants received placebo (3 ca...
Arm/Group Description:	Participants received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.	Participants received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	289	289
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Months
	6.5 (4.7 to 10.7)	4.6 (2.8 to 6.4)

7.Secondary Outcome


Title	Number of Participants With Clinically Relevant Shifts in Disease-Related Symptoms
Description	The disease-related symptoms included fatigue, weight loss, fevers, ni...
Description	The disease-related symptoms included fatigue, weight loss, fevers, night sweats, abdominal discomfort/splenomegaly and anorexia.
Time Frame	From the date of randomization to disease progression (Up to 2 years)

Outcome Measure Data

Analysis Population Description

ITT population included all participants randomized into the study regardless of treatment actually received.


Arm/Group Title	Ibrutinib+BR	Placebo+BR
Arm/Group Description:	Participants received ibrutinib 420...	Participants received placebo (3 ca...
Arm/Group Description:	Participants received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.	Participants received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	289	289
Measure Type: Count of Participants Unit of Measure: Participants
	0 0.0%	0 0.0%

8.Secondary Outcome


Title	Number of Participants Who Received Subsequent Antineoplastic Therapy
Description	Number of participants who received subsequent antineoplastic therapy ...
Description	Number of participants who received subsequent antineoplastic therapy was reported.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Safety analysis set included all the randomized participants who received at least 1 dose of study drug or placebo.


Arm/Group Title	Ibrutinib+BR	Placebo+BR
Arm/Group Description:	Participants received ibrutinib 420...	Participants received placebo (3 ca...
Arm/Group Description:	Participants received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.	Participants received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	287	287
Measure Type: Count of Participants Unit of Measure: Participants
	52 18.1%	61 21.3%

9.Secondary Outcome


Title	Change From Baseline in Beta2 Microglobulin at End of Treatment (EOT)
Description	Change from baseline in beta2 microglobulin at end of treatment at tim...
Description	Change from baseline in beta2 microglobulin at end of treatment at time of primary analysis was reported.
Time Frame	Baseline to EOT (Up to 2 years)

Outcome Measure Data

Analysis Population Description

ITT population included all participants randomized into the study regardless of treatment actually received. Here, 'N' (number of participants analyzed) signifies number of participants evaluable for this endpoint.


Arm/Group Title	Ibrutinib+BR	Placebo+BR
Arm/Group Description:	Participants received ibrutinib 420...	Participants received placebo (3 ca...
Arm/Group Description:	Participants received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.	Participants received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	39	106
Mean (Standard Deviation) Unit of Measure: milligram per liter (mg/L)
	-0.46 (1.77)	-0.23 (2.08)

10.Secondary Outcome


Title	Change From Baseline in FACIT-Fatigue Scale at End of Treatment
Description	FACIT-Fatigue is an instrument for use as a measure of the effect of f...
Description	FACIT-Fatigue is an instrument for use as a measure of the effect of fatigue in patients with cancer and other chronic diseases. Responses to the 13-item FACIT Fatigue Scale are reported on a 5-point categorical response scale ranging from 0 (not at all) to 4 (very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worst score) to 52 (best score).
Time Frame	Baseline to EOT (up to 2 years)

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Ibrutinib+BR	Placebo+BR
Arm/Group Description:	Participants received ibrutinib 420...	Participants received placebo (3 ca...
Arm/Group Description:	Participants received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.	Participants received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	38	104
Mean (Standard Deviation) Unit of Measure: Units on a scale
	-0.9 (11.22)	0.0 (11.01)

11.Secondary Outcome


Title	Change From Baseline in EORTC QLQ-C30 Physical Functioning Score at End of Treatment
Description	EORTC QLQ-C30 Physical Functioning Score is a questionnaire to assess ...
Description	EORTC QLQ-C30 Physical Functioning Score is a questionnaire to assess quality of life of cancer patients. It is composed of 30 items, multi-item measure (28 items) and 2 single-item measures. For the multiple item measure, 4-point scale is used and the score for each item range from "1 = not at all" to "4 = very much". Higher scores indicate worsening. The 2 single-item measure involves question about the overall health and overall quality of life which was rated on a 7-point scale ranging from "1 = very poor" to "7 = excellent". Lower scores indicate worsening. All scale and item scores were linearly transformed to be in range from 0-100. A higher score represents a higher (better) level of functioning, or a higher (worse) level of symptoms.
Time Frame	Baseline to EOT (up to 2 years)

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Ibrutinib+BR	Placebo+BR
Arm/Group Description:	Participants received ibrutinib 420...	Participants received placebo (3 ca...
Arm/Group Description:	Participants received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.	Participants received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	38	104
Mean (Standard Deviation) Unit of Measure: Units on a scale
	-2.1 (16.34)	-4.1 (22.52)

12.Secondary Outcome


Title	Change From Baseline in EORTC QLQ-CLL 16 Domain Scores at End of Treatment
Description	The EORTC QLQ-CLL 16 is a 16-item disease specific module that compris...
Description	The EORTC QLQ-CLL 16 is a 16-item disease specific module that comprises 5 domains of patient-reported health status important in CLL. There are three multi-item scales that include fatigue (2 items), treatment side effects and disease symptoms (8 items), and infection (4 items), and 2 single-item scales on social activities and future health worries. Responses are measured on a 4 point scale ranging from 1 (not at all) to 4 (very much).
Time Frame	Baseline to EOT (up to 2 years)

Outcome Measure Data

Analysis Population Description


Arm/Group Title		Ibrutinib+BR	Placebo+BR
Arm/Group Description:		Participants received ibrutinib 420...	Participants received placebo (3 ca...
Arm/Group Description:		Participants received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.	Participants received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed		38	104
Mean (Standard Deviation) Unit of Measure: Units on the scale
Lost weight	Number Analyzed	38 participants	104 participants
Lost weight		0.1 (0.86)	0.0 (0.74)
Dry mouth	Number Analyzed	38 participants	104 participants
Dry mouth		0.3 (0.96)	0.1 (0.85)
Bruises	Number Analyzed	38 participants	104 participants
Bruises		0.1 (0.61)	0.0 (0.65)
Abdominal discomfort	Number Analyzed	37 participants	104 participants
Abdominal discomfort		0.1 (0.81)	0.0 (0.76)
Temperature going up and down	Number Analyzed	38 participants	104 participants
Temperature going up and down		0.1 (0.93)	0.0 (0.72)
Night sweats	Number Analyzed	38 participants	103 participants
Night sweats		-0.6 (0.92)	-0.3 (1.07)
Skin problems	Number Analyzed	37 participants	104 participants
Skin problems		0.4 (1.14)	0.3 (0.96)
Feel ill	Number Analyzed	38 participants	104 participants
Feel ill		0.1 (1.08)	0.2 (0.98)
Feel lethargic	Number Analyzed	38 participants	104 participants
Feel lethargic		0.1 (1.01)	0.0 (0.91)
Felt slowed down	Number Analyzed	38 participants	103 participants
Felt slowed down		0.3 (0.80)	0.0 (0.97)
Limited in planning activities	Number Analyzed	38 participants	103 participants
Limited in planning activities		0.2 (0.97)	0.1 (0.90)
Worried about health in the future	Number Analyzed	38 participants	103 participants
Worried about health in the future		0.0 (0.94)	0.0 (0.97)
Trouble with chest infections	Number Analyzed	38 participants	104 participants
Trouble with chest infections		0.2 (1.05)	0.0 (0.82)
Trouble with other infections	Number Analyzed	38 participants	104 participants
Trouble with other infections		0.7 (1.07)	0.1 (0.86)
Repeated courses of antibiotics	Number Analyzed	38 participants	104 participants
Repeated courses of antibiotics		0.9 (1.22)	0.0 (0.97)
Worried about picking up infection	Number Analyzed	38 participants	103 participants
Worried about picking up infection		0.3 (0.96)	0.2 (1.00)

13.Secondary Outcome


Title	Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Visual Analog Scale at End of Treatment
Description	The EQ-5D questionnaire is a brief, generic health-related quality of ...
Description	The EQ-5D questionnaire is a brief, generic health-related quality of life assessment (HRQOL) that can also be used to incorporate participant preferences into health economic evaluations. The EQ-5D questionnaire assesses HRQOL in terms of degree of limitation on 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and as overall health using a visual analog scale with response options ranging from 0 (worst imaginable health) to 100 (best imaginable health).
Time Frame	Baseline to EOT (up to 2 years)

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Ibrutinib+BR	Placebo+BR
Arm/Group Description:	Participants received ibrutinib 420...	Participants received placebo (3 ca...
Arm/Group Description:	Participants received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.	Participants received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	38	110
Mean (Standard Deviation) Unit of Measure: Units on a scale
	-4.3 (19.58)	4.0 (18.21)

14.Secondary Outcome


Title	Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Utility Score Scale at End of Treatment
Description	The EuroQol-5 is a five dimensional health state classification. Each ...
Description	The EuroQol-5 is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1. High score indicating a high level of utility.
Time Frame	Baseline to EOT (up to 2 years)

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Ibrutinib+BR	Placebo+BR
Arm/Group Description:	Participants received ibrutinib 420...	Participants received placebo (3 ca...
Arm/Group Description:	Participants received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.	Participants received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	38	110
Mean (Standard Deviation) Unit of Measure: Units on a scale
	0.0 (0.28)	0.0 (0.24)

Adverse Events

Time Frame	From the time a signed and dated informed consent form is obtained until 30 days following the last dose of study treatment or until the start of a subsequent systemic antineoplastic therapy, if earlier (up to 5 years)
Adverse Event Reporting Description	Safety analysis set included all the randomized participants who received at least 1 dose of study drug or placebo.

Arm/Group Title	Ibrutinib+BR	Placebo+BR	Crossover to Ibrutinib
Arm/Group Description	Participants received ibrutinib 420...	Participants received placebo (3 ca...	Participants in the placebo+BR trea...
Arm/Group Description	Participants received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.	Participants received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.	Participants in the placebo+BR treatment group could cross over to receive next-line ibrutinib treatment (420 mg [3 * 140 mg capsules] orally once daily on a 28-day cycle) at the discretion of the investigator at the time of disease progression or if International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria for treatment were met.
All-Cause Mortality
	Ibrutinib+BR	Placebo+BR	Crossover to Ibrutinib
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	74/287 (25.78%)	107/287 (37.28%)	57/183 (31.15%)
Serious Adverse Events Serious Adverse Events
	Ibrutinib+BR	Placebo+BR	Crossover to Ibrutinib
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	198/287 (68.99%)	127/287 (44.25%)	105/183 (57.38%)
Blood and lymphatic system disorders
Anaemia ^* 1	3/287 (1.05%)	7/287 (2.44%)	2/183 (1.09%)
Aplasia Pure Red Cell ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Aplastic Anaemia ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Autoimmune Haemolytic Anaemia ^* 1	0/287 (0.00%)	5/287 (1.74%)	0/183 (0.00%)
Bone Marrow Failure ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Cytopenia ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Febrile Neutropenia ^* 1	30/287 (10.45%)	22/287 (7.67%)	2/183 (1.09%)
Haemolytic Anaemia ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Immune Thrombocytopenic Purpura ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Neutropenia ^* 1	7/287 (2.44%)	6/287 (2.09%)	0/183 (0.00%)
Pancytopenia ^* 1	2/287 (0.70%)	0/287 (0.00%)	0/183 (0.00%)
Thrombocytopenia ^* 1	4/287 (1.39%)	2/287 (0.70%)	0/183 (0.00%)
Cardiac disorders
Acute Coronary Syndrome ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Acute Myocardial Infarction ^* 1	0/287 (0.00%)	3/287 (1.05%)	1/183 (0.55%)
Angina Pectoris ^* 1	4/287 (1.39%)	1/287 (0.35%)	0/183 (0.00%)
Angina Unstable ^* 1	1/287 (0.35%)	0/287 (0.00%)	1/183 (0.55%)
Arrhythmia Supraventricular ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Atrial Fibrillation ^* 1	16/287 (5.57%)	2/287 (0.70%)	6/183 (3.28%)
Atrial Flutter ^* 1	1/287 (0.35%)	0/287 (0.00%)	1/183 (0.55%)
Atrioventricular Block ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Cardiac Arrest ^* 1	2/287 (0.70%)	0/287 (0.00%)	3/183 (1.64%)
Cardiac Failure ^* 1	3/287 (1.05%)	0/287 (0.00%)	0/183 (0.00%)
Cardio-Respiratory Arrest ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Cardiopulmonary Failure ^* 1	1/287 (0.35%)	0/287 (0.00%)	1/183 (0.55%)
Cardiovascular Insufficiency ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Carditis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Coronary Artery Occlusion ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Myocardial Infarction ^* 1	2/287 (0.70%)	2/287 (0.70%)	2/183 (1.09%)
Myocarditis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Pericardial Effusion ^* 1	2/287 (0.70%)	1/287 (0.35%)	1/183 (0.55%)
Sinus Node Dysfunction ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Sinus Tachycardia ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Tachycardia ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Ventricular Fibrillation ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Ventricular Flutter ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Ventricular Tachycardia ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Endocrine disorders
Addison's Disease ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Goitre ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Eye disorders
Cataract ^* 1	3/287 (1.05%)	0/287 (0.00%)	2/183 (1.09%)
Maculopathy ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Retinal Haemorrhage ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Scleral Disorder ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Vitreous Adhesions ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Vitreous Haemorrhage ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Gastrointestinal disorders
Abdominal Hernia ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Abdominal Incarcerated Hernia ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Abdominal Pain ^* 1	0/287 (0.00%)	0/287 (0.00%)	3/183 (1.64%)
Anal Fistula ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Ascites ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Colitis ^* 1	1/287 (0.35%)	2/287 (0.70%)	0/183 (0.00%)
Colitis Ischaemic ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Constipation ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Diarrhoea ^* 1	4/287 (1.39%)	1/287 (0.35%)	0/183 (0.00%)
Duodenal Ulcer Haemorrhage ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Dyspepsia ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Dysphagia ^* 1	0/287 (0.00%)	2/287 (0.70%)	0/183 (0.00%)
Enterocolitis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Gastric Haemorrhage ^* 1	1/287 (0.35%)	0/287 (0.00%)	1/183 (0.55%)
Gastric Ulcer Perforation ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Gastritis ^* 1	3/287 (1.05%)	0/287 (0.00%)	0/183 (0.00%)
Gastrointestinal Disorder ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Gastrointestinal Haemorrhage ^* 1	2/287 (0.70%)	0/287 (0.00%)	0/183 (0.00%)
Gastrointestinal Inflammation ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Haematemesis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Haematochezia ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Inguinal Hernia ^* 1	4/287 (1.39%)	0/287 (0.00%)	1/183 (0.55%)
Intestinal Obstruction ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Intra-Abdominal Haemorrhage ^* 1	1/287 (0.35%)	0/287 (0.00%)	1/183 (0.55%)
Large Intestine Perforation ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Lower Gastrointestinal Haemorrhage ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Mouth Ulceration ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Nausea ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Oesophageal Ulcer ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Oesophagitis ^* 1	0/287 (0.00%)	1/287 (0.35%)	1/183 (0.55%)
Pancreatitis ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Pancreatitis Acute ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Proctitis ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Small Intestinal Obstruction ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Stomatitis ^* 1	1/287 (0.35%)	0/287 (0.00%)	1/183 (0.55%)
Volvulus ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Vomiting ^* 1	1/287 (0.35%)	2/287 (0.70%)	1/183 (0.55%)
General disorders
Asthenia ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Chest Pain ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Chills ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Complication Associated with Device ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Condition Aggravated ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Death ^* 1	2/287 (0.70%)	0/287 (0.00%)	1/183 (0.55%)
Disease Progression ^* 1	1/287 (0.35%)	2/287 (0.70%)	0/183 (0.00%)
Fatigue ^* 1	3/287 (1.05%)	1/287 (0.35%)	1/183 (0.55%)
General Physical Health Deterioration ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Hernia ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Influenza Like Illness ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Infusion Site Extravasation ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Malaise ^* 1	1/287 (0.35%)	1/287 (0.35%)	1/183 (0.55%)
Mucosal Inflammation ^* 1	1/287 (0.35%)	1/287 (0.35%)	0/183 (0.00%)
Multiple Organ Dysfunction Syndrome ^* 1	1/287 (0.35%)	3/287 (1.05%)	3/183 (1.64%)
Non-Cardiac Chest Pain ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Oedema Peripheral ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Pneumatosis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Pyrexia ^* 1	11/287 (3.83%)	7/287 (2.44%)	4/183 (2.19%)
Sudden Cardiac Death ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Sudden Death ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Systemic Inflammatory Response Syndrome ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Hepatobiliary disorders
Cholangitis ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Cholecystitis ^* 1	1/287 (0.35%)	1/287 (0.35%)	1/183 (0.55%)
Cholecystitis Acute ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Cholecystitis Chronic ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Cholelithiasis ^* 1	2/287 (0.70%)	0/287 (0.00%)	1/183 (0.55%)
Cholestasis ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Gallbladder Obstruction ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Hepatic Cirrhosis ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Hepatitis Toxic ^* 1	0/287 (0.00%)	2/287 (0.70%)	0/183 (0.00%)
Hepatocellular Injury ^* 1	1/287 (0.35%)	1/287 (0.35%)	0/183 (0.00%)
Hepatosplenomegaly ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Immune system disorders
Anaphylactic Reaction ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Infections and infestations
Abscess Jaw ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Actinomycotic Pulmonary Infection ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Acute Sinusitis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Appendicitis ^* 1	1/287 (0.35%)	0/287 (0.00%)	2/183 (1.09%)
Arthritis Bacterial ^* 1	2/287 (0.70%)	0/287 (0.00%)	0/183 (0.00%)
Ascariasis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Atypical Pneumonia ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Bacteraemia ^* 1	2/287 (0.70%)	0/287 (0.00%)	0/183 (0.00%)
Brain Abscess ^* 1	2/287 (0.70%)	0/287 (0.00%)	0/183 (0.00%)
Breast Abscess ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Breast Cellulitis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Bronchitis ^* 1	8/287 (2.79%)	5/287 (1.74%)	1/183 (0.55%)
Bronchopulmonary Aspergillosis ^* 1	1/287 (0.35%)	1/287 (0.35%)	2/183 (1.09%)
Campylobacter Infection ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Cellulitis ^* 1	4/287 (1.39%)	2/287 (0.70%)	1/183 (0.55%)
Cellulitis Staphylococcal ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Central Nervous System Infection ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Chronic Sinusitis ^* 1	1/287 (0.35%)	1/287 (0.35%)	0/183 (0.00%)
Clostridium Difficile Colitis ^* 1	0/287 (0.00%)	1/287 (0.35%)	1/183 (0.55%)
Clostridium Difficile Infection ^* 1	0/287 (0.00%)	0/287 (0.00%)	2/183 (1.09%)
Conjunctivitis ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Cystitis ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Cytomegalovirus Colitis ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Cytomegalovirus Infection ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Dacryocystitis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Dermo-Hypodermitis ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Disseminated Cryptococcosis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Epstein-Barr Virus Infection ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Erysipelas ^* 1	1/287 (0.35%)	0/287 (0.00%)	3/183 (1.64%)
Escherichia Sepsis ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Escherichia Urinary Tract Infection ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Fungal Infection ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Gastroenteritis ^* 1	1/287 (0.35%)	1/287 (0.35%)	0/183 (0.00%)
Gastroenteritis Viral ^* 1	2/287 (0.70%)	0/287 (0.00%)	1/183 (0.55%)
Gastrointestinal Infection ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Haemophilus Infection ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Hepatitis B Reactivation ^* 1	1/287 (0.35%)	1/287 (0.35%)	0/183 (0.00%)
Herpes Zoster ^* 1	1/287 (0.35%)	2/287 (0.70%)	1/183 (0.55%)
Infection ^* 1	3/287 (1.05%)	2/287 (0.70%)	0/183 (0.00%)
Infectious Pleural Effusion ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Influenza ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Laryngitis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Lower Respiratory Tract Infection ^* 1	0/287 (0.00%)	2/287 (0.70%)	2/183 (1.09%)
Lung Infection ^* 1	3/287 (1.05%)	3/287 (1.05%)	0/183 (0.00%)
Lymphadenitis Bacterial ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Muscle Abscess ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Neutropenic Sepsis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Nocardiosis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Oral Candidiasis ^* 1	0/287 (0.00%)	2/287 (0.70%)	0/183 (0.00%)
Osteomyelitis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Otitis Media ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Periodontitis ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Periorbital Cellulitis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Peritonsillar Abscess ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Pharyngeal Abscess ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Pharyngitis ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Pharyngitis Streptococcal ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Pneumocystis Jirovecii Pneumonia ^* 1	2/287 (0.70%)	0/287 (0.00%)	0/183 (0.00%)
Pneumonia ^* 1	48/287 (16.72%)	26/287 (9.06%)	34/183 (18.58%)
Pneumonia Bacterial ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Pneumonia Haemophilus ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Pneumonia Pneumococcal ^* 1	1/287 (0.35%)	0/287 (0.00%)	1/183 (0.55%)
Pneumonia Streptococcal ^* 1	0/287 (0.00%)	1/287 (0.35%)	2/183 (1.09%)
Progressive Multifocal Leukoencephalopathy ^* 1	2/287 (0.70%)	0/287 (0.00%)	2/183 (1.09%)
Pseudomembranous Colitis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Pulmonary Tuberculoma ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Pulmonary Tuberculosis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Pyelonephritis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Rash Pustular ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Respiratory Syncytial Virus Infection ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Respiratory Tract Infection ^* 1	5/287 (1.74%)	2/287 (0.70%)	5/183 (2.73%)
Sepsis ^* 1	8/287 (2.79%)	4/287 (1.39%)	4/183 (2.19%)
Septic Shock ^* 1	6/287 (2.09%)	2/287 (0.70%)	5/183 (2.73%)
Sinusitis ^* 1	1/287 (0.35%)	2/287 (0.70%)	2/183 (1.09%)
Skin Candida ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Skin Infection ^* 1	2/287 (0.70%)	1/287 (0.35%)	1/183 (0.55%)
Soft Tissue Infection ^* 1	1/287 (0.35%)	0/287 (0.00%)	1/183 (0.55%)
Splenic Abscess ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Staphylococcal Infection ^* 1	2/287 (0.70%)	0/287 (0.00%)	0/183 (0.00%)
Staphylococcal Skin Infection ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Subcutaneous Abscess ^* 1	3/287 (1.05%)	1/287 (0.35%)	0/183 (0.00%)
Tooth Abscess ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Tuberculosis of Central Nervous System ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Upper Respiratory Tract Infection ^* 1	3/287 (1.05%)	3/287 (1.05%)	0/183 (0.00%)
Urinary Tract Infection ^* 1	6/287 (2.09%)	1/287 (0.35%)	2/183 (1.09%)
Urosepsis ^* 1	1/287 (0.35%)	0/287 (0.00%)	1/183 (0.55%)
Varicella ^* 1	1/287 (0.35%)	1/287 (0.35%)	0/183 (0.00%)
Varicella Zoster Virus Infection ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Viral Infection ^* 1	0/287 (0.00%)	1/287 (0.35%)	1/183 (0.55%)
Injury, poisoning and procedural complications
Abdominal Injury ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Ankle Fracture ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Fall ^* 1	2/287 (0.70%)	0/287 (0.00%)	1/183 (0.55%)
Femoral Neck Fracture ^* 1	2/287 (0.70%)	0/287 (0.00%)	2/183 (1.09%)
Femur Fracture ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Hip Fracture ^* 1	1/287 (0.35%)	1/287 (0.35%)	1/183 (0.55%)
Incision Site Haemorrhage ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Infusion Related Reaction ^* 1	4/287 (1.39%)	5/287 (1.74%)	0/183 (0.00%)
Pelvic Fracture ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Pneumoconiosis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Pneumothorax Traumatic ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Post Procedural Haemorrhage ^* 1	1/287 (0.35%)	0/287 (0.00%)	2/183 (1.09%)
Post Procedural Swelling ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Subdural Haematoma ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Thoracic Vertebral Fracture ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Investigations
Biopsy ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Blood Creatinine Increased ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Body Temperature Increased ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Neutrophil Count Decreased ^* 1	2/287 (0.70%)	0/287 (0.00%)	0/183 (0.00%)
Prostatic Specific Antigen Increased ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Weight Decreased ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Metabolism and nutrition disorders
Decreased Appetite ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Dehydration ^* 1	2/287 (0.70%)	1/287 (0.35%)	1/183 (0.55%)
Diabetes Mellitus ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Hypercalcaemia ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Hyperuricaemia ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Hyponatraemia ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Hypophosphataemia ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Tumour Lysis Syndrome ^* 1	6/287 (2.09%)	1/287 (0.35%)	0/183 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Arthritis ^* 1	2/287 (0.70%)	0/287 (0.00%)	1/183 (0.55%)
Back Pain ^* 1	1/287 (0.35%)	0/287 (0.00%)	1/183 (0.55%)
Chondrocalcinosis Pyrophosphate ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Femoroacetabular Impingement ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Groin Pain ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Lumbar Spinal Stenosis ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Muscle Haemorrhage ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Muscular Weakness ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Musculoskeletal Pain ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Osteoarthritis ^* 1	3/287 (1.05%)	0/287 (0.00%)	0/183 (0.00%)
Osteonecrosis ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Pain in Extremity ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute Lymphocytic Leukaemia ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Adenosquamous Cell Lung Cancer ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Anal Squamous Cell Carcinoma ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Basal Cell Carcinoma ^* 1	5/287 (1.74%)	1/287 (0.35%)	1/183 (0.55%)
Bladder Cancer ^* 1	2/287 (0.70%)	0/287 (0.00%)	0/183 (0.00%)
Bronchioloalveolar Carcinoma ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Chronic Myelomonocytic Leukaemia ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Intestinal Adenocarcinoma ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Intraductal Papilloma of Breast ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Lipoma ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Lung Adenocarcinoma ^* 1	0/287 (0.00%)	1/287 (0.35%)	1/183 (0.55%)
Malignant Melanoma ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Malignant Melanoma in Situ ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Maxillofacial Sinus Neoplasm ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Metastases to Central Nervous System ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Metastatic Renal Cell Carcinoma ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Myelodysplastic Syndrome ^* 1	2/287 (0.70%)	1/287 (0.35%)	0/183 (0.00%)
Myeloproliferative Neoplasm ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Neuroendocrine Carcinoma ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Prostate Cancer ^* 1	1/287 (0.35%)	1/287 (0.35%)	2/183 (1.09%)
Renal Cancer ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Renal Cancer Stage I ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Renal Oncocytoma ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Squamous Cell Carcinoma ^* 1	3/287 (1.05%)	1/287 (0.35%)	2/183 (1.09%)
Squamous Cell Carcinoma of Skin ^* 1	0/287 (0.00%)	2/287 (0.70%)	0/183 (0.00%)
Superficial Spreading Melanoma Stage Unspecified ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Transitional Cell Carcinoma ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Nervous system disorders
Carotid Sinus Syndrome ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Cerebral Disorder ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Cerebral Infarction ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Cerebral Ischaemia ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Cerebrovascular Accident ^* 1	3/287 (1.05%)	0/287 (0.00%)	1/183 (0.55%)
Cognitive Disorder ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Depressed Level of Consciousness ^* 1	1/287 (0.35%)	0/287 (0.00%)	1/183 (0.55%)
Encephalopathy ^* 1	0/287 (0.00%)	0/287 (0.00%)	2/183 (1.09%)
Facial Paresis ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Haemorrhage Intracranial ^* 1	1/287 (0.35%)	0/287 (0.00%)	1/183 (0.55%)
Haemorrhagic Stroke ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Headache ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Loss of Consciousness ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Meningism ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Peripheral Sensory Neuropathy ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Post Herpetic Neuralgia ^* 1	1/287 (0.35%)	1/287 (0.35%)	0/183 (0.00%)
Radiculopathy ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Syncope ^* 1	0/287 (0.00%)	1/287 (0.35%)	1/183 (0.55%)
Transient Global Amnesia ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Vascular Encephalopathy ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Psychiatric disorders
Acute Stress Disorder ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Alcoholic Psychosis ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Completed Suicide ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Confusional State ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Delirium ^* 1	1/287 (0.35%)	1/287 (0.35%)	0/183 (0.00%)
Mental Status Changes ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Renal and urinary disorders
Acute Kidney Injury ^* 1	2/287 (0.70%)	1/287 (0.35%)	0/183 (0.00%)
Calculus Bladder ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Dysuria ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Haematuria ^* 1	0/287 (0.00%)	0/287 (0.00%)	2/183 (1.09%)
Nephropathy ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Nephropathy Toxic ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Renal Failure ^* 1	1/287 (0.35%)	0/287 (0.00%)	2/183 (1.09%)
Renal Impairment ^* 1	2/287 (0.70%)	1/287 (0.35%)	0/183 (0.00%)
Ureteric Stenosis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Ureterolithiasis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Urge Incontinence ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Urinary Incontinence ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Urinary Retention ^* 1	1/287 (0.35%)	0/287 (0.00%)	1/183 (0.55%)
Reproductive system and breast disorders
Benign Prostatic Hyperplasia ^* 1	2/287 (0.70%)	0/287 (0.00%)	1/183 (0.55%)
Fibrocystic Breast Disease ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Genital Rash ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Pelvic Floor Muscle Weakness ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Penile Dysplasia ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Uterine Haemorrhage ^* 1	2/287 (0.70%)	0/287 (0.00%)	0/183 (0.00%)
Uterine Prolapse ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure ^* 1	0/287 (0.00%)	1/287 (0.35%)	1/183 (0.55%)
Chronic Obstructive Pulmonary Disease ^* 1	0/287 (0.00%)	1/287 (0.35%)	1/183 (0.55%)
Dyspnoea ^* 1	1/287 (0.35%)	3/287 (1.05%)	0/183 (0.00%)
Dyspnoea Exertional ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Haemoptysis ^* 1	0/287 (0.00%)	1/287 (0.35%)	1/183 (0.55%)
Haemothorax ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Lung Infiltration ^* 1	1/287 (0.35%)	1/287 (0.35%)	0/183 (0.00%)
Pleural Effusion ^* 1	3/287 (1.05%)	2/287 (0.70%)	2/183 (1.09%)
Pleuritic Pain ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Pneumonitis ^* 1	1/287 (0.35%)	1/287 (0.35%)	1/183 (0.55%)
Pneumothorax ^* 1	0/287 (0.00%)	1/287 (0.35%)	1/183 (0.55%)
Pulmonary Congestion ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Pulmonary Mass ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Pulmonary Sarcoidosis ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Respiratory Failure ^* 1	1/287 (0.35%)	0/287 (0.00%)	3/183 (1.64%)
Respiratory Tract Oedema ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Sleep Apnoea Syndrome ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Skin and subcutaneous tissue disorders
Acute Febrile Neutrophilic Dermatosis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Cellulitis ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Drug Eruption ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Excessive Granulation Tissue ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Hypersensitivity Vasculitis ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Pemphigoid ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Pemphigus ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Rash ^* 1	0/287 (0.00%)	2/287 (0.70%)	0/183 (0.00%)
Rash Erythematous ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Rash Maculo-Papular ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Skin Necrosis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Urticaria ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Vascular disorders
Aortic Aneurysm Rupture ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Arterial Stenosis ^* 1	0/287 (0.00%)	0/287 (0.00%)	1/183 (0.55%)
Deep Vein Thrombosis ^* 1	1/287 (0.35%)	3/287 (1.05%)	0/183 (0.00%)
Haematoma ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Hypertension ^* 1	2/287 (0.70%)	0/287 (0.00%)	1/183 (0.55%)
Hypertensive Crisis ^* 1	2/287 (0.70%)	0/287 (0.00%)	0/183 (0.00%)
Hypotension ^* 1	2/287 (0.70%)	0/287 (0.00%)	0/183 (0.00%)
Jugular Vein Thrombosis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Lymphoedema ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Peripheral Arterial Occlusive Disease ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Peripheral Artery Occlusion ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Peripheral Artery Thrombosis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Peripheral Ischaemia ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
Thrombophlebitis ^* 1	1/287 (0.35%)	1/287 (0.35%)	0/183 (0.00%)
Thrombosis ^* 1	1/287 (0.35%)	0/287 (0.00%)	0/183 (0.00%)
Vasculitis ^* 1	0/287 (0.00%)	1/287 (0.35%)	0/183 (0.00%)
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%
	Ibrutinib+BR	Placebo+BR	Crossover to Ibrutinib
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	268/287 (93.38%)	271/287 (94.43%)	157/183 (85.79%)
Blood and lymphatic system disorders
Anaemia ^* 1	73/287 (25.44%)	79/287 (27.53%)	33/183 (18.03%)
Leukopenia ^* 1	15/287 (5.23%)	18/287 (6.27%)	2/183 (1.09%)
Neutropenia ^* 1	170/287 (59.23%)	159/287 (55.40%)	40/183 (21.86%)
Thrombocytopenia ^* 1	90/287 (31.36%)	69/287 (24.04%)	24/183 (13.11%)
Cardiac disorders
Atrial Fibrillation ^* 1	23/287 (8.01%)	5/287 (1.74%)	19/183 (10.38%)
Eye disorders
Cataract ^* 1	20/287 (6.97%)	3/287 (1.05%)	8/183 (4.37%)
Dry Eye ^* 1	15/287 (5.23%)	9/287 (3.14%)	6/183 (3.28%)
Vision Blurred ^* 1	19/287 (6.62%)	19/287 (6.62%)	3/183 (1.64%)
Gastrointestinal disorders
Abdominal Pain ^* 1	39/287 (13.59%)	24/287 (8.36%)	3/183 (1.64%)
Abdominal Pain Upper ^* 1	23/287 (8.01%)	16/287 (5.57%)	11/183 (6.01%)
Constipation ^* 1	61/287 (21.25%)	50/287 (17.42%)	15/183 (8.20%)
Diarrhoea ^* 1	115/287 (40.07%)	68/287 (23.69%)	47/183 (25.68%)
Dyspepsia ^* 1	24/287 (8.36%)	21/287 (7.32%)	8/183 (4.37%)
Gastroesophageal Reflux Disease ^* 1	15/287 (5.23%)	12/287 (4.18%)	4/183 (2.19%)
Nausea ^* 1	108/287 (37.63%)	101/287 (35.19%)	16/183 (8.74%)
Toothache ^* 1	15/287 (5.23%)	5/287 (1.74%)	3/183 (1.64%)
Vomiting ^* 1	42/287 (14.63%)	45/287 (15.68%)	15/183 (8.20%)
General disorders
Asthenia ^* 1	26/287 (9.06%)	24/287 (8.36%)	5/183 (2.73%)
Chills ^* 1	33/287 (11.50%)	31/287 (10.80%)	5/183 (2.73%)
Fatigue ^* 1	69/287 (24.04%)	66/287 (23.00%)	32/183 (17.49%)
Influenza Like Illness ^* 1	9/287 (3.14%)	10/287 (3.48%)	12/183 (6.56%)
Mucosal Inflammation ^* 1	15/287 (5.23%)	7/287 (2.44%)	3/183 (1.64%)
Non-Cardiac Chest Pain ^* 1	17/287 (5.92%)	13/287 (4.53%)	3/183 (1.64%)
Oedema Peripheral ^* 1	49/287 (17.07%)	34/287 (11.85%)	21/183 (11.48%)
Pyrexia ^* 1	74/287 (25.78%)	60/287 (20.91%)	22/183 (12.02%)
Infections and infestations
Bronchitis ^* 1	51/287 (17.77%)	29/287 (10.10%)	19/183 (10.38%)
Cellulitis ^* 1	16/287 (5.57%)	8/287 (2.79%)	10/183 (5.46%)
Conjunctivitis ^* 1	20/287 (6.97%)	15/287 (5.23%)	10/183 (5.46%)
Herpes Zoster ^* 1	24/287 (8.36%)	17/287 (5.92%)	7/183 (3.83%)
Influenza ^* 1	22/287 (7.67%)	16/287 (5.57%)	7/183 (3.83%)
Oral Herpes ^* 1	15/287 (5.23%)	18/287 (6.27%)	7/183 (3.83%)
Pharyngitis ^* 1	18/287 (6.27%)	13/287 (4.53%)	2/183 (1.09%)
Pneumonia ^* 1	40/287 (13.94%)	25/287 (8.71%)	21/183 (11.48%)
Respiratory Tract Infection ^* 1	19/287 (6.62%)	10/287 (3.48%)	15/183 (8.20%)
Sinusitis ^* 1	38/287 (13.24%)	24/287 (8.36%)	25/183 (13.66%)
Upper Respiratory Tract Infection ^* 1	69/287 (24.04%)	50/287 (17.42%)	36/183 (19.67%)
Urinary Tract Infection ^* 1	28/287 (9.76%)	15/287 (5.23%)	26/183 (14.21%)
Injury, poisoning and procedural complications
Contusion ^* 1	30/287 (10.45%)	9/287 (3.14%)	15/183 (8.20%)
Infusion Related Reaction ^* 1	45/287 (15.68%)	64/287 (22.30%)	1/183 (0.55%)
Investigations
Alanine Aminotransferase Increased ^* 1	15/287 (5.23%)	12/287 (4.18%)	3/183 (1.64%)
Blood Creatinine Increased ^* 1	17/287 (5.92%)	7/287 (2.44%)	6/183 (3.28%)
Neutrophil Count Decreased ^* 1	21/287 (7.32%)	16/287 (5.57%)	3/183 (1.64%)
Platelet Count Decreased ^* 1	17/287 (5.92%)	9/287 (3.14%)	2/183 (1.09%)
Weight Decreased ^* 1	18/287 (6.27%)	18/287 (6.27%)	5/183 (2.73%)
Metabolism and nutrition disorders
Decreased Appetite ^* 1	42/287 (14.63%)	42/287 (14.63%)	16/183 (8.74%)
Hyperuricaemia ^* 1	36/287 (12.54%)	20/287 (6.97%)	7/183 (3.83%)
Hypokalaemia ^* 1	24/287 (8.36%)	12/287 (4.18%)	8/183 (4.37%)
Musculoskeletal and connective tissue disorders
Arthralgia ^* 1	47/287 (16.38%)	29/287 (10.10%)	25/183 (13.66%)
Back Pain ^* 1	41/287 (14.29%)	22/287 (7.67%)	23/183 (12.57%)
Muscle Spasms ^* 1	44/287 (15.33%)	14/287 (4.88%)	17/183 (9.29%)
Myalgia ^* 1	28/287 (9.76%)	15/287 (5.23%)	9/183 (4.92%)
Pain in Extremity ^* 1	21/287 (7.32%)	15/287 (5.23%)	12/183 (6.56%)
Nervous system disorders
Dysgeusia ^* 1	15/287 (5.23%)	15/287 (5.23%)	3/183 (1.64%)
Headache ^* 1	49/287 (17.07%)	47/287 (16.38%)	18/183 (9.84%)
Psychiatric disorders
Anxiety ^* 1	22/287 (7.67%)	11/287 (3.83%)	9/183 (4.92%)
Depression ^* 1	18/287 (6.27%)	8/287 (2.79%)	4/183 (2.19%)
Insomnia ^* 1	27/287 (9.41%)	21/287 (7.32%)	10/183 (5.46%)
Respiratory, thoracic and mediastinal disorders
Cough ^* 1	74/287 (25.78%)	75/287 (26.13%)	27/183 (14.75%)
Dyspnoea ^* 1	22/287 (7.67%)	29/287 (10.10%)	11/183 (6.01%)
Epistaxis ^* 1	22/287 (7.67%)	10/287 (3.48%)	15/183 (8.20%)
Nasal Congestion ^* 1	16/287 (5.57%)	9/287 (3.14%)	4/183 (2.19%)
Oropharyngeal Pain ^* 1	30/287 (10.45%)	20/287 (6.97%)	8/183 (4.37%)
Productive Cough ^* 1	21/287 (7.32%)	18/287 (6.27%)	9/183 (4.92%)
Viral Upper Respiratory Tract Infection ^* 1	30/287 (10.45%)	20/287 (6.97%)	13/183 (7.10%)
Skin and subcutaneous tissue disorders
Dry Skin ^* 1	27/287 (9.41%)	17/287 (5.92%)	7/183 (3.83%)
Ecchymosis ^* 1	14/287 (4.88%)	2/287 (0.70%)	10/183 (5.46%)
Onychoclasis ^* 1	10/287 (3.48%)	0/287 (0.00%)	10/183 (5.46%)
Pruritus ^* 1	34/287 (11.85%)	33/287 (11.50%)	9/183 (4.92%)
Rash ^* 1	63/287 (21.95%)	35/287 (12.20%)	15/183 (8.20%)
Rash Maculo-Papular ^* 1	17/287 (5.92%)	11/287 (3.83%)	7/183 (3.83%)
Skin Lesion ^* 1	30/287 (10.45%)	5/287 (1.74%)	11/183 (6.01%)
Vascular disorders
Haematoma ^* 1	26/287 (9.06%)	3/287 (1.05%)	14/183 (7.65%)
Hypertension ^* 1	47/287 (16.38%)	14/287 (4.88%)	27/183 (14.75%)
1 Term from vocabulary, MedDRA Version 20.0 * Indicates events were collected by non-systematic assessment

Limitations and Caveats

Study was planned to end when 80% of randomized participants died or 5 years after last participant randomized, whichever was first. Sponsor terminated study on 23-Jan-2019 (5 year after last participant randomized) and study was considered 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.

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

Layout table for Results Point of Contact information

Name/Title:	Medical Director Clinical Research
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):

Fraser GAM, Chanan-Khan A, Demirkan F, Santucci Silva R, Grosicki S, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Loscertales J, Avigdor A, Rule S, Samoilova O, Pavlovsky MA, Goy A, Mato A, Hallek M, Salman M, Tamegnon M, Sun S, Connor A, Nottage K, Schuier N, Balasubramanian S, Howes A, Cramer P. Final 5-year findings from the phase 3 HELIOS study of ibrutinib plus bendamustine and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Leuk Lymphoma. 2020 Dec;61(13):3188-3197. doi: 10.1080/10428194.2020.1795159. Epub 2020 Aug 6.

Lavezzi SM, de Jong J, Neyens M, Cramer P, Demirkan F, Fraser G, Bartlett N, Dilhuydy MS, Loscertales J, Avigdor A, Rule S, Samoilova O, Goy A, Ganguly S, Salman M, Howes A, Mahler M, De Nicolao G, Poggesi I. Systemic Exposure of Rituximab Increased by Ibrutinib: Pharmacokinetic Results and Modeling Based on the HELIOS Trial. Pharm Res. 2019 May 1;36(7):93. doi: 10.1007/s11095-019-2605-8.

Brown JR, Moslehi J, O'Brien S, Ghia P, Hillmen P, Cymbalista F, Shanafelt TD, Fraser G, Rule S, Kipps TJ, Coutre S, Dilhuydy MS, Cramer P, Tedeschi A, Jaeger U, Dreyling M, Byrd JC, Howes A, Todd M, Vermeulen J, James DF, Clow F, Styles L, Valentino R, Wildgust M, Mahler M, Burger JA. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica. 2017 Oct;102(10):1796-1805. doi: 10.3324/haematol.2017.171041. Epub 2017 Jul 27.

Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Mato A, Pavlovsky MA, Karlsson C, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Hallek M; HELIOS investigators. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016 Feb;17(2):200-211. doi: 10.1016/S1470-2045(15)00465-9. Epub 2015 Dec 5.

Layout table for additonal information

Responsible Party:	Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:	NCT01611090
Other Study ID Numbers:	CR100840 PCI-32765CLL3001 ( Other Identifier: Janssen Research & Development, LLC ) 2012-000600-15 ( EudraCT Number ) U1111-1135-3745 ( Other Identifier: Universal Trial Number )
First Submitted:	May 15, 2012
First Posted:	June 4, 2012
Results First Submitted:	January 23, 2020
Results First Posted:	March 3, 2020
Last Update Posted:	March 3, 2020

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