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

Sponsor
Janssen Research & Development, LLC (Industry)
Overall Status
Completed
CT.gov ID
NCT01611090
Collaborator
Pharmacyclics LLC. (Industry)
578
Enrollment
160
Locations
2
Arms
76.1
Actual Duration (Months)
3.6
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to examine the safety and efficacy of Ibrutinib administered in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

This is a randomized (patients will be assigned by chance to study treatments), double-blind (patients and study personnel will not know the identity of study treatments), placebo (an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical trial)-controlled study to determine the benefits and risks of combining ibrutinib with bendamustine and rituximab (BR) in patients with relapsed or refractory CLL/SLL following at least 1 line of prior systemic therapy. Approximately 580 patients will be randomized in a 1:1 ratio to either treatment arm A (placebo) or treatment arm B (ibrutinib 420 mg).

Study medication will be administered orally once daily on a continuous schedule. All patients will receive BR as the background therapy plus either ibrutinib or placebo for a maximum of 6 cycles, after which treatment with ibrutinib or placebo will continue until disease progression or unacceptable toxicity.

A treatment cycle will be defined as 28 days. The study will include a screening phase, a treatment phase, and a follow-up phase. Study end is defined as when either 80% of the patients have died or 5 years after the last patient is randomized into the study, whichever occurs first.

Patients in treatment arm A (placebo) who complete the treatment phase, with disease progression or (after interim analysis) meet International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria for treatment, may crossover to ibrutinib treatment (as in treatment arm B), at the investigators discretion. This open-label, next-line treatment with ibrutinib will continue until disease progression, unacceptable toxicity, withdrawal from study, or until the study end, whichever occurs earlier. One interim analysis is planned for the study. Efficacy evaluations will include computed tomography scans, laboratory testing, focused physical examinations, bone marrow biopsy and aspirate, and assessment of patient-reported outcomes. In both treatment arms, samples for the development of a population-based pharmacokinetic (PK; study of what the body does to a drug) approach will be collected. Safety will be assessed throughout the study.

Study Design

Study Type:
Interventional
Actual Enrollment :
578 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
Randomized, Double-blind, Placebo-controlled Phase 3 Study of Ibrutinib, a Bruton's Tyrosine Kinase (BTK) Inhibitor, in Combination With Bendamustine and Rituximab (BR) in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Actual Study Start Date :
Sep 19, 2012
Actual Primary Completion Date :
Jan 23, 2019
Actual Study Completion Date :
Jan 23, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Ibrutinib + BR

Ibrutinib 420 mg will be administered orally once daily on a continuous schedule. All subjects will receive background therapy with bendamustine and rituximab (BR) for a maximum of 6 cycles (a cycle is defined as 28 days, with the exception of Cycle 1, which will be 29 days to allow for rituximab dosing prior to bendamustine and study medication).

Drug: Ibrutinib
Type=exact number, unit=mg, number=420 , form=capsule, route=oral use. Capsule is taken once daily continuously.

Drug: Bendamustine hydrochloride
Type=exact number, unit=mg, number=70 mg/m2, route=intravenous use. Administered intravenously on Cycle 1, Days 2-3 and Cycles 2-6, Days 1-2.

Drug: Rituximab
Type=exact number, unit=mg, number=375 mg/m2 and 500 mg/m2, route=intravenous use. Administered intravenously on Cycle 1, Day 1, and Cycles 2-6, Day 1, respectively.
Placebo Comparator: Placebo + BR

Matching placebo will be administered orally once daily on a continuous schedule. All subjects will receive background therapy with BR for a maximum of 6 cycles (a cycle is defined as 28 days, with the exception of Cycle 1, which will be 29 days to allow for rituximab dosing prior to bendamustine and study medication).

Drug: Bendamustine hydrochloride
Type=exact number, unit=mg, number=70 mg/m2, route=intravenous use. Administered intravenously on Cycle 1, Days 2-3 and Cycles 2-6, Days 1-2.

Drug: Rituximab
Type=exact number, unit=mg, number=375 mg/m2 and 500 mg/m2, route=intravenous use. Administered intravenously on Cycle 1, Day 1, and Cycles 2-6, Day 1, respectively.

Drug: Placebo
Form=capsule, route=oral use. Capsule is taken once daily continuously.

Outcome Measures

Primary Outcome Measures

  1. Progression-free Survival (PFS) [Up to 5 years]

    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.

Secondary Outcome Measures

  1. Overall Response Rate (ORR) [Up to 5 years]

    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 >1.5*10^9/liter (L), platelets >100*10^9/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 >1.5*10^9/L, Platelets >100*10^9/L and Hgb>11 g/dL or >=50% improvement over baseline in any of these; no new enlarged nodes or new hepatosplenomegaly.

  2. Overall Survival (OS) [Up to 5 years]

    OS was defined as the interval between the date of randomization and the date of death from any cause.

  3. Percentage of Participants With Minimal Residual Disease (MRD)-Negative Response [Up to 5 years]

    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.

  4. Percentage of Participants With Sustained Hematologic Improvement [Up to 5 years]

    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.

  5. Median Time to Clinically Meaningful Improvement in FACIT-Fatigue Scale [Up to 2 years]

    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).

  6. Number of Participants With Clinically Relevant Shifts in Disease-Related Symptoms [From the date of randomization to disease progression (Up to 2 years)]

    The disease-related symptoms included fatigue, weight loss, fevers, night sweats, abdominal discomfort/splenomegaly and anorexia.

  7. Number of Participants Who Received Subsequent Antineoplastic Therapy [Up to 5 years]

    Number of participants who received subsequent antineoplastic therapy was reported.

  8. Change From Baseline in Beta2 Microglobulin at End of Treatment (EOT) [Baseline to EOT (Up to 2 years)]

    Change from baseline in beta2 microglobulin at end of treatment at time of primary analysis was reported.

  9. Change From Baseline in FACIT-Fatigue Scale at End of Treatment [Baseline to EOT (up to 2 years)]

    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).

  10. Change From Baseline in EORTC QLQ-C30 Physical Functioning Score at End of Treatment [Baseline to EOT (up to 2 years)]

    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.

  11. Change From Baseline in EORTC QLQ-CLL 16 Domain Scores at End of Treatment [Baseline to EOT (up to 2 years)]

    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).

  12. Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Visual Analog Scale at End of Treatment [Baseline to EOT (up to 2 years)]

    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).

  13. Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Utility Score Scale at End of Treatment [Baseline to EOT (up to 2 years)]

    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.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:

  • Diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that meets protocol-defined criteria

  • Active disease meeting at least 1 of the International Workshop on Chronic Lymphocytic Leukemia 2008 criteria for requiring treatment

  • Measurable nodal disease by computed tomography

  • Relapsed or refractory CLL or SLL following at least 1 prior line of systemic therapy consisting of at least 2 cycles of a chemotherapy-containing regimen

  • Eastern Cooperative Oncology Group Performance Status score of 0 or 1

  • Hematology and biochemical values within protocol-defined limits

  • Agrees to protocol-defined use of effective contraception

  • Women of childbearing potential must have negative blood or urine pregnancy test at screening

Exclusion Criteria:

  • Recent therapeutic interventions within 3 (chemotherapy/radiotherapy) to 10 weeks (immunotherapy)

  • Prior treatment with ibrutinib or other Bruton's tyrosine kinase inhibitors or prior randomization in any other clinical study evaluating ibrutinib

  • The presence of deletion of the short arm of chromosome 17

  • Patients previously treated with a bendamustine-containing regimen who did not achieve a response or who relapsed and required treatment within 24 months of treatment with that regimen

  • Patients for whom the goal of therapy is tumor debulking prior to stem cell transplant

  • Received a hematopoietic stem cell transplant

  • Known central nervous system leukemia/lymphoma or Richter's transformation

  • Patients with uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia

  • Chronic use of corticosteroids

  • History of prior malignancy, except: malignancy treated with curative intent and with no known active disease present for >=3 years before randomization; adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; adequately treated cervical carcinoma in situ without evidence of disease

  • History of stroke or intracranial hemorrhage within 6 months prior to randomization; or clinically significant cardiovascular disease

  • Requires anticoagulation with warfarin or equivalent vitamin K antagonists or treatment with strong CYP3A4/5 inhibitors

  • Known history of human immunodeficiency virus or hepatitis C, or active infection with hepatitis B or C

  • Any uncontrolled active systemic infection or any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk

  • A woman who is pregnant or breast feeding, or a man who plans to father a child while enrolled in this study or within 3 months after the last dose of study drug

Contacts and Locations

Locations

Site City State Country Postal Code
1 Birmingham Alabama United States
2 Phoenix Arizona United States
3 Berkeley California United States
4 Duarte California United States
5 Greenbrae California United States
6 Stamford Connecticut United States
7 Washington District of Columbia United States
8 Boca Raton Florida United States
9 Jacksonville Florida United States
10 Atlanta Georgia United States
11 Marietta Georgia United States
12 Chicago Illinois United States
13 Springfield Illinois United States
14 Fort Wayne Indiana United States
15 Goshen Indiana United States
16 Indianapolis Indiana United States
17 Iowa City Iowa United States
18 Westwood Kansas United States
19 Louisville Kentucky United States
20 Paducah Kentucky United States
21 Marrero Louisiana United States
22 Baltimore Maryland United States
23 Worcester Massachusetts United States
24 Ann Arbor Michigan United States
25 Battle Creek Michigan United States
26 Detroit Michigan United States
27 Lansing Michigan United States
28 Saint Louis Missouri United States
29 Lincoln Nebraska United States
30 Lebanon New Hampshire United States
31 Hackensack New Jersey United States
32 Albuquerque New Mexico United States
33 Dunkirk New York United States
34 Hawthorne New York United States
35 New York New York United States
36 Bismarck North Dakota United States
37 Cleveland Ohio United States
38 Portland Oregon United States
39 Charleston South Carolina United States
40 Sioux Falls South Dakota United States
41 Temple Texas United States
42 Morgantown West Virginia United States
43 Buenos Aires Argentina
44 Ciudad Autonoma Buenos Aires Argentina
45 Ciudad Autonoma de Buenos Aires Argentina
46 Cordoba Argentina
47 Aalst Belgium
48 Brugge Belgium
49 Brussels Belgium
50 Gent Belgium
51 Leuven Belgium
52 Rio de Janeiro Brazil
53 Salvador Brazil
54 Sao Paulo Brazil
55 Edmonton Alberta Canada
56 Vancouver N/a British Columbia Canada
57 Hamilton Ontario Canada
58 London Ontario Canada
59 Ottawa Ontario Canada
60 Toronto Ontario Canada
61 Montreal Quebec Canada
62 Bogota Colombia
63 Floridablanca Colombia
64 Brno Czechia
65 Praha 10 Czechia
66 Praha 2 Czechia
67 Creteil France
68 Montpellier France
69 Paris Cedex 13 France
70 Pessac France
71 Pierre Benite France
72 Tours France
73 Villejuif France
74 Aschaffenburg Germany
75 Augsburg Germany
76 Dresden Germany
77 Erlangen Germany
78 Essen Germany
79 Frankfurt Germany
80 Frechen Germany
81 Hamm Germany
82 Heidelberg Germany
83 Homburg/Saar Germany
84 Kassel Germany
85 Kiel Germany
86 Koblenz Germany
87 Köln Germany
88 Kÿln N/a Germany
89 Lebach Germany
90 Magdeburg Germany
91 Mannheim Germany
92 Marburg Germany
93 Mutlangen Germany
94 Ulm Germany
95 Würzburg Germany
96 Athens Greece
97 Thessalonikis Greece
98 Haifa Israel
99 Jerusalem Israel
100 Nahariya Israel
101 Netanya Israel
102 Petah Tikva Israel
103 Ramat-Gan Israel
104 Tel Aviv Israel
105 Seoul Korea, Republic of
106 Mexico Mexico
107 Monterrey Mexico
108 Oaxaca Mexico
109 Brzozow Poland
110 Chorzów Poland
111 Krakow Poland
112 Opole Poland
113 Slupsk Poland
114 Coimbra Portugal
115 Lisboa Portugal
116 Ponta Delgada Portugal
117 Porto Portugal
118 Arkhangelsk Russian Federation
119 Dzerzhinsk Russian Federation
120 Ekaterinburg Russian Federation
121 Krasnodar Russian Federation
122 Moscow N/a Russian Federation
123 Moscow Russian Federation
124 Nizhniy Novgorod Russian Federation
125 Obninsk Russian Federation
126 Perm Russian Federation
127 Rostov-Na-Donu Russian Federation
128 Ryazan Russian Federation
129 Saint Petersburg Russian Federation
130 Samara Russian Federation
131 Sochi Russian Federation
132 St. Petersburg Russian Federation
133 St.-Petersburg Russian Federation
134 Syktyvkar Russian Federation
135 Barcelona Spain
136 L'hospitalet De Llobregat Spain
137 Madrid Spain
138 Salamanca Spain
139 Valencia Spain
140 Göteborg Sweden
141 Huddinge Sweden
142 Stockholm Sweden
143 UMEå Sweden
144 Ankara Turkey
145 Istanbul Turkey
146 Izmir Turkey
147 Kayseri Turkey
148 Cherkassy Ukraine
149 Dnepropetrovsk Ukraine
150 Donetsk Ukraine
151 Khakhiv Ukraine
152 Khmelnitskiy Ukraine
153 Kiev Ukraine
154 Lviv Ukraine
155 Vinnitsa Ukraine
156 Birmingham United Kingdom
157 Harrow United Kingdom
158 Plymouth United Kingdom
159 Sheffield Yorks United Kingdom
160 Sutton United Kingdom

Sponsors and Collaborators

  • Janssen Research & Development, LLC
  • Pharmacyclics LLC.

Investigators

  • Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Study Documents (Full-Text)

More Information

Publications

None provided.
Responsible Party:
Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:
NCT01611090
Other Study ID Numbers:
  • CR100840
  • PCI-32765CLL3001
  • 2012-000600-15
  • U1111-1135-3745
First Posted:
Jun 4, 2012
Last Update Posted:
Mar 3, 2020
Last Verified:
Feb 1, 2020
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Janssen Research & Development, LLC
Chronic lymphocytic leukemia
Small lymphocytic lymphoma
Relapsed or refractory chronic lymphocytic leukemia
Relapsed or refractory small lymphocytic lymphoma
Ibrutinib
PCI-32765
JNJ-54179060
Bruton's tyrosine kinase inhibitor
Bendamustine
Rituximab
Additional relevant MeSH terms:
Lymphoma
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Rituximab
Bendamustine Hydrochloride

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail 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 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
Period Title: Randomized Period
STARTED 0 0 183
Treated 0 0 183
COMPLETED 0 0 178
NOT COMPLETED 0 0 5

Baseline Characteristics

Arm/Group Title Ibrutinib+BR Placebo+BR Total
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 Participants 289 289 578
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
63.7
(9.82)
63.3
(9.3)
63.5
(9.56)
Sex: Female, Male (Count of Participants)
Female
96
33.2%
100
34.6%
196
33.9%
Male
193
66.8%
189
65.4%
382
66.1%
Ethnicity (NIH/OMB) (Count of 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 (Count of 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%
Other
3
1%
7
2.4%
10
1.7%
Unknown or not reported
12
4.2%
9
3.1%
21
3.6%
Region of Enrollment (Count of Participants)
ARGENTINA
3
1%
3
1%
6
1%
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%
1
0.3%
1
0.2%
CZECH REPUBLIC
12
4.2%
11
3.8%
23
4%
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%
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%
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%
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 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 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.
Measure Participants 289 289
Median (95% Confidence Interval) [Months]
65.12
14.32
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ibrutinib+BR, Placebo+BR
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Log Rank
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.229
Confidence Interval (2-Sided) 95%
0.183 to 0.286
Parameter Dispersion Type:
Value:
Estimation Comments
2. Secondary Outcome
Title Overall Response Rate (ORR)
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 >1.5*10^9/liter (L), platelets >100*10^9/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 >1.5*10^9/L, Platelets >100*10^9/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 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.
Measure Participants 289 289
Number [Percentage of participants]
87.2
30.2%
66.1
22.9%
3. Secondary Outcome
Title Overall Survival (OS)
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 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.
Measure Participants 289 289
Median (95% Confidence Interval) [Months]
NA
NA
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 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 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.
Measure Participants 289 289
Number [Percentage of participants]
28.7
9.9%
5.9
2%
5. Secondary Outcome
Title Percentage of Participants With Sustained Hematologic Improvement
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 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.
Measure Participants 289 289
Hemoglobin
36.7
12.7%
29.1
10.1%
Platelets
30.8
10.7%
21.8
7.5%
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 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 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.
Measure Participants 289 289
Number (95% Confidence Interval) [Months]
6.5
4.6
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, 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 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.
Measure Participants 289 289
Count of Participants [Participants]
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 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 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.
Measure Participants 287 287
Count of Participants [Participants]
52
18%
61
21.1%
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 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 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.
Measure Participants 39 106
Mean (Standard Deviation) [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 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
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 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.
Measure Participants 38 104
Mean (Standard Deviation) [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 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
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 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.
Measure Participants 38 104
Mean (Standard Deviation) [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 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
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. Here, 'n' signifies the number of participants analyzed for the specified symptoms.
Arm/Group Title Ibrutinib+BR Placebo+BR
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.
Measure Participants 38 104
Lost weight
0.1
(0.86)
0.0
(0.74)
Dry mouth
0.3
(0.96)
0.1
(0.85)
Bruises
0.1
(0.61)
0.0
(0.65)
Abdominal discomfort
0.1
(0.81)
0.0
(0.76)
Temperature going up and down
0.1
(0.93)
0.0
(0.72)
Night sweats
-0.6
(0.92)
-0.3
(1.07)
Skin problems
0.4
(1.14)
0.3
(0.96)
Feel ill
0.1
(1.08)
0.2
(0.98)
Feel lethargic
0.1
(1.01)
0.0
(0.91)
Felt slowed down
0.3
(0.80)
0.0
(0.97)
Limited in planning activities
0.2
(0.97)
0.1
(0.90)
Worried about health in the future
0.0
(0.94)
0.0
(0.97)
Trouble with chest infections
0.2
(1.05)
0.0
(0.82)
Trouble with other infections
0.7
(1.07)
0.1
(0.86)
Repeated courses of antibiotics
0.9
(1.22)
0.0
(0.97)
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 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
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 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.
Measure Participants 38 110
Mean (Standard Deviation) [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 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
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 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.
Measure Participants 38 110
Mean (Standard Deviation) [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 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 (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 74/287 (25.8%) 107/287 (37.3%) 57/183 (31.1%)
Serious Adverse Events
Ibrutinib+BR Placebo+BR Crossover to Ibrutinib
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 198/287 (69%) 127/287 (44.3%) 105/183 (57.4%)
Blood and lymphatic system disorders
Anaemia 3/287 (1%) 7/287 (2.4%) 2/183 (1.1%)
Aplasia Pure Red Cell 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Aplastic Anaemia 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Autoimmune Haemolytic Anaemia 0/287 (0%) 5/287 (1.7%) 0/183 (0%)
Bone Marrow Failure 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Cytopenia 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Febrile Neutropenia 30/287 (10.5%) 22/287 (7.7%) 2/183 (1.1%)
Haemolytic Anaemia 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Immune Thrombocytopenic Purpura 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Neutropenia 7/287 (2.4%) 6/287 (2.1%) 0/183 (0%)
Pancytopenia 2/287 (0.7%) 0/287 (0%) 0/183 (0%)
Thrombocytopenia 4/287 (1.4%) 2/287 (0.7%) 0/183 (0%)
Cardiac disorders
Acute Coronary Syndrome 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Acute Myocardial Infarction 0/287 (0%) 3/287 (1%) 1/183 (0.5%)
Angina Pectoris 4/287 (1.4%) 1/287 (0.3%) 0/183 (0%)
Angina Unstable 1/287 (0.3%) 0/287 (0%) 1/183 (0.5%)
Arrhythmia Supraventricular 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Atrial Fibrillation 16/287 (5.6%) 2/287 (0.7%) 6/183 (3.3%)
Atrial Flutter 1/287 (0.3%) 0/287 (0%) 1/183 (0.5%)
Atrioventricular Block 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Cardiac Arrest 2/287 (0.7%) 0/287 (0%) 3/183 (1.6%)
Cardiac Failure 3/287 (1%) 0/287 (0%) 0/183 (0%)
Cardio-Respiratory Arrest 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Cardiopulmonary Failure 1/287 (0.3%) 0/287 (0%) 1/183 (0.5%)
Cardiovascular Insufficiency 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Carditis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Coronary Artery Occlusion 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Myocardial Infarction 2/287 (0.7%) 2/287 (0.7%) 2/183 (1.1%)
Myocarditis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Pericardial Effusion 2/287 (0.7%) 1/287 (0.3%) 1/183 (0.5%)
Sinus Node Dysfunction 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Sinus Tachycardia 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Tachycardia 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Ventricular Fibrillation 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Ventricular Flutter 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Ventricular Tachycardia 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Endocrine disorders
Addison's Disease 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Goitre 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Eye disorders
Cataract 3/287 (1%) 0/287 (0%) 2/183 (1.1%)
Maculopathy 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Retinal Haemorrhage 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Scleral Disorder 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Vitreous Adhesions 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Vitreous Haemorrhage 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Gastrointestinal disorders
Abdominal Hernia 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Abdominal Incarcerated Hernia 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Abdominal Pain 0/287 (0%) 0/287 (0%) 3/183 (1.6%)
Anal Fistula 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Ascites 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Colitis 1/287 (0.3%) 2/287 (0.7%) 0/183 (0%)
Colitis Ischaemic 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Constipation 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Diarrhoea 4/287 (1.4%) 1/287 (0.3%) 0/183 (0%)
Duodenal Ulcer Haemorrhage 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Dyspepsia 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Dysphagia 0/287 (0%) 2/287 (0.7%) 0/183 (0%)
Enterocolitis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Gastric Haemorrhage 1/287 (0.3%) 0/287 (0%) 1/183 (0.5%)
Gastric Ulcer Perforation 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Gastritis 3/287 (1%) 0/287 (0%) 0/183 (0%)
Gastrointestinal Disorder 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Gastrointestinal Haemorrhage 2/287 (0.7%) 0/287 (0%) 0/183 (0%)
Gastrointestinal Inflammation 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Haematemesis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Haematochezia 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Inguinal Hernia 4/287 (1.4%) 0/287 (0%) 1/183 (0.5%)
Intestinal Obstruction 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Intra-Abdominal Haemorrhage 1/287 (0.3%) 0/287 (0%) 1/183 (0.5%)
Large Intestine Perforation 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Lower Gastrointestinal Haemorrhage 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Mouth Ulceration 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Nausea 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Oesophageal Ulcer 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Oesophagitis 0/287 (0%) 1/287 (0.3%) 1/183 (0.5%)
Pancreatitis 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Pancreatitis Acute 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Proctitis 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Small Intestinal Obstruction 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Stomatitis 1/287 (0.3%) 0/287 (0%) 1/183 (0.5%)
Volvulus 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Vomiting 1/287 (0.3%) 2/287 (0.7%) 1/183 (0.5%)
General disorders
Asthenia 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Chest Pain 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Chills 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Complication Associated with Device 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Condition Aggravated 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Death 2/287 (0.7%) 0/287 (0%) 1/183 (0.5%)
Disease Progression 1/287 (0.3%) 2/287 (0.7%) 0/183 (0%)
Fatigue 3/287 (1%) 1/287 (0.3%) 1/183 (0.5%)
General Physical Health Deterioration 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Hernia 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Influenza Like Illness 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Infusion Site Extravasation 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Malaise 1/287 (0.3%) 1/287 (0.3%) 1/183 (0.5%)
Mucosal Inflammation 1/287 (0.3%) 1/287 (0.3%) 0/183 (0%)
Multiple Organ Dysfunction Syndrome 1/287 (0.3%) 3/287 (1%) 3/183 (1.6%)
Non-Cardiac Chest Pain 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Oedema Peripheral 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Pneumatosis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Pyrexia 11/287 (3.8%) 7/287 (2.4%) 4/183 (2.2%)
Sudden Cardiac Death 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Sudden Death 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Systemic Inflammatory Response Syndrome 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Hepatobiliary disorders
Cholangitis 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Cholecystitis 1/287 (0.3%) 1/287 (0.3%) 1/183 (0.5%)
Cholecystitis Acute 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Cholecystitis Chronic 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Cholelithiasis 2/287 (0.7%) 0/287 (0%) 1/183 (0.5%)
Cholestasis 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Gallbladder Obstruction 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Hepatic Cirrhosis 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Hepatitis Toxic 0/287 (0%) 2/287 (0.7%) 0/183 (0%)
Hepatocellular Injury 1/287 (0.3%) 1/287 (0.3%) 0/183 (0%)
Hepatosplenomegaly 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Immune system disorders
Anaphylactic Reaction 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Infections and infestations
Abscess Jaw 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Actinomycotic Pulmonary Infection 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Acute Sinusitis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Appendicitis 1/287 (0.3%) 0/287 (0%) 2/183 (1.1%)
Arthritis Bacterial 2/287 (0.7%) 0/287 (0%) 0/183 (0%)
Ascariasis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Atypical Pneumonia 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Bacteraemia 2/287 (0.7%) 0/287 (0%) 0/183 (0%)
Brain Abscess 2/287 (0.7%) 0/287 (0%) 0/183 (0%)
Breast Abscess 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Breast Cellulitis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Bronchitis 8/287 (2.8%) 5/287 (1.7%) 1/183 (0.5%)
Bronchopulmonary Aspergillosis 1/287 (0.3%) 1/287 (0.3%) 2/183 (1.1%)
Campylobacter Infection 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Cellulitis 4/287 (1.4%) 2/287 (0.7%) 1/183 (0.5%)
Cellulitis Staphylococcal 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Central Nervous System Infection 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Chronic Sinusitis 1/287 (0.3%) 1/287 (0.3%) 0/183 (0%)
Clostridium Difficile Colitis 0/287 (0%) 1/287 (0.3%) 1/183 (0.5%)
Clostridium Difficile Infection 0/287 (0%) 0/287 (0%) 2/183 (1.1%)
Conjunctivitis 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Cystitis 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Cytomegalovirus Colitis 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Cytomegalovirus Infection 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Dacryocystitis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Dermo-Hypodermitis 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Disseminated Cryptococcosis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Epstein-Barr Virus Infection 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Erysipelas 1/287 (0.3%) 0/287 (0%) 3/183 (1.6%)
Escherichia Sepsis 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Escherichia Urinary Tract Infection 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Fungal Infection 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Gastroenteritis 1/287 (0.3%) 1/287 (0.3%) 0/183 (0%)
Gastroenteritis Viral 2/287 (0.7%) 0/287 (0%) 1/183 (0.5%)
Gastrointestinal Infection 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Haemophilus Infection 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Hepatitis B Reactivation 1/287 (0.3%) 1/287 (0.3%) 0/183 (0%)
Herpes Zoster 1/287 (0.3%) 2/287 (0.7%) 1/183 (0.5%)
Infection 3/287 (1%) 2/287 (0.7%) 0/183 (0%)
Infectious Pleural Effusion 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Influenza 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Laryngitis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Lower Respiratory Tract Infection 0/287 (0%) 2/287 (0.7%) 2/183 (1.1%)
Lung Infection 3/287 (1%) 3/287 (1%) 0/183 (0%)
Lymphadenitis Bacterial 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Muscle Abscess 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Neutropenic Sepsis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Nocardiosis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Oral Candidiasis 0/287 (0%) 2/287 (0.7%) 0/183 (0%)
Osteomyelitis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Otitis Media 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Periodontitis 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Periorbital Cellulitis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Peritonsillar Abscess 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Pharyngeal Abscess 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Pharyngitis 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Pharyngitis Streptococcal 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Pneumocystis Jirovecii Pneumonia 2/287 (0.7%) 0/287 (0%) 0/183 (0%)
Pneumonia 48/287 (16.7%) 26/287 (9.1%) 34/183 (18.6%)
Pneumonia Bacterial 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Pneumonia Haemophilus 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Pneumonia Pneumococcal 1/287 (0.3%) 0/287 (0%) 1/183 (0.5%)
Pneumonia Streptococcal 0/287 (0%) 1/287 (0.3%) 2/183 (1.1%)
Progressive Multifocal Leukoencephalopathy 2/287 (0.7%) 0/287 (0%) 2/183 (1.1%)
Pseudomembranous Colitis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Pulmonary Tuberculoma 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Pulmonary Tuberculosis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Pyelonephritis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Rash Pustular 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Respiratory Syncytial Virus Infection 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Respiratory Tract Infection 5/287 (1.7%) 2/287 (0.7%) 5/183 (2.7%)
Sepsis 8/287 (2.8%) 4/287 (1.4%) 4/183 (2.2%)
Septic Shock 6/287 (2.1%) 2/287 (0.7%) 5/183 (2.7%)
Sinusitis 1/287 (0.3%) 2/287 (0.7%) 2/183 (1.1%)
Skin Candida 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Skin Infection 2/287 (0.7%) 1/287 (0.3%) 1/183 (0.5%)
Soft Tissue Infection 1/287 (0.3%) 0/287 (0%) 1/183 (0.5%)
Splenic Abscess 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Staphylococcal Infection 2/287 (0.7%) 0/287 (0%) 0/183 (0%)
Staphylococcal Skin Infection 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Subcutaneous Abscess 3/287 (1%) 1/287 (0.3%) 0/183 (0%)
Tooth Abscess 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Tuberculosis of Central Nervous System 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Upper Respiratory Tract Infection 3/287 (1%) 3/287 (1%) 0/183 (0%)
Urinary Tract Infection 6/287 (2.1%) 1/287 (0.3%) 2/183 (1.1%)
Urosepsis 1/287 (0.3%) 0/287 (0%) 1/183 (0.5%)
Varicella 1/287 (0.3%) 1/287 (0.3%) 0/183 (0%)
Varicella Zoster Virus Infection 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Viral Infection 0/287 (0%) 1/287 (0.3%) 1/183 (0.5%)
Injury, poisoning and procedural complications
Abdominal Injury 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Ankle Fracture 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Fall 2/287 (0.7%) 0/287 (0%) 1/183 (0.5%)
Femoral Neck Fracture 2/287 (0.7%) 0/287 (0%) 2/183 (1.1%)
Femur Fracture 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Hip Fracture 1/287 (0.3%) 1/287 (0.3%) 1/183 (0.5%)
Incision Site Haemorrhage 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Infusion Related Reaction 4/287 (1.4%) 5/287 (1.7%) 0/183 (0%)
Pelvic Fracture 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Pneumoconiosis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Pneumothorax Traumatic 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Post Procedural Haemorrhage 1/287 (0.3%) 0/287 (0%) 2/183 (1.1%)
Post Procedural Swelling 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Subdural Haematoma 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Thoracic Vertebral Fracture 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Investigations
Biopsy 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Blood Creatinine Increased 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Body Temperature Increased 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Neutrophil Count Decreased 2/287 (0.7%) 0/287 (0%) 0/183 (0%)
Prostatic Specific Antigen Increased 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Weight Decreased 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Metabolism and nutrition disorders
Decreased Appetite 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Dehydration 2/287 (0.7%) 1/287 (0.3%) 1/183 (0.5%)
Diabetes Mellitus 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Hypercalcaemia 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Hyperuricaemia 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Hyponatraemia 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Hypophosphataemia 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Tumour Lysis Syndrome 6/287 (2.1%) 1/287 (0.3%) 0/183 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Arthritis 2/287 (0.7%) 0/287 (0%) 1/183 (0.5%)
Back Pain 1/287 (0.3%) 0/287 (0%) 1/183 (0.5%)
Chondrocalcinosis Pyrophosphate 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Femoroacetabular Impingement 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Groin Pain 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Lumbar Spinal Stenosis 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Muscle Haemorrhage 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Muscular Weakness 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Musculoskeletal Pain 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Osteoarthritis 3/287 (1%) 0/287 (0%) 0/183 (0%)
Osteonecrosis 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Pain in Extremity 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute Lymphocytic Leukaemia 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Adenosquamous Cell Lung Cancer 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Anal Squamous Cell Carcinoma 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Basal Cell Carcinoma 5/287 (1.7%) 1/287 (0.3%) 1/183 (0.5%)
Bladder Cancer 2/287 (0.7%) 0/287 (0%) 0/183 (0%)
Bronchioloalveolar Carcinoma 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Chronic Myelomonocytic Leukaemia 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Intestinal Adenocarcinoma 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Intraductal Papilloma of Breast 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Lipoma 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Lung Adenocarcinoma 0/287 (0%) 1/287 (0.3%) 1/183 (0.5%)
Malignant Melanoma 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Malignant Melanoma in Situ 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Maxillofacial Sinus Neoplasm 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Metastases to Central Nervous System 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Metastatic Renal Cell Carcinoma 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Myelodysplastic Syndrome 2/287 (0.7%) 1/287 (0.3%) 0/183 (0%)
Myeloproliferative Neoplasm 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Neuroendocrine Carcinoma 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Prostate Cancer 1/287 (0.3%) 1/287 (0.3%) 2/183 (1.1%)
Renal Cancer 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Renal Cancer Stage I 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Renal Oncocytoma 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Squamous Cell Carcinoma 3/287 (1%) 1/287 (0.3%) 2/183 (1.1%)
Squamous Cell Carcinoma of Skin 0/287 (0%) 2/287 (0.7%) 0/183 (0%)
Superficial Spreading Melanoma Stage Unspecified 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Transitional Cell Carcinoma 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Nervous system disorders
Carotid Sinus Syndrome 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Cerebral Disorder 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Cerebral Infarction 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Cerebral Ischaemia 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Cerebrovascular Accident 3/287 (1%) 0/287 (0%) 1/183 (0.5%)
Cognitive Disorder 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Depressed Level of Consciousness 1/287 (0.3%) 0/287 (0%) 1/183 (0.5%)
Encephalopathy 0/287 (0%) 0/287 (0%) 2/183 (1.1%)
Facial Paresis 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Haemorrhage Intracranial 1/287 (0.3%) 0/287 (0%) 1/183 (0.5%)
Haemorrhagic Stroke 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Headache 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Loss of Consciousness 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Meningism 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Peripheral Sensory Neuropathy 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Post Herpetic Neuralgia 1/287 (0.3%) 1/287 (0.3%) 0/183 (0%)
Radiculopathy 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Syncope 0/287 (0%) 1/287 (0.3%) 1/183 (0.5%)
Transient Global Amnesia 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Vascular Encephalopathy 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Psychiatric disorders
Acute Stress Disorder 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Alcoholic Psychosis 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Completed Suicide 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Confusional State 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Delirium 1/287 (0.3%) 1/287 (0.3%) 0/183 (0%)
Mental Status Changes 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Renal and urinary disorders
Acute Kidney Injury 2/287 (0.7%) 1/287 (0.3%) 0/183 (0%)
Calculus Bladder 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Dysuria 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Haematuria 0/287 (0%) 0/287 (0%) 2/183 (1.1%)
Nephropathy 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Nephropathy Toxic 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Renal Failure 1/287 (0.3%) 0/287 (0%) 2/183 (1.1%)
Renal Impairment 2/287 (0.7%) 1/287 (0.3%) 0/183 (0%)
Ureteric Stenosis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Ureterolithiasis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Urge Incontinence 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Urinary Incontinence 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Urinary Retention 1/287 (0.3%) 0/287 (0%) 1/183 (0.5%)
Reproductive system and breast disorders
Benign Prostatic Hyperplasia 2/287 (0.7%) 0/287 (0%) 1/183 (0.5%)
Fibrocystic Breast Disease 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Genital Rash 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Pelvic Floor Muscle Weakness 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Penile Dysplasia 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Uterine Haemorrhage 2/287 (0.7%) 0/287 (0%) 0/183 (0%)
Uterine Prolapse 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure 0/287 (0%) 1/287 (0.3%) 1/183 (0.5%)
Chronic Obstructive Pulmonary Disease 0/287 (0%) 1/287 (0.3%) 1/183 (0.5%)
Dyspnoea 1/287 (0.3%) 3/287 (1%) 0/183 (0%)
Dyspnoea Exertional 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Haemoptysis 0/287 (0%) 1/287 (0.3%) 1/183 (0.5%)
Haemothorax 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Lung Infiltration 1/287 (0.3%) 1/287 (0.3%) 0/183 (0%)
Pleural Effusion 3/287 (1%) 2/287 (0.7%) 2/183 (1.1%)
Pleuritic Pain 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Pneumonitis 1/287 (0.3%) 1/287 (0.3%) 1/183 (0.5%)
Pneumothorax 0/287 (0%) 1/287 (0.3%) 1/183 (0.5%)
Pulmonary Congestion 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Pulmonary Mass 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Pulmonary Sarcoidosis 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Respiratory Failure 1/287 (0.3%) 0/287 (0%) 3/183 (1.6%)
Respiratory Tract Oedema 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Sleep Apnoea Syndrome 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Skin and subcutaneous tissue disorders
Acute Febrile Neutrophilic Dermatosis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Cellulitis 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Drug Eruption 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Excessive Granulation Tissue 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Hypersensitivity Vasculitis 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Pemphigoid 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Pemphigus 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Rash 0/287 (0%) 2/287 (0.7%) 0/183 (0%)
Rash Erythematous 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Rash Maculo-Papular 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Skin Necrosis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Urticaria 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Vascular disorders
Aortic Aneurysm Rupture 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Arterial Stenosis 0/287 (0%) 0/287 (0%) 1/183 (0.5%)
Deep Vein Thrombosis 1/287 (0.3%) 3/287 (1%) 0/183 (0%)
Haematoma 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Hypertension 2/287 (0.7%) 0/287 (0%) 1/183 (0.5%)
Hypertensive Crisis 2/287 (0.7%) 0/287 (0%) 0/183 (0%)
Hypotension 2/287 (0.7%) 0/287 (0%) 0/183 (0%)
Jugular Vein Thrombosis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Lymphoedema 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Peripheral Arterial Occlusive Disease 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Peripheral Artery Occlusion 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Peripheral Artery Thrombosis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Peripheral Ischaemia 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Thrombophlebitis 1/287 (0.3%) 1/287 (0.3%) 0/183 (0%)
Thrombosis 1/287 (0.3%) 0/287 (0%) 0/183 (0%)
Vasculitis 0/287 (0%) 1/287 (0.3%) 0/183 (0%)
Other (Not Including Serious) Adverse Events
Ibrutinib+BR Placebo+BR Crossover to Ibrutinib
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 268/287 (93.4%) 271/287 (94.4%) 157/183 (85.8%)
Blood and lymphatic system disorders
Anaemia 73/287 (25.4%) 79/287 (27.5%) 33/183 (18%)
Leukopenia 15/287 (5.2%) 18/287 (6.3%) 2/183 (1.1%)
Neutropenia 170/287 (59.2%) 159/287 (55.4%) 40/183 (21.9%)
Thrombocytopenia 90/287 (31.4%) 69/287 (24%) 24/183 (13.1%)
Cardiac disorders
Atrial Fibrillation 23/287 (8%) 5/287 (1.7%) 19/183 (10.4%)
Eye disorders
Cataract 20/287 (7%) 3/287 (1%) 8/183 (4.4%)
Dry Eye 15/287 (5.2%) 9/287 (3.1%) 6/183 (3.3%)
Vision Blurred 19/287 (6.6%) 19/287 (6.6%) 3/183 (1.6%)
Gastrointestinal disorders
Abdominal Pain 39/287 (13.6%) 24/287 (8.4%) 3/183 (1.6%)
Abdominal Pain Upper 23/287 (8%) 16/287 (5.6%) 11/183 (6%)
Constipation 61/287 (21.3%) 50/287 (17.4%) 15/183 (8.2%)
Diarrhoea 115/287 (40.1%) 68/287 (23.7%) 47/183 (25.7%)
Dyspepsia 24/287 (8.4%) 21/287 (7.3%) 8/183 (4.4%)
Gastroesophageal Reflux Disease 15/287 (5.2%) 12/287 (4.2%) 4/183 (2.2%)
Nausea 108/287 (37.6%) 101/287 (35.2%) 16/183 (8.7%)
Toothache 15/287 (5.2%) 5/287 (1.7%) 3/183 (1.6%)
Vomiting 42/287 (14.6%) 45/287 (15.7%) 15/183 (8.2%)
General disorders
Asthenia 26/287 (9.1%) 24/287 (8.4%) 5/183 (2.7%)
Chills 33/287 (11.5%) 31/287 (10.8%) 5/183 (2.7%)
Fatigue 69/287 (24%) 66/287 (23%) 32/183 (17.5%)
Influenza Like Illness 9/287 (3.1%) 10/287 (3.5%) 12/183 (6.6%)
Mucosal Inflammation 15/287 (5.2%) 7/287 (2.4%) 3/183 (1.6%)
Non-Cardiac Chest Pain 17/287 (5.9%) 13/287 (4.5%) 3/183 (1.6%)
Oedema Peripheral 49/287 (17.1%) 34/287 (11.8%) 21/183 (11.5%)
Pyrexia 74/287 (25.8%) 60/287 (20.9%) 22/183 (12%)
Infections and infestations
Bronchitis 51/287 (17.8%) 29/287 (10.1%) 19/183 (10.4%)
Cellulitis 16/287 (5.6%) 8/287 (2.8%) 10/183 (5.5%)
Conjunctivitis 20/287 (7%) 15/287 (5.2%) 10/183 (5.5%)
Herpes Zoster 24/287 (8.4%) 17/287 (5.9%) 7/183 (3.8%)
Influenza 22/287 (7.7%) 16/287 (5.6%) 7/183 (3.8%)
Oral Herpes 15/287 (5.2%) 18/287 (6.3%) 7/183 (3.8%)
Pharyngitis 18/287 (6.3%) 13/287 (4.5%) 2/183 (1.1%)
Pneumonia 40/287 (13.9%) 25/287 (8.7%) 21/183 (11.5%)
Respiratory Tract Infection 19/287 (6.6%) 10/287 (3.5%) 15/183 (8.2%)
Sinusitis 38/287 (13.2%) 24/287 (8.4%) 25/183 (13.7%)
Upper Respiratory Tract Infection 69/287 (24%) 50/287 (17.4%) 36/183 (19.7%)
Urinary Tract Infection 28/287 (9.8%) 15/287 (5.2%) 26/183 (14.2%)
Injury, poisoning and procedural complications
Contusion 30/287 (10.5%) 9/287 (3.1%) 15/183 (8.2%)
Infusion Related Reaction 45/287 (15.7%) 64/287 (22.3%) 1/183 (0.5%)
Investigations
Alanine Aminotransferase Increased 15/287 (5.2%) 12/287 (4.2%) 3/183 (1.6%)
Blood Creatinine Increased 17/287 (5.9%) 7/287 (2.4%) 6/183 (3.3%)
Neutrophil Count Decreased 21/287 (7.3%) 16/287 (5.6%) 3/183 (1.6%)
Platelet Count Decreased 17/287 (5.9%) 9/287 (3.1%) 2/183 (1.1%)
Weight Decreased 18/287 (6.3%) 18/287 (6.3%) 5/183 (2.7%)
Metabolism and nutrition disorders
Decreased Appetite 42/287 (14.6%) 42/287 (14.6%) 16/183 (8.7%)
Hyperuricaemia 36/287 (12.5%) 20/287 (7%) 7/183 (3.8%)
Hypokalaemia 24/287 (8.4%) 12/287 (4.2%) 8/183 (4.4%)
Musculoskeletal and connective tissue disorders
Arthralgia 47/287 (16.4%) 29/287 (10.1%) 25/183 (13.7%)
Back Pain 41/287 (14.3%) 22/287 (7.7%) 23/183 (12.6%)
Muscle Spasms 44/287 (15.3%) 14/287 (4.9%) 17/183 (9.3%)
Myalgia 28/287 (9.8%) 15/287 (5.2%) 9/183 (4.9%)
Pain in Extremity 21/287 (7.3%) 15/287 (5.2%) 12/183 (6.6%)
Nervous system disorders
Dysgeusia 15/287 (5.2%) 15/287 (5.2%) 3/183 (1.6%)
Headache 49/287 (17.1%) 47/287 (16.4%) 18/183 (9.8%)
Psychiatric disorders
Anxiety 22/287 (7.7%) 11/287 (3.8%) 9/183 (4.9%)
Depression 18/287 (6.3%) 8/287 (2.8%) 4/183 (2.2%)
Insomnia 27/287 (9.4%) 21/287 (7.3%) 10/183 (5.5%)
Respiratory, thoracic and mediastinal disorders
Cough 74/287 (25.8%) 75/287 (26.1%) 27/183 (14.8%)
Dyspnoea 22/287 (7.7%) 29/287 (10.1%) 11/183 (6%)
Epistaxis 22/287 (7.7%) 10/287 (3.5%) 15/183 (8.2%)
Nasal Congestion 16/287 (5.6%) 9/287 (3.1%) 4/183 (2.2%)
Oropharyngeal Pain 30/287 (10.5%) 20/287 (7%) 8/183 (4.4%)
Productive Cough 21/287 (7.3%) 18/287 (6.3%) 9/183 (4.9%)
Viral Upper Respiratory Tract Infection 30/287 (10.5%) 20/287 (7%) 13/183 (7.1%)
Skin and subcutaneous tissue disorders
Dry Skin 27/287 (9.4%) 17/287 (5.9%) 7/183 (3.8%)
Ecchymosis 14/287 (4.9%) 2/287 (0.7%) 10/183 (5.5%)
Onychoclasis 10/287 (3.5%) 0/287 (0%) 10/183 (5.5%)
Pruritus 34/287 (11.8%) 33/287 (11.5%) 9/183 (4.9%)
Rash 63/287 (22%) 35/287 (12.2%) 15/183 (8.2%)
Rash Maculo-Papular 17/287 (5.9%) 11/287 (3.8%) 7/183 (3.8%)
Skin Lesion 30/287 (10.5%) 5/287 (1.7%) 11/183 (6%)
Vascular disorders
Haematoma 26/287 (9.1%) 3/287 (1%) 14/183 (7.7%)
Hypertension 47/287 (16.4%) 14/287 (4.9%) 27/183 (14.8%)

Limitations/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.

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 Medical Director Clinical Research
Organization Janssen Research & Development, LLC
Phone 844-434-4210
Email ClinicalTrialDisclosure@its.jnj.com
Responsible Party:
Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:
NCT01611090
Other Study ID Numbers:
  • CR100840
  • PCI-32765CLL3001
  • 2012-000600-15
  • U1111-1135-3745
First Posted:
Jun 4, 2012
Last Update Posted:
Mar 3, 2020
Last Verified:
Feb 1, 2020