Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Rituximab and Bendamustine Hydrochloride, Rituximab and Ibrutinib, or Ibrutinib Alone in Treating Older Patients With Previously Untreated Chronic Lymphocytic Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01886872
Recruitment Status : Active, not recruiting
First Posted : June 26, 2013
Results First Posted : December 30, 2019
Last Update Posted : September 28, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Stage I Chronic Lymphocytic Leukemia
Stage II Chronic Lymphocytic Leukemia
Stage III Chronic Lymphocytic Leukemia
Stage IV Chronic Lymphocytic Leukemia
Interventions Drug: Bendamustine Hydrochloride
Drug: Ibrutinib
Other: Laboratory Biomarker Analysis
Other: Quality-of-Life Assessment
Biological: Rituximab
Enrollment 547
Recruitment Details  
Pre-assignment Details Of the 644 patients screened, 52 did not meet eligibility criteria, 19 did not register per Investigator decision, 16 did not register per patient decision, and 10 did not register for other reasons; these patients are thus excluded from the study before randomization.
Arm/Group Title Arm A (Rituximab, Bendamustine Hydrochloride) Arm B (Ibrutinib) Arm C (Ibrutinib, Rituximab)
Hide Arm/Group Description Patients receive rituximab 375 mg/m2 IV on day 0 of course 1 and ritixumab 500 mg/m2 IV on day 1 of courses 2-6. Patients receive bendamustine hydrochloride 90 mg/m2 IV over 30 minutes on days 1-2 of courses 1-6. Courses repeat every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm B. Patients receive ibrutinib 420mg PO daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients receive ibrutinib as in Arm B. Patients receive rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
Started [1] 183 182 182
Evaluable for Secondary Endpoints 183 182 182
Evaluable for Adverse Events [2] 176 180 181
Crossover Cohort [3] 30 0 0
Completed [4] 176 178 170
Not Completed 7 4 12
Reason Not Completed
Ineligible             7             4             12
[1]
Registered/Randomized
[2]
All Patients who Started Therapy
[3]
Arm A to Arm B
[4]
All Eligible Patients Evaluable for the Primary Endpoint
Arm/Group Title Arm A (Rituximab, Bendamustine Hydrochloride) Arm B (Ibrutinib) Arm C (Ibrutinib, Rituximab) Total
Hide Arm/Group Description Patients receive rituximab 375 mg/m2 IV on day 0 of course 1 and ritixumab 500 mg/m2 IV on day 1 of courses 2-6. Patients receive bendamustine hydrochloride 90 mg/m2 IV over 30 minutes on days 1-2 of courses 1-6. Courses repeat every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm B. Patients receive ibrutinib 420mg PO daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients receive ibrutinib as in Arm B. Patients receive rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Total of all reporting groups
Overall Number of Baseline Participants 183 182 182 547
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 183 participants 182 participants 182 participants 547 participants
70
(65 to 86)
71
(65 to 89)
71
(65 to 86)
71
(65 to 89)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 183 participants 182 participants 182 participants 547 participants
Female
64
  35.0%
59
  32.4%
57
  31.3%
180
  32.9%
Male
119
  65.0%
123
  67.6%
125
  68.7%
367
  67.1%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 183 participants 182 participants 182 participants 547 participants
American Indian or Alaska Native
1
   0.5%
0
   0.0%
1
   0.5%
2
   0.4%
Asian
4
   2.2%
2
   1.1%
0
   0.0%
6
   1.1%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
9
   4.9%
7
   3.8%
7
   3.8%
23
   4.2%
White
167
  91.3%
169
  92.9%
173
  95.1%
509
  93.1%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
2
   1.1%
4
   2.2%
1
   0.5%
7
   1.3%
ECOG Performance Status   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 183 participants 182 participants 182 participants 547 participants
0
98
  53.6%
87
  47.8%
86
  47.3%
271
  49.5%
1
75
  41.0%
90
  49.5%
94
  51.6%
259
  47.3%
2
10
   5.5%
5
   2.7%
2
   1.1%
17
   3.1%
[1]
Measure Description: Eastern Cooperative Oncology Group PS Scale: 0)Fully active, able to carry on all pre-disease performance without restriction; 1)Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2)Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; 3)Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; 4)Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.
1.Primary Outcome
Title Progression Free Survival (PFS)
Hide Description The Kaplan-Meier method will be used to estimate the progression free survival distributions for each arm, with median estimates provided. Progression is defined as any one of the following: an increase in number of blood lymphocytes by >= 50% with >= 5000 B lymphocytes/mL in patients on Arm A or those on Arms 2 or 3 no longer receiving ibrutinib, >= 50% increase in the products of at least 2 lymph nodes on 2 consecutive determination 2 weeks apart, >= 50% increase in the size of the liver/spleen, transformation to a more aggressive histology, progression of any cytopenia (i.e. decrease of Hb levels > 2g/dL). Progression free survival time will be the time to either progression or death whichever occurs first.
Time Frame Time from study entry to the time of documented disease progression or death. The analysis was event driven, performed at 2.5 years after the last patient enrolled;up to 4 years.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Arm A (Rituximab, Bendamustine Hydrochloride) Arm B (Ibrutinib) Arm C (Ibrutinib, Rituximab)
Hide Arm/Group Description:
Patients receive rituximab 375 mg/m2 IV on day 0 of course 1 and ritixumab 500 mg/m2 IV on day 1 of courses 2-6. Patients receive bendamustine hydrochloride 90 mg/m2 IV over 30 minutes on days 1-2 of courses 1-6. Courses repeat every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm B.
Patients receive ibrutinib 420mg PO daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients receive ibrutinib as in Arm B. Patients receive rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 176 178 170
Median (95% Confidence Interval)
Unit of Measure: months
43 [1] 
(38 to NA)
NA [2] 
(NA to NA)
NA [2] 
(NA to NA)
[1]
95% Confidence interval (CI) upper limit has not been reached.
[2]
Median and 95% CI has not been reached.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A (Rituximab, Bendamustine Hydrochloride), Arm B (Ibrutinib)
Comments Arm B (Ibrutinib) versus Arm A (Rituximab, Bendamustine Hydrochloride)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments (1-sided)
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.39
Confidence Interval (2-Sided) 95%
0.26 to 0.58
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm A (Rituximab, Bendamustine Hydrochloride), Arm C (Ibrutinib, Rituximab)
Comments Arm C (Ibrutinib, Rituximab) versus Arm A (Rituximab, Bendamustine Hydrochloride)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments (1-sided)
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.38
Confidence Interval (2-Sided) 95%
0.25 to 0.59
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Arm B (Ibrutinib), Arm C (Ibrutinib, Rituximab)
Comments Arm C (Ibrutinib, Rituximab) versus Arm B (Ibrutinib)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.49
Comments (1-sided)
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.00
Confidence Interval (2-Sided) 95%
0.62 to 1.62
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Progression Free Survival (PFS) Rate at 2 Years
Hide Description The Kaplan-Meier method will be used to estimate the rate of progression free survival at 2 years in each treatment arm. Progression is defined as any one of the following: an increase in number of blood lymphocytes by >= 50%, >= 50% increase in the products of at least 2 lymph nodes on 2 consecutive determination 2 weeks apart, >= 50% increase in the size of the liver/spleen, transformation to a more aggressive histology, progression of any cytopenia (i.e. decrease of Hb levels > 2g/dL). Progression free survival time will be the time to either progression or death whichever occurs first.
Time Frame Time from study entry to the time of documented disease progression or death, assessed up to 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
Patient evaluable for the primary endpoint are included in this analysis.
Arm/Group Title Arm A (Rituximab, Bendamustine Hydrochloride) Arm B (Ibrutinib) Arm C (Ibrutinib, Rituximab)
Hide Arm/Group Description:
Patients receive rituximab 375 mg/m2 IV on day 0 of course 1 and ritixumab 500 mg/m2 IV on day 1 of courses 2-6. Patients receive bendamustine hydrochloride 90 mg/m2 IV over 30 minutes on days 1-2 of courses 1-6. Courses repeat every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm B.
Patients receive ibrutinib 420mg PO daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients receive ibrutinib as in Arm B. Patients receive rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 176 178 170
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of patients
74
(66 to 80)
87
(81 to 92)
88
(81 to 92)
3.Secondary Outcome
Title Overall Survival (OS) at 2 Years
Hide Description The Kaplan-Meier method will be used to estimate the rate of overall survival at 2 years in each treatment arm. OS will be measured from the date of registration to the date of the event (i.e., death) or the date of last follow-up to evaluate that event. Patients who are event-free at their last follow-up evaluation will be censored at that time point.
Time Frame From the date of registration to the date of death, assessed up to 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat analysis population.
Arm/Group Title Arm A (Rituximab, Bendamustine Hydrochloride) Arm B (Ibrutinib) Arm C (Ibrutinib, Rituximab)
Hide Arm/Group Description:
Patients receive rituximab 375 mg/m2 IV on day 0 of course 1 and ritixumab 500 mg/m2 IV on day 1 of courses 2-6. Patients receive bendamustine hydrochloride 90 mg/m2 IV over 30 minutes on days 1-2 of courses 1-6. Courses repeat every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm B.
Patients receive ibrutinib 420mg PO daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients receive ibrutinib as in Arm B. Patients receive rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 183 182 182
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of patients
95
(91 to 98)
90
(85 to 94)
94
(89 to 97)
4.Secondary Outcome
Title Duration of Response (DOR) (Complete Response [CR], CCR, Nodular Partial Response [nPR], Partial Response [PR], and PRL)
Hide Description The Kaplan-Meier method will be used to estimate median DOR. DOR is the time from first objective status to progression or death. CR requires all of the following: absence of lymphadenopathy > 1.5 cm on physical exam/CT scan, no hepatomegaly/splenomegaly on physical exam, no clonal B-cells in the blood, Normal CBC, bone marrow aspirate & biopsy must be normocellular for age. PR requires >= 50% decrease in peripheral lymphocyte count from pre-treatment value, >= 50% reduction in lymphadenopathy, and/or ≥ 50% reduction in splenomegaly/hepatomegaly. CR with exception of having bone marrow lymphoid CLL nodules will be considered a nodular PR (nPR). CR with exception of not having a bone marrow biopsy performed will be considered a clinical CR (CCR). PR with the exception of having less than a 50% reduction in peripheral lymphocyte count will be considered a PR except persistent lymphocytosis (PRL).
Time Frame From the date of first response until progression or death, performed at 2.5 years after the last patient enrolled; up to 4 years.
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat analysis population achieving objective response
Arm/Group Title Arm A (Rituximab, Bendamustine Hydrochloride) Arm B (Ibrutinib) Arm C (Ibrutinib, Rituximab)
Hide Arm/Group Description:
Patients receive rituximab 375 mg/m2 IV on day 0 of course 1 and ritixumab 500 mg/m2 IV on day 1 of courses 2-6. Patients receive bendamustine hydrochloride 90 mg/m2 IV over 30 minutes on days 1-2 of courses 1-6. Courses repeat every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm B.
Patients receive ibrutinib 420mg PO daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients receive ibrutinib as in Arm B. Patients receive rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 138 169 171
Median (95% Confidence Interval)
Unit of Measure: months
50 [1] 
(40 to NA)
NA [2] 
(NA to NA)
NA [2] 
(NA to NA)
[1]
95% Confidence interval (CI) upper limit has not been reached.
[2]
Median and 95% CI has not been reached.
5.Secondary Outcome
Title Percentage of Patients Achieving Any Response to Treatment (Overall Response Rate [ORR] [Complete Response [CR], CCR, Nodular Partial Response [nPR], Partial Response [PR], and PRL])
Hide Description Complete response (CR) requires all of the following: absence of lymphadenopathy >1.5 cm on physical exam/CT scan, no hepatomegaly/splenomegaly on physical exam, no clonal B-cells in the blood, Normal CBC, bone marrow aspirate & biopsy must be normocellular for age. Partial response (PR) requires >= 50% decrease in peripheral lymphocyte count from pre-treatment value, >= 50% reduction in lymphadenopathy, and/or ≥ 50% reduction in splenomegaly/hepatomegaly. CR with exception of having bone marrow lymphoid CLL nodules will be considered a nodular PR (nPR). CR with exception of not having a bone marrow biopsy performed will be considered a clinical CR (CCR). PR with the exception of having less than a 50% reduction in peripheral lymphocyte count will be considered a PR except persistent lymphocytosis (PRL).Overall response rate and corresponding exact binomial 95% CI provided.
Time Frame Performed at 2.5 years after the last patient enrolled;up to 4 years.
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat analysis population
Arm/Group Title Arm A (Rituximab, Bendamustine Hydrochloride) Arm B (Ibrutinib) Arm C (Ibrutinib, Rituximab)
Hide Arm/Group Description:
Patients receive rituximab 375 mg/m2 IV on day 0 of course 1 and ritixumab 500 mg/m2 IV on day 1 of courses 2-6. Patients receive bendamustine hydrochloride 90 mg/m2 IV over 30 minutes on days 1-2 of courses 1-6. Courses repeat every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm B.
Patients receive ibrutinib 420mg PO daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients receive ibrutinib as in Arm B. Patients receive rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 183 182 182
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of patients
75
(69 to 81)
93
(88 to 96)
94
(89 to 97)
6.Secondary Outcome
Title Percentage of Patients Achieving a Biopsy-proven Complete Response (CR)
Hide Description Complete response (CR) requires all of the following: absence of lymphadenopathy > 1.5 cm on physical exam/CT scan, no hepatomegaly or splenomegaly on physical exam, no clonal B-cells in the blood, Normal CBC, bone marrow aspirate and biopsy must be normocellular for age. Complete response rate and corresponding exact binomial 95% confidence intervals provided.
Time Frame Performed at 2.5 years after the last patient enrolled; up to 4 years.
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat analysis population
Arm/Group Title Arm A (Rituximab, Bendamustine Hydrochloride) Arm B (Ibrutinib) Arm C (Ibrutinib, Rituximab)
Hide Arm/Group Description:
Patients receive rituximab 375 mg/m2 IV on day 0 of course 1 and ritixumab 500 mg/m2 IV on day 1 of courses 2-6. Patients receive bendamustine hydrochloride 90 mg/m2 IV over 30 minutes on days 1-2 of courses 1-6. Courses repeat every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm B.
Patients receive ibrutinib 420mg PO daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients receive ibrutinib as in Arm B. Patients receive rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 183 182 182
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of patients
26
(20 to 33)
7
(4 to 12)
12
(8 to 18)
7.Secondary Outcome
Title Percentage of Patients Achieving Complete (CR and CCR) or Nodular Partial Response (nPR)
Hide Description Complete response (CR) requires all of the following: absence of lymphadenopathy > 1.5 cm on physical exam/CT scan, no hepatomegaly or splenomegaly on physical exam, no clonal B-cells in the blood, Normal CBC, bone marrow aspirate and biopsy must be normocellular for age. CR with exception of having bone marrow lymphoid CLL nodules will be considered a nodular PR (nPR). CR with exception of not having a bone marrow biopsy performed will be considered a clinical CR (CCR). Response rate and corresponding exact binomial 95% confidence intervals provided.
Time Frame Performed at 2.5 years after the last patient enrolled; up to 4 years.
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat analysis population
Arm/Group Title Arm A (Rituximab, Bendamustine Hydrochloride) Arm B (Ibrutinib) Arm C (Ibrutinib, Rituximab)
Hide Arm/Group Description:
Patients receive rituximab 375 mg/m2 IV on day 0 of course 1 and ritixumab 500 mg/m2 IV on day 1 of courses 2-6. Patients receive bendamustine hydrochloride 90 mg/m2 IV over 30 minutes on days 1-2 of courses 1-6. Courses repeat every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm B.
Patients receive ibrutinib 420mg PO daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients receive ibrutinib as in Arm B. Patients receive rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 183 182 182
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of patients
33
(27 to 41)
10
(6 to 16)
23
(17 to 30)
8.Secondary Outcome
Title Percentage of Patients Who Attain Minimal Residual Disease (MRD) Negative Status
Hide Description Estimated using the number of patients who achieve minimal residual disease divided by the total number randomized to that treatment arm. Corresponding exact binomial 95% confidence intervals for MRD rates will be calculated.
Time Frame Cycle 9 Day 1 Evaluation
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat analysis population
Arm/Group Title Arm A (Rituximab, Bendamustine Hydrochloride) Arm B (Ibrutinib) Arm C (Ibrutinib, Rituximab)
Hide Arm/Group Description:
Patients receive rituximab 375 mg/m2 IV on day 0 of course 1 and ritixumab 500 mg/m2 IV on day 1 of courses 2-6. Patients receive bendamustine hydrochloride 90 mg/m2 IV over 30 minutes on days 1-2 of courses 1-6. Courses repeat every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm B.
Patients receive ibrutinib 420mg PO daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients receive ibrutinib as in Arm B. Patients receive rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 183 182 182
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of patients
8
(5 to 13)
1
(0.1 to 3)
4
(2 to 8)
9.Secondary Outcome
Title The Rate of Grade 3, 4, or 5 Treatment-related Non-hematologic Adverse Events (Toxicities)
Hide Description The rate of grade 3, 4, or 5 treatment-related non-hematologic adverse events (toxicities) by arm; excludes adverse events occurring post-crossover for patients in Arm A
Time Frame Performed at 2.5 years after the last patient enrolled; up to 4 years.
Hide Outcome Measure Data
Hide Analysis Population Description
Patients who started treatment.
Arm/Group Title Arm A (Rituximab, Bendamustine Hydrochloride) Arm B (Ibrutinib) Arm C (Ibrutinib, Rituximab)
Hide Arm/Group Description:
Patients receive rituximab 375 mg/m2 IV on day 0 of course 1 and ritixumab 500 mg/m2 IV on day 1 of courses 2-6. Patients receive bendamustine hydrochloride 90 mg/m2 IV over 30 minutes on days 1-2 of courses 1-6. Courses repeat every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm B.
Patients receive ibrutinib 420mg PO daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients receive ibrutinib as in Arm B. Patients receive rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 176 180 181
Measure Type: Number
Unit of Measure: percentage of patients
41 48 39
10.Other Pre-specified Outcome
Title Geriatric Functional Status (Optional)
Hide Description Assessed using the Older Americans' Resources and Services Multidimensional Functional Assessment Questionnaire, Activities of Daily Living, Medical Outcomes Study physical functioning, Karnofsky performance status rated by a health care professional, Karnofsky performance status rated by the patient, timed "Up and Go", and number of falls in the last six months.
Time Frame Performed at 2.5 years after the last patient enrolled
Outcome Measure Data Not Reported
Time Frame Performed at 2.5 years after the last patient enrolled; up to 4 years.
Adverse Event Reporting Description Patients who started treatment AND submitted at least one Adverse Events Form are included below.
 
Arm/Group Title Arm A (Rituximab, Bendamustine Hydrochloride) Arm B (Ibrutinib) Arm C (Ibrutinib, Rituximab) Arm B Crossover
Hide Arm/Group Description Patients receive rituximab 375 mg/m2 IV on day 0 of course 1 and ritixumab 500 mg/m2 IV on day 1 of courses 2-6. Patients receive bendamustine hydrochloride 90 mg/m2 IV over 30 minutes on days 1-2 of courses 1-6. Courses repeat every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm B. Patients receive ibrutinib 420mg PO daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients receive ibrutinib as in Arm B. Patients receive rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Arm A patients experiencing disease progression crossover to Arm B.
All-Cause Mortality
Arm A (Rituximab, Bendamustine Hydrochloride) Arm B (Ibrutinib) Arm C (Ibrutinib, Rituximab) Arm B Crossover
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   15/176 (8.52%)      24/180 (13.33%)      22/181 (12.15%)      2/27 (7.41%)    
Hide Serious Adverse Events
Arm A (Rituximab, Bendamustine Hydrochloride) Arm B (Ibrutinib) Arm C (Ibrutinib, Rituximab) Arm B Crossover
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   87/176 (49.43%)      112/180 (62.22%)      108/181 (59.67%)      16/27 (59.26%)    
Blood and lymphatic system disorders         
Anemia  1  6/176 (3.41%)  6 9/180 (5.00%)  13 6/181 (3.31%)  7 2/27 (7.41%)  4
Febrile neutropenia  1  13/176 (7.39%)  14 3/180 (1.67%)  4 1/181 (0.55%)  1 2/27 (7.41%)  2
Leukocytosis  1  1/176 (0.57%)  1 2/180 (1.11%)  4 0/181 (0.00%)  0 0/27 (0.00%)  0
Cardiac disorders         
Atrial fibrillation  1  2/176 (1.14%)  2 19/180 (10.56%)  23 8/181 (4.42%)  11 2/27 (7.41%)  4
Atrial flutter  1  1/176 (0.57%)  1 2/180 (1.11%)  2 1/181 (0.55%)  1 1/27 (3.70%)  1
Atrioventricular block complete  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Atrioventricular block first degree  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Cardiac arrest  1  0/176 (0.00%)  0 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
Cardiac disorders - Other, specify  1  0/176 (0.00%)  0 3/180 (1.67%)  3 2/181 (1.10%)  2 0/27 (0.00%)  0
Chest pain - cardiac  1  1/176 (0.57%)  1 5/180 (2.78%)  6 3/181 (1.66%)  4 0/27 (0.00%)  0
Heart failure  1  2/176 (1.14%)  2 5/180 (2.78%)  6 5/181 (2.76%)  6 1/27 (3.70%)  1
Myocardial infarction  1  2/176 (1.14%)  2 2/180 (1.11%)  2 1/181 (0.55%)  2 0/27 (0.00%)  0
Palpitations  1  0/176 (0.00%)  0 1/180 (0.56%)  2 1/181 (0.55%)  1 0/27 (0.00%)  0
Pericardial effusion  1  0/176 (0.00%)  0 3/180 (1.67%)  4 1/181 (0.55%)  1 1/27 (3.70%)  1
Pericardial tamponade  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Pericarditis  1  0/176 (0.00%)  0 2/180 (1.11%)  2 1/181 (0.55%)  1 0/27 (0.00%)  0
Sick sinus syndrome  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Sinus bradycardia  1  0/176 (0.00%)  0 0/180 (0.00%)  0 2/181 (1.10%)  2 0/27 (0.00%)  0
Tricuspid valve disease  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Ventricular arrhythmia  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Ventricular tachycardia  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Ear and labyrinth disorders         
Hearing impaired  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Eye disorders         
Cataract  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Eye disorders - Other, specify  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Gastrointestinal disorders         
Abdominal distension  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Abdominal pain  1  0/176 (0.00%)  0 3/180 (1.67%)  4 2/181 (1.10%)  2 0/27 (0.00%)  0
Ascites  1  0/176 (0.00%)  0 0/180 (0.00%)  0 0/181 (0.00%)  0 1/27 (3.70%)  1
Colitis  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Constipation  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Diarrhea  1  2/176 (1.14%)  2 5/180 (2.78%)  6 6/181 (3.31%)  6 3/27 (11.11%)  3
Dyspepsia  1  0/176 (0.00%)  0 1/180 (0.56%)  1 2/181 (1.10%)  4 0/27 (0.00%)  0
Dysphagia  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Enterocolitis  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Esophageal hemorrhage  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Flatulence  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Gastric hemorrhage  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Gastrointestinal disorders - Other, specify  1  1/176 (0.57%)  1 2/180 (1.11%)  2 2/181 (1.10%)  2 0/27 (0.00%)  0
Ileus  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Mucositis oral  1  1/176 (0.57%)  1 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Nausea  1  0/176 (0.00%)  0 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
Oral hemorrhage  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Pancreatitis  1  0/176 (0.00%)  0 4/180 (2.22%)  5 1/181 (0.55%)  1 0/27 (0.00%)  0
Small intestinal obstruction  1  0/176 (0.00%)  0 0/180 (0.00%)  0 2/181 (1.10%)  2 0/27 (0.00%)  0
Vomiting  1  0/176 (0.00%)  0 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
General disorders         
Chills  1  3/176 (1.70%)  3 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Death NOS  1  6/176 (3.41%)  6 8/180 (4.44%)  8 7/181 (3.87%)  7 1/27 (3.70%)  1
Edema face  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Edema limbs  1  0/176 (0.00%)  0 4/180 (2.22%)  4 1/181 (0.55%)  1 0/27 (0.00%)  0
Fatigue  1  3/176 (1.70%)  3 4/180 (2.22%)  5 7/181 (3.87%)  7 0/27 (0.00%)  0
Fever  1  16/176 (9.09%)  19 4/180 (2.22%)  4 7/181 (3.87%)  7 1/27 (3.70%)  1
Flu like symptoms  1  0/176 (0.00%)  0 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
Gait disturbance  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
General disorders and administration site conditions - Other, specify  1  1/176 (0.57%)  1 0/180 (0.00%)  0 2/181 (1.10%)  2 0/27 (0.00%)  0
Infusion related reaction  1  9/176 (5.11%)  10 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Multi-organ failure  1  1/176 (0.57%)  1 2/180 (1.11%)  2 0/181 (0.00%)  0 0/27 (0.00%)  0
Non-cardiac chest pain  1  1/176 (0.57%)  1 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
Pain  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 2/27 (7.41%)  2
Sudden death NOS  1  2/176 (1.14%)  2 5/180 (2.78%)  5 2/181 (1.10%)  2 0/27 (0.00%)  0
Hepatobiliary disorders         
Cholecystitis  1  1/176 (0.57%)  1 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Hepatobiliary disorders - Other, specify  1  0/176 (0.00%)  0 0/180 (0.00%)  0 0/181 (0.00%)  0 1/27 (3.70%)  1
Immune system disorders         
Allergic reaction  1  3/176 (1.70%)  3 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Anaphylaxis  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Cytokine release syndrome  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Immune system disorders - Other, specify  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Infections and infestations         
Abdominal infection  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Appendicitis  1  0/176 (0.00%)  0 1/180 (0.56%)  2 1/181 (0.55%)  1 0/27 (0.00%)  0
Bladder infection  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Bone infection  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Bronchial infection  1  1/176 (0.57%)  1 1/180 (0.56%)  1 2/181 (1.10%)  2 0/27 (0.00%)  0
Encephalitis infection  1  1/176 (0.57%)  1 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Gallbladder infection  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Infections and infestations - Other, specify  1  3/176 (1.70%)  3 4/180 (2.22%)  4 5/181 (2.76%)  5 1/27 (3.70%)  1
Joint infection  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Lung infection  1  6/176 (3.41%)  6 8/180 (4.44%)  9 12/181 (6.63%)  17 1/27 (3.70%)  1
Meningitis  1  0/176 (0.00%)  0 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
Pharyngitis  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Sepsis  1  8/176 (4.55%)  8 5/180 (2.78%)  5 8/181 (4.42%)  9 0/27 (0.00%)  0
Skin infection  1  0/176 (0.00%)  0 6/180 (3.33%)  7 9/181 (4.97%)  9 0/27 (0.00%)  0
Upper respiratory infection  1  2/176 (1.14%)  2 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Urinary tract infection  1  1/176 (0.57%)  1 0/180 (0.00%)  0 4/181 (2.21%)  4 1/27 (3.70%)  1
Wound infection  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Injury, poisoning and procedural complications         
Bruising  1  0/176 (0.00%)  0 1/180 (0.56%)  1 6/181 (3.31%)  8 0/27 (0.00%)  0
Fall  1  1/176 (0.57%)  1 4/180 (2.22%)  6 2/181 (1.10%)  2 0/27 (0.00%)  0
Fracture  1  1/176 (0.57%)  1 2/180 (1.11%)  2 0/181 (0.00%)  0 0/27 (0.00%)  0
Injury, poisoning and procedural complications - Other, specify  1  0/176 (0.00%)  0 1/180 (0.56%)  1 2/181 (1.10%)  2 0/27 (0.00%)  0
Postoperative hemorrhage  1  0/176 (0.00%)  0 0/180 (0.00%)  0 0/181 (0.00%)  0 1/27 (3.70%)  1
Seroma  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Spinal fracture  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Investigations         
Alanine aminotransferase increased  1  0/176 (0.00%)  0 0/180 (0.00%)  0 3/181 (1.66%)  3 0/27 (0.00%)  0
Alkaline phosphatase increased  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Aspartate aminotransferase increased  1  0/176 (0.00%)  0 0/180 (0.00%)  0 2/181 (1.10%)  2 0/27 (0.00%)  0
Blood bilirubin increased  1  0/176 (0.00%)  0 3/180 (1.67%)  3 1/181 (0.55%)  1 0/27 (0.00%)  0
CPK increased  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Cardiac troponin I increased  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Creatinine increased  1  2/176 (1.14%)  2 2/180 (1.11%)  2 0/181 (0.00%)  0 1/27 (3.70%)  1
Ejection fraction decreased  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Investigations - Other, specify  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Lymphocyte count decreased  1  7/176 (3.98%)  13 0/180 (0.00%)  0 2/181 (1.10%)  2 0/27 (0.00%)  0
Lymphocyte count increased  1  0/176 (0.00%)  0 1/180 (0.56%)  2 0/181 (0.00%)  0 1/27 (3.70%)  1
Neutrophil count decreased  1  15/176 (8.52%)  17 10/180 (5.56%)  11 11/181 (6.08%)  16 1/27 (3.70%)  2
Platelet count decreased  1  5/176 (2.84%)  6 3/180 (1.67%)  3 6/181 (3.31%)  6 1/27 (3.70%)  1
Weight gain  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
White blood cell decreased  1  3/176 (1.70%)  3 0/180 (0.00%)  0 3/181 (1.66%)  3 0/27 (0.00%)  0
Metabolism and nutrition disorders         
Anorexia  1  0/176 (0.00%)  0 2/180 (1.11%)  2 0/181 (0.00%)  0 0/27 (0.00%)  0
Dehydration  1  0/176 (0.00%)  0 3/180 (1.67%)  3 1/181 (0.55%)  1 0/27 (0.00%)  0
Hyperglycemia  1  0/176 (0.00%)  0 1/180 (0.56%)  2 0/181 (0.00%)  0 0/27 (0.00%)  0
Hyperkalemia  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Hypernatremia  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Hyperuricemia  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Hypoalbuminemia  1  0/176 (0.00%)  0 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
Hypocalcemia  1  1/176 (0.57%)  1 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Hypokalemia  1  0/176 (0.00%)  0 2/180 (1.11%)  2 1/181 (0.55%)  1 0/27 (0.00%)  0
Hyponatremia  1  1/176 (0.57%)  1 3/180 (1.67%)  3 5/181 (2.76%)  5 1/27 (3.70%)  1
Hypophosphatemia  1  0/176 (0.00%)  0 0/180 (0.00%)  0 0/181 (0.00%)  0 1/27 (3.70%)  2
Tumor lysis syndrome  1  2/176 (1.14%)  2 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Musculoskeletal and connective tissue disorders         
Back pain  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Chest wall pain  1  0/176 (0.00%)  0 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
Flank pain  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Generalized muscle weakness  1  1/176 (0.57%)  1 3/180 (1.67%)  3 2/181 (1.10%)  2 0/27 (0.00%)  0
Muscle weakness left-sided  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Muscle weakness lower limb  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Musculoskeletal and connective tissue disorder - Other, specify  1  0/176 (0.00%)  0 2/180 (1.11%)  3 1/181 (0.55%)  1 0/27 (0.00%)  0
Myalgia  1  0/176 (0.00%)  0 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
Neck pain  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Leukemia secondary to oncology chemotherapy  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Myelodysplastic syndrome  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify  1  16/176 (9.09%)  21 20/180 (11.11%)  33 28/181 (15.47%)  39 7/27 (25.93%)  10
Treatment related secondary malignancy  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Nervous system disorders         
Ataxia  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Cognitive disturbance  1  0/176 (0.00%)  0 1/180 (0.56%)  2 0/181 (0.00%)  0 0/27 (0.00%)  0
Depressed level of consciousness  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Dizziness  1  0/176 (0.00%)  0 2/180 (1.11%)  2 2/181 (1.10%)  4 0/27 (0.00%)  0
Encephalopathy  1  0/176 (0.00%)  0 0/180 (0.00%)  0 2/181 (1.10%)  2 0/27 (0.00%)  0
Headache  1  0/176 (0.00%)  0 2/180 (1.11%)  2 0/181 (0.00%)  0 0/27 (0.00%)  0
Intracranial hemorrhage  1  0/176 (0.00%)  0 3/180 (1.67%)  3 3/181 (1.66%)  3 0/27 (0.00%)  0
Lethargy  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Leukoencephalopathy  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Nervous system disorders - Other, specify  1  0/176 (0.00%)  0 0/180 (0.00%)  0 2/181 (1.10%)  2 0/27 (0.00%)  0
Paresthesia  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Peripheral motor neuropathy  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Peripheral sensory neuropathy  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Presyncope  1  1/176 (0.57%)  1 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Seizure  1  0/176 (0.00%)  0 2/180 (1.11%)  2 0/181 (0.00%)  0 0/27 (0.00%)  0
Stroke  1  0/176 (0.00%)  0 0/180 (0.00%)  0 4/181 (2.21%)  4 0/27 (0.00%)  0
Syncope  1  3/176 (1.70%)  3 2/180 (1.11%)  2 3/181 (1.66%)  3 0/27 (0.00%)  0
Transient ischemic attacks  1  0/176 (0.00%)  0 1/180 (0.56%)  1 2/181 (1.10%)  2 0/27 (0.00%)  0
Psychiatric disorders         
Confusion  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Delirium  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Psychiatric disorders - Other, specify  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Renal and urinary disorders         
Acute kidney injury  1  2/176 (1.14%)  2 2/180 (1.11%)  2 1/181 (0.55%)  1 0/27 (0.00%)  0
Chronic kidney disease  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  2 0/27 (0.00%)  0
Hematuria  1  0/176 (0.00%)  0 1/180 (0.56%)  1 3/181 (1.66%)  3 0/27 (0.00%)  0
Renal and urinary disorders - Other, specify  1  0/176 (0.00%)  0 1/180 (0.56%)  1 2/181 (1.10%)  2 1/27 (3.70%)  1
Urinary incontinence  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Urinary retention  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Urinary tract obstruction  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Reproductive system and breast disorders         
Reproductive system and breast disorders - Other, specify  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Respiratory, thoracic and mediastinal disorders         
Adult respiratory distress syndrome  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Aspiration  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Bronchopulmonary hemorrhage  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Chylothorax  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Cough  1  2/176 (1.14%)  2 2/180 (1.11%)  2 3/181 (1.66%)  5 0/27 (0.00%)  0
Dyspnea  1  3/176 (1.70%)  3 6/180 (3.33%)  7 4/181 (2.21%)  4 0/27 (0.00%)  0
Epistaxis  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Hypoxia  1  2/176 (1.14%)  2 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Pleural effusion  1  4/176 (2.27%)  5 9/180 (5.00%)  10 3/181 (1.66%)  4 1/27 (3.70%)  1
Pneumonitis  1  1/176 (0.57%)  1 2/180 (1.11%)  3 1/181 (0.55%)  1 0/27 (0.00%)  0
Pulmonary edema  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Pulmonary hypertension  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Respiratory failure  1  3/176 (1.70%)  3 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
Respiratory, thoracic and mediastinal disorders - Other, specify  1  1/176 (0.57%)  1 0/180 (0.00%)  0 3/181 (1.66%)  3 0/27 (0.00%)  0
Sleep apnea  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Wheezing  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Skin and subcutaneous tissue disorders         
Alopecia  1  0/176 (0.00%)  0 1/180 (0.56%)  2 0/181 (0.00%)  0 0/27 (0.00%)  0
Dry skin  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Pruritus  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Rash maculo-papular  1  4/176 (2.27%)  5 3/180 (1.67%)  3 2/181 (1.10%)  2 0/27 (0.00%)  0
Skin and subcutaneous tissue disorders - Other, specify  1  1/176 (0.57%)  1 4/180 (2.22%)  7 4/181 (2.21%)  4 0/27 (0.00%)  0
Surgical and medical procedures         
Surgical and medical procedures - Other, specify  1  0/176 (0.00%)  0 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
Vascular disorders         
Hematoma  1  0/176 (0.00%)  0 1/180 (0.56%)  1 3/181 (1.66%)  4 0/27 (0.00%)  0
Hypertension  1  0/176 (0.00%)  0 6/180 (3.33%)  6 6/181 (3.31%)  6 1/27 (3.70%)  1
Hypotension  1  6/176 (3.41%)  6 0/180 (0.00%)  0 0/181 (0.00%)  0 1/27 (3.70%)  1
Thromboembolic event  1  3/176 (1.70%)  3 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
1
Term from vocabulary, MedDRA 12
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Arm A (Rituximab, Bendamustine Hydrochloride) Arm B (Ibrutinib) Arm C (Ibrutinib, Rituximab) Arm B Crossover
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   176/176 (100.00%)      180/180 (100.00%)      181/181 (100.00%)      26/27 (96.30%)    
Blood and lymphatic system disorders         
Anemia  1  148/176 (84.09%)  511 134/180 (74.44%)  743 131/181 (72.38%)  756 20/27 (74.07%)  118
Blood and lymphatic system disorders - Other, specify  1  7/176 (3.98%)  15 7/180 (3.89%)  14 4/181 (2.21%)  11 1/27 (3.70%)  1
Bone marrow hypocellular  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Hemolytic uremic syndrome  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Leukocytosis  1  4/176 (2.27%)  4 15/180 (8.33%)  43 12/181 (6.63%)  23 2/27 (7.41%)  8
Lymph node pain  1  2/176 (1.14%)  2 2/180 (1.11%)  2 1/181 (0.55%)  1 0/27 (0.00%)  0
Spleen disorder  1  0/176 (0.00%)  0 2/180 (1.11%)  7 0/181 (0.00%)  0 0/27 (0.00%)  0
Thrombotic thrombocytopenic purpura  1  0/176 (0.00%)  0 1/180 (0.56%)  1 3/181 (1.66%)  3 0/27 (0.00%)  0
Cardiac disorders         
Aortic valve disease  1  2/176 (1.14%)  4 0/180 (0.00%)  0 1/181 (0.55%)  2 0/27 (0.00%)  0
Atrial fibrillation  1  3/176 (1.70%)  3 18/180 (10.00%)  41 18/181 (9.94%)  45 4/27 (14.81%)  17
Atrial flutter  1  0/176 (0.00%)  0 1/180 (0.56%)  1 5/181 (2.76%)  6 0/27 (0.00%)  0
Cardiac disorders - Other, specify  1  2/176 (1.14%)  2 2/180 (1.11%)  3 2/181 (1.10%)  2 0/27 (0.00%)  0
Chest pain - cardiac  1  0/176 (0.00%)  0 3/180 (1.67%)  11 2/181 (1.10%)  2 0/27 (0.00%)  0
Conduction disorder  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Heart failure  1  0/176 (0.00%)  0 1/180 (0.56%)  5 1/181 (0.55%)  3 1/27 (3.70%)  4
Left ventricular systolic dysfunction  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  6 0/27 (0.00%)  0
Myocardial infarction  1  1/176 (0.57%)  1 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Palpitations  1  0/176 (0.00%)  0 9/180 (5.00%)  15 7/181 (3.87%)  14 0/27 (0.00%)  0
Paroxysmal atrial tachycardia  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Pericardial effusion  1  1/176 (0.57%)  1 2/180 (1.11%)  2 0/181 (0.00%)  0 0/27 (0.00%)  0
Pericarditis  1  0/176 (0.00%)  0 1/180 (0.56%)  4 0/181 (0.00%)  0 0/27 (0.00%)  0
Sick sinus syndrome  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Sinus bradycardia  1  2/176 (1.14%)  2 3/180 (1.67%)  18 5/181 (2.76%)  7 1/27 (3.70%)  1
Sinus tachycardia  1  3/176 (1.70%)  3 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Supraventricular tachycardia  1  0/176 (0.00%)  0 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
Ear and labyrinth disorders         
Ear and labyrinth disorders - Other, specify  1  0/176 (0.00%)  0 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
Ear pain  1  1/176 (0.57%)  1 0/180 (0.00%)  0 3/181 (1.66%)  3 0/27 (0.00%)  0
Hearing impaired  1  2/176 (1.14%)  10 1/180 (0.56%)  10 2/181 (1.10%)  2 0/27 (0.00%)  0
Middle ear inflammation  1  1/176 (0.57%)  1 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Tinnitus  1  1/176 (0.57%)  1 1/180 (0.56%)  3 1/181 (0.55%)  15 0/27 (0.00%)  0
Vertigo  1  1/176 (0.57%)  1 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Endocrine disorders         
Endocrine disorders - Other, specify  1  0/176 (0.00%)  0 1/180 (0.56%)  2 0/181 (0.00%)  0 0/27 (0.00%)  0
Hypothyroidism  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Eye disorders         
Blurred vision  1  4/176 (2.27%)  4 5/180 (2.78%)  17 2/181 (1.10%)  9 2/27 (7.41%)  2
Cataract  1  1/176 (0.57%)  1 2/180 (1.11%)  6 2/181 (1.10%)  2 0/27 (0.00%)  0
Conjunctivitis  1  3/176 (1.70%)  3 1/180 (0.56%)  1 3/181 (1.66%)  4 0/27 (0.00%)  0
Dry eye  1  1/176 (0.57%)  1 0/180 (0.00%)  0 4/181 (2.21%)  14 1/27 (3.70%)  1
Eye disorders - Other, specify  1  1/176 (0.57%)  1 3/180 (1.67%)  8 5/181 (2.76%)  7 1/27 (3.70%)  1
Floaters  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 1/27 (3.70%)  1
Glaucoma  1  0/176 (0.00%)  0 1/180 (0.56%)  6 1/181 (0.55%)  1 0/27 (0.00%)  0
Photophobia  1  0/176 (0.00%)  0 1/180 (0.56%)  5 0/181 (0.00%)  0 0/27 (0.00%)  0
Retinopathy  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  2 0/27 (0.00%)  0
Scleral disorder  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Watering eyes  1  0/176 (0.00%)  0 0/180 (0.00%)  0 3/181 (1.66%)  7 1/27 (3.70%)  5
Gastrointestinal disorders         
Abdominal pain  1  5/176 (2.84%)  6 19/180 (10.56%)  36 4/181 (2.21%)  4 0/27 (0.00%)  0
Anal hemorrhage  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Ascites  1  3/176 (1.70%)  6 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Bloating  1  1/176 (0.57%)  1 2/180 (1.11%)  15 0/181 (0.00%)  0 0/27 (0.00%)  0
Colitis  1  2/176 (1.14%)  4 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
Constipation  1  33/176 (18.75%)  73 11/180 (6.11%)  42 28/181 (15.47%)  51 0/27 (0.00%)  0
Diarrhea  1  57/176 (32.39%)  95 95/180 (52.78%)  410 98/181 (54.14%)  453 12/27 (44.44%)  58
Dry mouth  1  5/176 (2.84%)  9 7/180 (3.89%)  37 9/181 (4.97%)  33 2/27 (7.41%)  2
Dyspepsia  1  30/176 (17.05%)  71 55/180 (30.56%)  225 73/181 (40.33%)  311 8/27 (29.63%)  42
Dysphagia  1  1/176 (0.57%)  1 3/180 (1.67%)  4 1/181 (0.55%)  2 0/27 (0.00%)  0
Enterocolitis  1  2/176 (1.14%)  2 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Esophageal pain  1  0/176 (0.00%)  0 1/180 (0.56%)  3 0/181 (0.00%)  0 0/27 (0.00%)  0
Esophageal ulcer  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Esophagitis  1  0/176 (0.00%)  0 1/180 (0.56%)  3 1/181 (0.55%)  1 0/27 (0.00%)  0
Fecal incontinence  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Flatulence  1  2/176 (1.14%)  6 1/180 (0.56%)  4 2/181 (1.10%)  2 0/27 (0.00%)  0
Gastric hemorrhage  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Gastritis  1  0/176 (0.00%)  0 1/180 (0.56%)  2 2/181 (1.10%)  2 0/27 (0.00%)  0
Gastroesophageal reflux disease  1  0/176 (0.00%)  0 8/180 (4.44%)  26 7/181 (3.87%)  12 1/27 (3.70%)  5
Gastrointestinal disorders - Other, specify  1  6/176 (3.41%)  21 9/180 (5.00%)  19 5/181 (2.76%)  10 0/27 (0.00%)  0
Gastrointestinal pain  1  0/176 (0.00%)  0 1/180 (0.56%)  8 0/181 (0.00%)  0 0/27 (0.00%)  0
Gingival pain  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Hemorrhoidal hemorrhage  1  0/176 (0.00%)  0 1/180 (0.56%)  6 0/181 (0.00%)  0 0/27 (0.00%)  0
Lower gastrointestinal hemorrhage  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Mucositis oral  1  11/176 (6.25%)  14 26/180 (14.44%)  79 17/181 (9.39%)  53 1/27 (3.70%)  1
Nausea  1  62/176 (35.23%)  134 25/180 (13.89%)  65 35/181 (19.34%)  50 2/27 (7.41%)  3
Oral dysesthesia  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Oral hemorrhage  1  1/176 (0.57%)  3 2/180 (1.11%)  2 1/181 (0.55%)  2 0/27 (0.00%)  0
Oral pain  1  0/176 (0.00%)  0 2/180 (1.11%)  6 4/181 (2.21%)  6 0/27 (0.00%)  0
Periodontal disease  1  0/176 (0.00%)  0 1/180 (0.56%)  6 1/181 (0.55%)  2 0/27 (0.00%)  0
Rectal hemorrhage  1  0/176 (0.00%)  0 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
Rectal mucositis  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Salivary duct inflammation  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Stomach pain  1  0/176 (0.00%)  0 2/180 (1.11%)  2 0/181 (0.00%)  0 0/27 (0.00%)  0
Toothache  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Upper gastrointestinal hemorrhage  1  1/176 (0.57%)  1 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Vomiting  1  14/176 (7.95%)  20 7/180 (3.89%)  9 15/181 (8.29%)  19 0/27 (0.00%)  0
General disorders         
Chills  1  22/176 (12.50%)  27 2/180 (1.11%)  2 11/181 (6.08%)  13 0/27 (0.00%)  0
Edema face  1  2/176 (1.14%)  3 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Edema limbs  1  41/176 (23.30%)  76 89/180 (49.44%)  383 96/181 (53.04%)  420 8/27 (29.63%)  23
Fatigue  1  158/176 (89.77%)  578 150/180 (83.33%)  1165 158/181 (87.29%)  1210 25/27 (92.59%)  167
Fever  1  21/176 (11.93%)  24 5/180 (2.78%)  5 5/181 (2.76%)  5 0/27 (0.00%)  0
Flu like symptoms  1  1/176 (0.57%)  1 4/180 (2.22%)  9 4/181 (2.21%)  5 0/27 (0.00%)  0
Gait disturbance  1  1/176 (0.57%)  1 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
General disorders and administration site conditions - Other, specify  1  3/176 (1.70%)  7 11/180 (6.11%)  23 13/181 (7.18%)  23 3/27 (11.11%)  4
Infusion related reaction  1  73/176 (41.48%)  97 0/180 (0.00%)  0 24/181 (13.26%)  24 0/27 (0.00%)  0
Injection site reaction  1  3/176 (1.70%)  7 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Localized edema  1  0/176 (0.00%)  0 3/180 (1.67%)  7 1/181 (0.55%)  2 0/27 (0.00%)  0
Malaise  1  4/176 (2.27%)  5 2/180 (1.11%)  5 0/181 (0.00%)  0 0/27 (0.00%)  0
Non-cardiac chest pain  1  3/176 (1.70%)  3 3/180 (1.67%)  3 6/181 (3.31%)  9 0/27 (0.00%)  0
Pain  1  4/176 (2.27%)  4 3/180 (1.67%)  6 12/181 (6.63%)  17 1/27 (3.70%)  5
Hepatobiliary disorders         
Cholecystitis  1  1/176 (0.57%)  5 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Hepatobiliary disorders - Other, specify  1  1/176 (0.57%)  1 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Immune system disorders         
Allergic reaction  1  11/176 (6.25%)  12 5/180 (2.78%)  5 10/181 (5.52%)  18 1/27 (3.70%)  5
Autoimmune disorder  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Cytokine release syndrome  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Immune system disorders - Other, specify  1  4/176 (2.27%)  7 0/180 (0.00%)  0 1/181 (0.55%)  1 1/27 (3.70%)  2
Serum sickness  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Infections and infestations         
Bronchial infection  1  2/176 (1.14%)  2 3/180 (1.67%)  3 1/181 (0.55%)  1 0/27 (0.00%)  0
Catheter related infection  1  1/176 (0.57%)  3 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Duodenal infection  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  2 0/27 (0.00%)  0
Enterocolitis infectious  1  0/176 (0.00%)  0 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
Eye infection  1  1/176 (0.57%)  1 0/180 (0.00%)  0 2/181 (1.10%)  2 0/27 (0.00%)  0
Hepatitis viral  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Infections and infestations - Other, specify  1  7/176 (3.98%)  9 7/180 (3.89%)  12 13/181 (7.18%)  18 1/27 (3.70%)  1
Laryngitis  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Lung infection  1  8/176 (4.55%)  11 5/180 (2.78%)  5 9/181 (4.97%)  9 1/27 (3.70%)  2
Lymph gland infection  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Mucosal infection  1  3/176 (1.70%)  3 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Nail infection  1  0/176 (0.00%)  0 1/180 (0.56%)  1 2/181 (1.10%)  4 0/27 (0.00%)  0
Otitis media  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Papulopustular rash  1  0/176 (0.00%)  0 1/180 (0.56%)  1 1/181 (0.55%)  3 0/27 (0.00%)  0
Paronychia  1  0/176 (0.00%)  0 3/180 (1.67%)  3 2/181 (1.10%)  10 0/27 (0.00%)  0
Penile infection  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Pharyngitis  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Prostate infection  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Rhinitis infective  1  1/176 (0.57%)  2 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Scrotal infection  1  0/176 (0.00%)  0 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
Sepsis  1  0/176 (0.00%)  0 1/180 (0.56%)  2 1/181 (0.55%)  1 1/27 (3.70%)  1
Sinusitis  1  4/176 (2.27%)  4 5/180 (2.78%)  12 1/181 (0.55%)  1 1/27 (3.70%)  1
Skin infection  1  7/176 (3.98%)  8 7/180 (3.89%)  22 14/181 (7.73%)  19 1/27 (3.70%)  1
Soft tissue infection  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Tooth infection  1  1/176 (0.57%)  1 1/180 (0.56%)  1 0/181 (0.00%)  0 1/27 (3.70%)  1
Upper respiratory infection  1  9/176 (5.11%)  9 8/180 (4.44%)  10 14/181 (7.73%)  23 1/27 (3.70%)  1
Urinary tract infection  1  6/176 (3.41%)  6 12/180 (6.67%)  13 9/181 (4.97%)  13 0/27 (0.00%)  0
Wound infection  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Injury, poisoning and procedural complications         
Ankle fracture  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Bruising  1  24/176 (13.64%)  43 117/180 (65.00%)  724 114/181 (62.98%)  738 14/27 (51.85%)  68
Fall  1  1/176 (0.57%)  1 7/180 (3.89%)  8 4/181 (2.21%)  6 0/27 (0.00%)  0
Fracture  1  0/176 (0.00%)  0 3/180 (1.67%)  3 1/181 (0.55%)  1 1/27 (3.70%)  1
Hip fracture  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Injury, poisoning and procedural complications - Other, specify  1  0/176 (0.00%)  0 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
Postoperative hemorrhage  1  0/176 (0.00%)  0 1/180 (0.56%)  2 0/181 (0.00%)  0 0/27 (0.00%)  0
Wound complication  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Investigations         
Alanine aminotransferase increased  1  5/176 (2.84%)  11 14/180 (7.78%)  30 6/181 (3.31%)  13 0/27 (0.00%)  0
Alkaline phosphatase increased  1  6/176 (3.41%)  16 10/180 (5.56%)  27 9/181 (4.97%)  20 0/27 (0.00%)  0
Aspartate aminotransferase increased  1  9/176 (5.11%)  21 16/180 (8.89%)  28 7/181 (3.87%)  12 0/27 (0.00%)  0
Blood bilirubin increased  1  9/176 (5.11%)  27 21/180 (11.67%)  54 28/181 (15.47%)  119 1/27 (3.70%)  4
CD4 lymphocytes decreased  1  2/176 (1.14%)  8 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Cardiac troponin I increased  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Creatinine increased  1  14/176 (7.95%)  24 18/180 (10.00%)  74 23/181 (12.71%)  82 1/27 (3.70%)  1
Ejection fraction decreased  1  0/176 (0.00%)  0 2/180 (1.11%)  2 1/181 (0.55%)  2 0/27 (0.00%)  0
GGT increased  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Hemoglobin increased  1  0/176 (0.00%)  0 3/180 (1.67%)  4 1/181 (0.55%)  1 0/27 (0.00%)  0
INR increased  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Investigations - Other, specify  1  6/176 (3.41%)  7 8/180 (4.44%)  13 8/181 (4.42%)  13 2/27 (7.41%)  4
Lymphocyte count decreased  1  48/176 (27.27%)  232 12/180 (6.67%)  30 24/181 (13.26%)  62 7/27 (25.93%)  14
Lymphocyte count increased  1  17/176 (9.66%)  22 42/180 (23.33%)  192 30/181 (16.57%)  80 10/27 (37.04%)  22
Neutrophil count decreased  1  128/176 (72.73%)  356 61/180 (33.89%)  143 68/181 (37.57%)  178 14/27 (51.85%)  41
Platelet count decreased  1  138/176 (78.41%)  490 129/180 (71.67%)  995 131/181 (72.38%)  956 19/27 (70.37%)  104
Urine output decreased  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Weight gain  1  1/176 (0.57%)  2 4/180 (2.22%)  7 7/181 (3.87%)  23 0/27 (0.00%)  0
Weight loss  1  13/176 (7.39%)  26 10/180 (5.56%)  25 14/181 (7.73%)  30 0/27 (0.00%)  0
White blood cell decreased  1  54/176 (30.68%)  175 8/180 (4.44%)  12 17/181 (9.39%)  37 2/27 (7.41%)  2
Metabolism and nutrition disorders         
Alkalosis  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Anorexia  1  25/176 (14.20%)  35 20/180 (11.11%)  49 23/181 (12.71%)  40 0/27 (0.00%)  0
Dehydration  1  4/176 (2.27%)  4 1/180 (0.56%)  1 3/181 (1.66%)  6 0/27 (0.00%)  0
Glucose intolerance  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Hypercalcemia  1  4/176 (2.27%)  5 6/180 (3.33%)  9 0/181 (0.00%)  0 0/27 (0.00%)  0
Hyperglycemia  1  13/176 (7.39%)  31 16/180 (8.89%)  37 10/181 (5.52%)  38 1/27 (3.70%)  4
Hyperkalemia  1  6/176 (3.41%)  9 12/180 (6.67%)  25 7/181 (3.87%)  13 1/27 (3.70%)  2
Hypernatremia  1  3/176 (1.70%)  3 0/180 (0.00%)  0 4/181 (2.21%)  6 0/27 (0.00%)  0
Hyperuricemia  1  1/176 (0.57%)  1 8/180 (4.44%)  23 4/181 (2.21%)  6 0/27 (0.00%)  0
Hypoalbuminemia  1  9/176 (5.11%)  9 11/180 (6.11%)  19 10/181 (5.52%)  24 1/27 (3.70%)  1
Hypocalcemia  1  13/176 (7.39%)  17 9/180 (5.00%)  17 7/181 (3.87%)  8 0/27 (0.00%)  0
Hypoglycemia  1  0/176 (0.00%)  0 1/180 (0.56%)  4 1/181 (0.55%)  2 0/27 (0.00%)  0
Hypokalemia  1  5/176 (2.84%)  6 6/180 (3.33%)  14 8/181 (4.42%)  13 2/27 (7.41%)  5
Hypomagnesemia  1  0/176 (0.00%)  0 3/180 (1.67%)  4 5/181 (2.76%)  11 0/27 (0.00%)  0
Hyponatremia  1  9/176 (5.11%)  10 7/180 (3.89%)  11 12/181 (6.63%)  34 2/27 (7.41%)  2
Hypophosphatemia  1  2/176 (1.14%)  2 2/180 (1.11%)  8 3/181 (1.66%)  4 1/27 (3.70%)  2
Metabolism and nutrition disorders - Other, specify  1  6/176 (3.41%)  10 1/180 (0.56%)  1 1/181 (0.55%)  1 0/27 (0.00%)  0
Tumor lysis syndrome  1  3/176 (1.70%)  4 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Musculoskeletal and connective tissue disorders         
Arthralgia  1  5/176 (2.84%)  7 22/180 (12.22%)  84 26/181 (14.36%)  79 2/27 (7.41%)  4
Arthritis  1  0/176 (0.00%)  0 5/180 (2.78%)  8 2/181 (1.10%)  6 0/27 (0.00%)  0
Back pain  1  5/176 (2.84%)  10 9/180 (5.00%)  16 10/181 (5.52%)  15 0/27 (0.00%)  0
Bone pain  1  5/176 (2.84%)  5 2/180 (1.11%)  3 1/181 (0.55%)  2 1/27 (3.70%)  1
Chest wall pain  1  0/176 (0.00%)  0 1/180 (0.56%)  1 2/181 (1.10%)  2 0/27 (0.00%)  0
Flank pain  1  0/176 (0.00%)  0 0/180 (0.00%)  0 2/181 (1.10%)  5 0/27 (0.00%)  0
Generalized muscle weakness  1  6/176 (3.41%)  7 4/180 (2.22%)  5 9/181 (4.97%)  22 1/27 (3.70%)  1
Joint effusion  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Joint range of motion decreased  1  0/176 (0.00%)  0 0/180 (0.00%)  0 0/181 (0.00%)  0 1/27 (3.70%)  1
Muscle weakness lower limb  1  1/176 (0.57%)  1 3/180 (1.67%)  5 2/181 (1.10%)  2 0/27 (0.00%)  0
Muscle weakness right-sided  1  0/176 (0.00%)  0 1/180 (0.56%)  1 1/181 (0.55%)  4 0/27 (0.00%)  0
Muscle weakness trunk  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Muscle weakness upper limb  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Musculoskeletal and connective tissue disorder - Other, specify  1  3/176 (1.70%)  13 14/180 (7.78%)  51 14/181 (7.73%)  44 0/27 (0.00%)  0
Musculoskeletal deformity  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Myalgia  1  9/176 (5.11%)  18 13/180 (7.22%)  49 25/181 (13.81%)  64 4/27 (14.81%)  7
Neck pain  1  0/176 (0.00%)  0 4/180 (2.22%)  5 3/181 (1.66%)  7 0/27 (0.00%)  0
Pain in extremity  1  6/176 (3.41%)  9 22/180 (12.22%)  37 16/181 (8.84%)  24 1/27 (3.70%)  3
Soft tissue necrosis lower limb  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify  1  4/176 (2.27%)  7 5/180 (2.78%)  9 5/181 (2.76%)  11 1/27 (3.70%)  1
Nervous system disorders         
Ataxia  1  0/176 (0.00%)  0 0/180 (0.00%)  0 2/181 (1.10%)  2 0/27 (0.00%)  0
Cognitive disturbance  1  1/176 (0.57%)  1 0/180 (0.00%)  0 1/181 (0.55%)  4 0/27 (0.00%)  0
Concentration impairment  1  0/176 (0.00%)  0 2/180 (1.11%)  6 1/181 (0.55%)  1 0/27 (0.00%)  0
Dizziness  1  47/176 (26.70%)  86 70/180 (38.89%)  236 72/181 (39.78%)  248 10/27 (37.04%)  29
Dysesthesia  1  1/176 (0.57%)  2 0/180 (0.00%)  0 1/181 (0.55%)  7 0/27 (0.00%)  0
Dysgeusia  1  16/176 (9.09%)  30 7/180 (3.89%)  22 6/181 (3.31%)  10 0/27 (0.00%)  0
Encephalopathy  1  0/176 (0.00%)  0 0/180 (0.00%)  0 2/181 (1.10%)  2 0/27 (0.00%)  0
Headache  1  7/176 (3.98%)  22 16/180 (8.89%)  39 16/181 (8.84%)  27 1/27 (3.70%)  1
Hydrocephalus  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Intracranial hemorrhage  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Lethargy  1  1/176 (0.57%)  1 1/180 (0.56%)  3 0/181 (0.00%)  0 0/27 (0.00%)  0
Memory impairment  1  2/176 (1.14%)  2 4/180 (2.22%)  7 3/181 (1.66%)  12 1/27 (3.70%)  3
Movements involuntary  1  0/176 (0.00%)  0 1/180 (0.56%)  3 0/181 (0.00%)  0 0/27 (0.00%)  0
Nervous system disorders - Other, specify  1  1/176 (0.57%)  1 2/180 (1.11%)  6 4/181 (2.21%)  6 0/27 (0.00%)  0
Neuralgia  1  1/176 (0.57%)  1 0/180 (0.00%)  0 2/181 (1.10%)  2 0/27 (0.00%)  0
Nystagmus  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Paresthesia  1  0/176 (0.00%)  0 1/180 (0.56%)  1 2/181 (1.10%)  3 0/27 (0.00%)  0
Peripheral motor neuropathy  1  0/176 (0.00%)  0 2/180 (1.11%)  2 1/181 (0.55%)  3 0/27 (0.00%)  0
Peripheral sensory neuropathy  1  5/176 (2.84%)  5 9/180 (5.00%)  24 12/181 (6.63%)  31 1/27 (3.70%)  1
Presyncope  1  1/176 (0.57%)  1 2/180 (1.11%)  3 0/181 (0.00%)  0 0/27 (0.00%)  0
Radiculitis  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Seizure  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Sinus pain  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Somnolence  1  1/176 (0.57%)  1 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Spasticity  1  0/176 (0.00%)  0 2/180 (1.11%)  2 2/181 (1.10%)  13 0/27 (0.00%)  0
Stroke  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Syncope  1  3/176 (1.70%)  3 3/180 (1.67%)  4 3/181 (1.66%)  5 0/27 (0.00%)  0
Transient ischemic attacks  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Tremor  1  2/176 (1.14%)  2 0/180 (0.00%)  0 2/181 (1.10%)  2 0/27 (0.00%)  0
Psychiatric disorders         
Agitation  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Anxiety  1  7/176 (3.98%)  14 3/180 (1.67%)  6 5/181 (2.76%)  9 0/27 (0.00%)  0
Confusion  1  4/176 (2.27%)  4 5/180 (2.78%)  5 2/181 (1.10%)  2 0/27 (0.00%)  0
Depression  1  2/176 (1.14%)  8 5/180 (2.78%)  17 2/181 (1.10%)  5 0/27 (0.00%)  0
Insomnia  1  3/176 (1.70%)  4 15/180 (8.33%)  35 8/181 (4.42%)  13 0/27 (0.00%)  0
Libido decreased  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Psychiatric disorders - Other, specify  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Restlessness  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Renal and urinary disorders         
Acute kidney injury  1  1/176 (0.57%)  1 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Bladder spasm  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Chronic kidney disease  1  3/176 (1.70%)  8 2/180 (1.11%)  5 6/181 (3.31%)  21 2/27 (7.41%)  2
Hematuria  1  1/176 (0.57%)  1 10/180 (5.56%)  22 10/181 (5.52%)  18 1/27 (3.70%)  1
Proteinuria  1  3/176 (1.70%)  3 2/180 (1.11%)  3 1/181 (0.55%)  1 0/27 (0.00%)  0
Renal and urinary disorders - Other, specify  1  1/176 (0.57%)  1 3/180 (1.67%)  5 4/181 (2.21%)  16 0/27 (0.00%)  0
Renal calculi  1  0/176 (0.00%)  0 2/180 (1.11%)  5 0/181 (0.00%)  0 0/27 (0.00%)  0
Urinary frequency  1  4/176 (2.27%)  5 1/180 (0.56%)  3 3/181 (1.66%)  3 0/27 (0.00%)  0
Urinary incontinence  1  0/176 (0.00%)  0 1/180 (0.56%)  2 0/181 (0.00%)  0 0/27 (0.00%)  0
Urinary retention  1  2/176 (1.14%)  2 1/180 (0.56%)  1 2/181 (1.10%)  4 0/27 (0.00%)  0
Urinary tract pain  1  2/176 (1.14%)  4 1/180 (0.56%)  1 2/181 (1.10%)  3 0/27 (0.00%)  0
Urinary urgency  1  1/176 (0.57%)  3 1/180 (0.56%)  4 1/181 (0.55%)  2 0/27 (0.00%)  0
Reproductive system and breast disorders         
Erectile dysfunction  1  0/176 (0.00%)  0 1/180 (0.56%)  2 0/181 (0.00%)  0 0/27 (0.00%)  0
Gynecomastia  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0 0/27 (0.00%)  0
Prostatic obstruction  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Reproductive system and breast disorders - Other, specify  1  1/176 (0.57%)  4 1/180 (0.56%)  8 0/181 (0.00%)  0 0/27 (0.00%)  0
Testicular pain  1  0/176 (0.00%)  0 0/180 (0.00%)  0 1/181 (0.55%)  1 0/27 (0.00%)  0
Respiratory, thoracic and mediastinal disorders         
Allergic rhinitis  1  1/176 (0.57%)  2 3/180 (1.67%)  9 2/181 (1.10%)  2 0/27 (0.00%)  0
Apnea  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Aspiration  1  0/176 (0.00%)  0 3/180 (1.67%)  3 1/181 (0.55%)  1 0/27 (0.00%)  0
Atelectasis  1  2/176 (1.14%)  2 1/180 (0.56%)  2 0/181 (0.00%)  0 0/27 (0.00%)  0
Bronchial obstruction  1  1/176 (0.57%)  1 0/180 (0.00%)  0 0/181 (0.00%)  0 0/27 (0.00%)  0
Bronchopulmonary hemorrhage  1  0/176 (0.00%)  0 1/180 (0.56%)  1 0/181 (0.00%)  0