Trial Outcomes & Findings for A Study of PCI-32765 (Ibrutinib) Versus Rituximab in Relapsed or Refractory Chronic Leukemia/Lymphoma (NCT NCT01973387)

NCT ID: NCT01973387

Last Updated: 2018-07-24

Results Overview

Progression-free survival was defined as the interval between the date of randomization and the date of disease progression or death, whichever was first reported. International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for progressive disease (PD): New enlarged nodes greater than (\>)1.5 centimeter (cm), new hepatomegaly or splenomegaly, or other organ infiltrates; greater than or equal to (\>=)50 percent (%) increase from nadir in existing lymph node or \>=50% increase from nadir in sum of product of diameters of multiple nodes; \>=50% increase from nadir in enlargement of liver or spleen; \>=50% increase from baseline in lymphocyte count (and to \>=5\*10\^9/L) unless considered treatment-related lymphocytosis; New cytopenia (Hemoglobin b \[Hgb\] or platelets) attributable to chronic lymphocytic leukemia (CLL) and transformation to a more aggressive histology.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

160 participants

Primary outcome timeframe

From the date of randomization to the date of disease progression or death, whichever was first reported (Up to 3.7 years)

Results posted on

2018-07-24

Participant Flow

A Randomized, Multicenter, Open-Label, Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor PCI-32765 (Ibrutinib) versus Rituximab in Subjects with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Participant milestones

Participant milestones
Measure	Ibrutinib Receive 420 mg ibrutinib (3 x 140-mg capsules) by mouth once daily continuous (without interruption) self-administered home treatment until disease progression or unacceptable toxicity, whichever occurs first.	Rituximab Receive rituximab IV infusion 375 mg/m2 on Day 1 of Cycle 1 and 500 mg/m2 on Day 15 of Cycle 1 (Weeks 1-4); 500 mg/m2 on Day 1 and Day 15 of Cycle 2 (Weeks 5-8); 500 mg/m2 on Day 1 of Cycles 3-6 (Weeks 9-24).
Overall Study STARTED	106	54
Overall Study Treated	104	52
Overall Study COMPLETED	0	36
Overall Study NOT COMPLETED	106	18

Reasons for withdrawal

Reasons for withdrawal
Measure	Ibrutinib Receive 420 mg ibrutinib (3 x 140-mg capsules) by mouth once daily continuous (without interruption) self-administered home treatment until disease progression or unacceptable toxicity, whichever occurs first.	Rituximab Receive rituximab IV infusion 375 mg/m2 on Day 1 of Cycle 1 and 500 mg/m2 on Day 15 of Cycle 1 (Weeks 1-4); 500 mg/m2 on Day 1 and Day 15 of Cycle 2 (Weeks 5-8); 500 mg/m2 on Day 1 of Cycles 3-6 (Weeks 9-24).
Overall Study Adverse Event	14	4
Overall Study Withdrawal by Subject	7	4
Overall Study Study terminated by sponsor	63	0
Overall Study Progressive disease or relapse	16	5
Overall Study Death	4	3
Overall Study Randomized, not treated	2	2

Baseline Characteristics

A Study of PCI-32765 (Ibrutinib) Versus Rituximab in Relapsed or Refractory Chronic Leukemia/Lymphoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ibrutinib n=106 Participants Receive 420 mg ibrutinib (3 x 140-mg capsules) by mouth once daily continuous (without interruption) self-administered home treatment until disease progression or unacceptable toxicity, whichever occurs first.	Rituximab n=54 Participants Receive rituximab IV infusion 375 mg/m2 on Day 1 of Cycle 1 and 500 mg/m2 on Day 15 of Cycle 1 (Weeks 1-4); 500 mg/m2 on Day 1 and Day 15 of Cycle 2 (Weeks 5-8); 500 mg/m2 on Day 1 of Cycles 3-6 (Weeks 9-24).	Total n=160 Participants Total of all reporting groups
Age, Continuous	63.6 years STANDARD_DEVIATION 10.36 • n=5 Participants	63.6 years STANDARD_DEVIATION 13.04 • n=7 Participants	63.6 years STANDARD_DEVIATION 11.3 • n=5 Participants
Sex: Female, Male Female	29 Participants n=5 Participants	18 Participants n=7 Participants	47 Participants n=5 Participants
Sex: Female, Male Male	77 Participants n=5 Participants	36 Participants n=7 Participants	113 Participants n=5 Participants
Region of Enrollment Australia	15 Participants n=5 Participants	9 Participants n=7 Participants	24 Participants n=5 Participants
Region of Enrollment China	87 Participants n=5 Participants	44 Participants n=7 Participants	131 Participants n=5 Participants
Region of Enrollment Malaysia	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment Taiwan, Province Of China	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants

PRIMARY outcome

Timeframe: From the date of randomization to the date of disease progression or death, whichever was first reported (Up to 3.7 years)

Population: Intent-to-Treat (ITT) analysis set is defined as all participants randomized into the study and analyzed according to assigned treatment group, regardless of the actual treatment received.

Outcome measures

Outcome measures
Measure	Ibrutinib n=106 Participants Treatment Arm A received 420 milligram (mg) ibrutinib (3\*140-mg capsules) by mouth once daily continuous (without interruption) self-administered home treatment until disease progression or unacceptable toxicity, whichever occurs first.	Rituximab n=54 Participants Treatment Arm B received rituximab intravenous (IV) infusion 375 milligrams per meter square (mg/m\^2) on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 15 of Cycle 1 (Weeks 1-4); 500 mg/m\^2 on Day 1 and Day 15 of Cycle 2 (Weeks 5-8); 500 mg/m\^2 on Day 1 of Cycles 3-6 (Weeks 9-24).
Progression-free Survival (PFS)	NA months Median, lower limit and upper limit of 95% CI was not estimable due to lesser number of events.	8.38 months Interval 8.31 to 9.03

SECONDARY outcome

Timeframe: From the date of randomization to disease progression (Up to 3.7 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- \>=50% drop in lymphocyte count from baseline or \<=4.0\*10\^9/L with following: \>=50% decrease in sum products of up to 6 lymph nodes, no new enlarged lymph nodes, When abnormal, \>=50% decrease in enlargement of spleen from baseline or normalization and a response in 1 of following: Neutrophils \>1.5\*10\^9/L, Platelets\>100000/mcL and Hgb\>11 g/dL or \>=50% improvement over baseline in all.

Outcome measures

Outcome measures
Measure	Ibrutinib n=106 Participants Treatment Arm A received 420 milligram (mg) ibrutinib (3\*140-mg capsules) by mouth once daily continuous (without interruption) self-administered home treatment until disease progression or unacceptable toxicity, whichever occurs first.	Rituximab n=54 Participants Treatment Arm B received rituximab intravenous (IV) infusion 375 milligrams per meter square (mg/m\^2) on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 15 of Cycle 1 (Weeks 1-4); 500 mg/m\^2 on Day 1 and Day 15 of Cycle 2 (Weeks 5-8); 500 mg/m\^2 on Day 1 of Cycles 3-6 (Weeks 9-24).
Overall Response Rate (ORR)	66 participants	4 participants

SECONDARY outcome

Timeframe: From the date of randomization to the date of death (Up to 3.7 years)

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

Outcome measures

Outcome measures
Measure	Ibrutinib n=106 Participants Treatment Arm A received 420 milligram (mg) ibrutinib (3\*140-mg capsules) by mouth once daily continuous (without interruption) self-administered home treatment until disease progression or unacceptable toxicity, whichever occurs first.	Rituximab n=54 Participants Treatment Arm B received rituximab intravenous (IV) infusion 375 milligrams per meter square (mg/m\^2) on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 15 of Cycle 1 (Weeks 1-4); 500 mg/m\^2 on Day 1 and Day 15 of Cycle 2 (Weeks 5-8); 500 mg/m\^2 on Day 1 of Cycles 3-6 (Weeks 9-24).
Overall Survival (OS)	NA months Median, upper limit and lower limit of 95% CI was not estimable due to lesser number of events.	NA months Interval 19.52 to Median and upper limit of 95% CI was not estimable due to lesser number of events.

SECONDARY outcome

Timeframe: From the date of randomization to disease progression (Up to 3.7 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.

Outcome measures

Outcome measures
Measure	Ibrutinib n=106 Participants Treatment Arm A received 420 milligram (mg) ibrutinib (3\*140-mg capsules) by mouth once daily continuous (without interruption) self-administered home treatment until disease progression or unacceptable toxicity, whichever occurs first.	Rituximab n=54 Participants Treatment Arm B received rituximab intravenous (IV) infusion 375 milligrams per meter square (mg/m\^2) on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 15 of Cycle 1 (Weeks 1-4); 500 mg/m\^2 on Day 1 and Day 15 of Cycle 2 (Weeks 5-8); 500 mg/m\^2 on Day 1 of Cycles 3-6 (Weeks 9-24).
Number of Participants With Sustained Hematologic Improvement Hemoglobin	43 participants	14 participants
Number of Participants With Sustained Hematologic Improvement Platelets	48 participants	12 participants

SECONDARY outcome

Timeframe: From the date of randomization to disease progression (Up to 3.7 years)

The most common disease-related symptoms associated with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (fatigue, weight loss, fevers, night sweats, and abdominal discomfort/splenomegaly) were reported by grade.

Outcome measures

Outcome measures
Measure	Ibrutinib n=106 Participants Treatment Arm A received 420 milligram (mg) ibrutinib (3\*140-mg capsules) by mouth once daily continuous (without interruption) self-administered home treatment until disease progression or unacceptable toxicity, whichever occurs first.	Rituximab n=54 Participants Treatment Arm B received rituximab intravenous (IV) infusion 375 milligrams per meter square (mg/m\^2) on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 15 of Cycle 1 (Weeks 1-4); 500 mg/m\^2 on Day 1 and Day 15 of Cycle 2 (Weeks 5-8); 500 mg/m\^2 on Day 1 of Cycles 3-6 (Weeks 9-24).
Number of Participants With Clinically Relevant Shifts in Disease-Related Symptoms	0 participants	0 participants

Adverse Events

Ibrutinib

Serious events: 56 serious events

Other events: 103 other events

Deaths: 21 deaths

Rituximab

Serious events: 17 serious events

Other events: 46 other events

Deaths: 20 deaths

Serious adverse events

Other adverse events

Additional Information

Vice President (VP)

Janssen Research & Development, LLC

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Ibrutinib n=104 participants at risk Receive 420 mg ibrutinib (3 x 140-mg capsules) by mouth once daily continuous (without interruption) self-administered home treatment until disease progression or unacceptable toxicity, whichever occurs first.	Rituximab n=52 participants at risk Receive rituximab IV infusion 375 mg/m2 on Day 1 of Cycle 1 and 500 mg/m2 on Day 15 of Cycle 1 (Weeks 1-4); 500 mg/m2 on Day 1 and Day 15 of Cycle 2 (Weeks 5-8); 500 mg/m2 on Day 1 of Cycles 3-6 (Weeks 9-24).
Injury, poisoning and procedural complications Lumbar Vertebral Fracture	1.9% 2/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Post Procedural Haemorrhage	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Infection	0.00% 0/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	3.8% 2/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Infective Exacerbation of Bronchiectasis	0.00% 0/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	1.9% 1/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Laceration	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Influenza	0.00% 0/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	1.9% 1/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Lung Abscess	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Lung Infection	11.5% 12/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	11.5% 6/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Pneumonia	4.8% 5/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	1.9% 1/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Pneumonia Viral	0.00% 0/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	1.9% 1/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Postoperative Wound Infection	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Pyelonephritis Chronic	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Salmonella Sepsis	0.00% 0/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	1.9% 1/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Sepsis	1.9% 2/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Septic Shock	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Serratia Bacteraemia	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Skin Infection	1.9% 2/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Staphylococcal Sepsis	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Tonsillitis	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Upper Respiratory Tract Infection	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Urinary Tract Infection	2.9% 3/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Femoral Neck Fracture	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Blood and lymphatic system disorders Agranulocytosis	1.9% 2/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Blood and lymphatic system disorders Anaemia	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Blood and lymphatic system disorders Bone Marrow Failure	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Blood and lymphatic system disorders Febrile Neutropenia	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	1.9% 1/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Blood and lymphatic system disorders Haemolytic Anaemia	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Blood and lymphatic system disorders Haemorrhagic Diathesis	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Blood and lymphatic system disorders Lymphadenitis	2.9% 3/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Blood and lymphatic system disorders Lymphadenopathy	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Blood and lymphatic system disorders Splenic Infarction	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Blood and lymphatic system disorders Thrombocytopenia	1.9% 2/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Cardiac disorders Acute Myocardial Infarction	0.00% 0/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	1.9% 1/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Cardiac disorders Atrial Fibrillation	2.9% 3/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Cardiac disorders Cardiac Arrest	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Cardiac disorders Cardiac Failure	2.9% 3/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	1.9% 1/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Cardiac disorders Cardiac Tamponade	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Cardiac disorders Coronary Artery Disease	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Cardiac disorders Myocardial Infarction	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Eye disorders Cataract	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.

Other adverse events
Measure	Ibrutinib n=104 participants at risk Receive 420 mg ibrutinib (3 x 140-mg capsules) by mouth once daily continuous (without interruption) self-administered home treatment until disease progression or unacceptable toxicity, whichever occurs first.	Rituximab n=52 participants at risk Receive rituximab IV infusion 375 mg/m2 on Day 1 of Cycle 1 and 500 mg/m2 on Day 15 of Cycle 1 (Weeks 1-4); 500 mg/m2 on Day 1 and Day 15 of Cycle 2 (Weeks 5-8); 500 mg/m2 on Day 1 of Cycles 3-6 (Weeks 9-24).
Blood and lymphatic system disorders Anaemia	19.2% 20/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	9.6% 5/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Blood and lymphatic system disorders Leukocytosis	12.5% 13/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Blood and lymphatic system disorders Monocytopenia	0.00% 0/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	5.8% 3/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Blood and lymphatic system disorders Neutropenia	25.0% 26/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	21.2% 11/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Blood and lymphatic system disorders Thrombocytopenia	17.3% 18/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	5.8% 3/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Ear and labyrinth disorders Vertigo	12.5% 13/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Abdominal Pain	5.8% 6/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Abdominal Pain Upper	6.7% 7/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	1.9% 1/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Constipation	17.3% 18/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Diarrhoea	39.4% 41/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	7.7% 4/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Mouth Ulceration	14.4% 15/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	5.8% 3/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Nausea	17.3% 18/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	1.9% 1/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Vomiting	7.7% 8/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	5.8% 3/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
General disorders Chills	0.96% 1/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	17.3% 9/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
General disorders Fatigue	28.8% 30/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	11.5% 6/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
General disorders Oedema Peripheral	9.6% 10/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	3.8% 2/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
General disorders Pyrexia	26.0% 27/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	26.9% 14/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Lung Infection	16.3% 17/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	5.8% 3/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Nasopharyngitis	18.3% 19/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Upper Respiratory Tract Infection	27.9% 29/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	13.5% 7/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Contusion	5.8% 6/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Infusion Related Reaction	0.00% 0/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	5.8% 3/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Investigations Alanine Aminotransferase Increased	6.7% 7/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	5.8% 3/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Investigations Aspartate Aminotransferase Increased	5.8% 6/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	5.8% 3/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Investigations Blood Creatinine Increased	5.8% 6/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Investigations Blood Lactate Dehydrogenase Increased	9.6% 10/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	1.9% 1/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Investigations Haemoglobin Decreased	14.4% 15/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	11.5% 6/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Investigations Lymphocyte Count Increased	14.4% 15/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Investigations Neutrophil Count Decreased	34.6% 36/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	38.5% 20/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Investigations Platelet Count Decreased	31.7% 33/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	26.9% 14/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Investigations Weight Decreased	7.7% 8/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	5.8% 3/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Investigations White Blood Cell Count Decreased	8.7% 9/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	17.3% 9/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Metabolism and nutrition disorders Decreased Appetite	10.6% 11/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	3.8% 2/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Metabolism and nutrition disorders Hyperglycaemia	10.6% 11/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	3.8% 2/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Metabolism and nutrition disorders Hyperuricaemia	7.7% 8/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	3.8% 2/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Metabolism and nutrition disorders Hypokalaemia	6.7% 7/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	11.5% 6/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Arthralgia	9.6% 10/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	1.9% 1/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Back Pain	8.7% 9/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Muscle Spasms	8.7% 9/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Pain in Extremity	6.7% 7/104 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.	0.00% 0/52 • Screening up to follow up phase (approximately 3.7 years) Safety analysis set included all randomized participants who received at least 1 dose of study drug.