Trial Outcomes & Findings for A Phase 3 Study of Ibrutinib (PCI-32765) Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (NCT NCT01578707)

Last Updated: 2019-12-18

Results Overview

The primary objective of this study was to evaluate the efficacy of ibrutinib compared to ofatumumab based on independent review committee (IRC) assessment of progression-free survival (PFS) according to 2008 IWCLL guidelines.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

391 participants

Primary outcome timeframe

Analysis was conducted after observing approximately 117 PFS events, which occurred about 18 months after the first subject was enrolled.

Results posted on

2019-12-18

Participant Flow

Participant milestones

Participant milestones
Measure	Ofatumumab (Arm A) An anti-CD20 monoclonal antibody ofatumumab: The ofatumumab (IV) dosage and schedule is 12 doses administered over 24 weeks or until disease progression, unacceptable toxicity. Week 1: 300 mg initial dose Week 2 through 8: 2,000 mg (once weekly) Week 12, 16, 20 and 24: 2,000 mg (every 4 weeks)	Ibrutinib (Arm B) A Bruton Tyrosine Kinase Inhibitor ibrutinib: ibrutinib 420 mg (3 x 140-mg capsules) will be administered orally once daily until disease progression or unacceptable toxicity
Overall Study STARTED	196	195
Overall Study COMPLETED	196	195
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Phase 3 Study of Ibrutinib (PCI-32765) Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ofatumumab (Arm A) n=196 Participants An anti-CD20 monoclonal antibody ofatumumab: The ofatumumab (IV) dosage and schedule is 12 doses administered over 24 weeks or until disease progression, unacceptable toxicity. Week 1: 300 mg initial dose Week 2 through 8: 2,000 mg (once weekly) Week 12, 16, 20 and 24: 2,000 mg (every 4 weeks)	Ibrutinib (Arm B) n=195 Participants A Bruton Tyrosine Kinase Inhibitor ibrutinib: ibrutinib 420 mg (3 x 140-mg capsules) will be administered orally once daily until disease progression or unacceptable toxicity	Total n=391 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	75 Participants n=5 Participants	77 Participants n=7 Participants	152 Participants n=5 Participants
Age, Categorical >=65 years	121 Participants n=5 Participants	118 Participants n=7 Participants	239 Participants n=5 Participants
Age, Continuous	66.8 years STANDARD_DEVIATION 8.88 • n=5 Participants	66.1 years STANDARD_DEVIATION 10.15 • n=7 Participants	66.5 years STANDARD_DEVIATION 9.53 • n=5 Participants
Sex: Female, Male Female	59 Participants n=5 Participants	66 Participants n=7 Participants	125 Participants n=5 Participants
Sex: Female, Male Male	137 Participants n=5 Participants	129 Participants n=7 Participants	266 Participants n=5 Participants

PRIMARY outcome

Timeframe: Analysis was conducted after observing approximately 117 PFS events, which occurred about 18 months after the first subject was enrolled.

Outcome measures

Outcome measures
Measure	Ofatumumab (Arm A) n=196 Participants An anti-CD20 monoclonal antibody ofatumumab: The ofatumumab (IV) dosage and schedule is 12 doses administered over 24 weeks or until disease progression, unacceptable toxicity. Week 1: 300 mg initial dose Week 2 through 8: 2,000 mg (once weekly) Week 12, 16, 20 and 24: 2,000 mg (every 4 weeks)	Ibrutinib (Arm B) n=195 Participants A Bruton Tyrosine Kinase Inhibitor ibrutinib: ibrutinib 420 mg (3 x 140-mg capsules) will be administered orally once daily until disease progression or unacceptable toxicity
PFS (Progression Free Survival) by Independent Review Committee (IRC), Limited to the Time of Primary Analysis 06 November 2013	8.1 months Interval 7.2 to 8.3	NA months IBR: Median PFS was not reached so 95% CI for median PFS is not applicable.

SECONDARY outcome

Timeframe: About 18 months after the first subject was enrolled

Overall Response Rate per the IWCLL 2008 criteria as assessed by IRC, limited to the time of primary analysis 06 November 2013

Outcome measures

Outcome measures
Measure	Ofatumumab (Arm A) n=196 Participants An anti-CD20 monoclonal antibody ofatumumab: The ofatumumab (IV) dosage and schedule is 12 doses administered over 24 weeks or until disease progression, unacceptable toxicity. Week 1: 300 mg initial dose Week 2 through 8: 2,000 mg (once weekly) Week 12, 16, 20 and 24: 2,000 mg (every 4 weeks)	Ibrutinib (Arm B) n=195 Participants A Bruton Tyrosine Kinase Inhibitor ibrutinib: ibrutinib 420 mg (3 x 140-mg capsules) will be administered orally once daily until disease progression or unacceptable toxicity
Overall Response Rate (ORR) by Independent Review Committee (IRC)	4.1 percentage of participants	42.6 percentage of participants

SECONDARY outcome

Timeframe: OS analysis was conducted at the time of study closure, including up to 6 years of study follow-up

OS analysis was conducted at the time of study closure, with no adjustment for crossover from the ofatumumab arm to the ibrutinib arm

Outcome measures

Outcome measures
Measure	Ofatumumab (Arm A) n=196 Participants An anti-CD20 monoclonal antibody ofatumumab: The ofatumumab (IV) dosage and schedule is 12 doses administered over 24 weeks or until disease progression, unacceptable toxicity. Week 1: 300 mg initial dose Week 2 through 8: 2,000 mg (once weekly) Week 12, 16, 20 and 24: 2,000 mg (every 4 weeks)	Ibrutinib (Arm B) n=195 Participants A Bruton Tyrosine Kinase Inhibitor ibrutinib: ibrutinib 420 mg (3 x 140-mg capsules) will be administered orally once daily until disease progression or unacceptable toxicity
OS (Overall Survival)	65.1 months Interval 50.6 to OFA: Upper limit of 95% CI for median OS is not estimable due to sparse events in the data / insufficient number of participants with events.	67.7 months Interval 61.0 to IBR: Upper limit of 95% CI for median OS is not estimable due to sparse events in the data / insufficient number of participants with events.

SECONDARY outcome

Timeframe: From study initiation to study closure, including up to 6 years of study follow-up

Proportion of subjects with hemoglobin (HgB) increase \>=20 g/L and platelet (PLT) increase \>=50% over baseline continuously for \>=56 days without blood transfusions or growth factors.

Outcome measures

Outcome measures
Measure	Ofatumumab (Arm A) n=196 Participants An anti-CD20 monoclonal antibody ofatumumab: The ofatumumab (IV) dosage and schedule is 12 doses administered over 24 weeks or until disease progression, unacceptable toxicity. Week 1: 300 mg initial dose Week 2 through 8: 2,000 mg (once weekly) Week 12, 16, 20 and 24: 2,000 mg (every 4 weeks)	Ibrutinib (Arm B) n=195 Participants A Bruton Tyrosine Kinase Inhibitor ibrutinib: ibrutinib 420 mg (3 x 140-mg capsules) will be administered orally once daily until disease progression or unacceptable toxicity
Rate of Sustained Hemoglobin and Platelet Improvement Hgb Improvement in patient with baseline anemia	32.6 percentage of participants	69.7 percentage of participants
Rate of Sustained Hemoglobin and Platelet Improvement Platelet improvement in baseline thrombocytopenia	9.4 percentage of participants	78.4 percentage of participants

OTHER_PRE_SPECIFIED outcome

Timeframe: From study initiation to study closure, including up to 6 years of study follow-up

Long-Term Progression Free Survival as assessed by the investigator with up to 6 years of study follow-up

Outcome measures

Outcome measures
Measure	Ofatumumab (Arm A) n=196 Participants An anti-CD20 monoclonal antibody ofatumumab: The ofatumumab (IV) dosage and schedule is 12 doses administered over 24 weeks or until disease progression, unacceptable toxicity. Week 1: 300 mg initial dose Week 2 through 8: 2,000 mg (once weekly) Week 12, 16, 20 and 24: 2,000 mg (every 4 weeks)	Ibrutinib (Arm B) n=195 Participants A Bruton Tyrosine Kinase Inhibitor ibrutinib: ibrutinib 420 mg (3 x 140-mg capsules) will be administered orally once daily until disease progression or unacceptable toxicity
Progression Free Survival (PFS) by Investigator With up to 6 Years of Study Follow-up	8.1 months Interval 7.79 to 8.25	44.1 months Interval 38.47 to 56.18

OTHER_PRE_SPECIFIED outcome

Timeframe: From study initiation to study closure, including up to 6 years of study follow-up

Overall response per the IWCLL 2008 criteria as assessed by Investigator with up to 6 years of study follow-up

Outcome measures

Outcome measures
Measure	Ofatumumab (Arm A) n=196 Participants An anti-CD20 monoclonal antibody ofatumumab: The ofatumumab (IV) dosage and schedule is 12 doses administered over 24 weeks or until disease progression, unacceptable toxicity. Week 1: 300 mg initial dose Week 2 through 8: 2,000 mg (once weekly) Week 12, 16, 20 and 24: 2,000 mg (every 4 weeks)	Ibrutinib (Arm B) n=195 Participants A Bruton Tyrosine Kinase Inhibitor ibrutinib: ibrutinib 420 mg (3 x 140-mg capsules) will be administered orally once daily until disease progression or unacceptable toxicity
Overall Response Rate (ORR) by Investigator	22.4 percentage of participants	87.7 percentage of participants

Adverse Events

Ofatumumab (Arm A)

Serious events: 59 serious events

Other events: 185 other events

Deaths: 16 deaths

Ibrutinib (Arm B)

Serious events: 141 serious events

Other events: 194 other events

Deaths: 24 deaths

Serious adverse events

Other adverse events

Additional Information

Anita Szoke

Pharmacyclics, LLC

Phone: (669) 215-7235

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Ofatumumab (Arm A) n=191 participants at risk An anti-CD20 monoclonal antibody ofatumumab: The ofatumumab (IV) dosage and schedule is 12 doses administered over 24 weeks or until disease progression, unacceptable toxicity. Week 1: 300 mg initial dose Week 2 through 8: 2,000 mg (once weekly) Week 12, 16, 20 and 24: 2,000 mg (every 4 weeks)	Ibrutinib (Arm B) n=195 participants at risk A Bruton Tyrosine Kinase Inhibitor ibrutinib: ibrutinib 420 mg (3 x 140-mg capsules) will be administered orally once daily until disease progression or unacceptable toxicity
Cardiac disorders Angina Pectoris	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Blood and lymphatic system disorders Febrile Neutropenia	2.1% 4/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	3.6% 7/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Blood and lymphatic system disorders Anaemia	2.1% 4/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	2.6% 5/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Blood and lymphatic system disorders Neutropenia	1.0% 2/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	2.1% 4/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Blood and lymphatic system disorders Spontaneous Haematoma	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	1.0% 2/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Blood and lymphatic system disorders Lymphadenopathy	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Blood and lymphatic system disorders Autoimmune Haemolytic Anaemia	0.52% 1/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.00% 0/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Blood and lymphatic system disorders Haemolytic Anaemia	0.52% 1/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.00% 0/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Blood and lymphatic system disorders Methaemoglobinaemia	0.52% 1/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.00% 0/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Cardiac disorders Atrial Fibrillation	0.52% 1/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	5.6% 11/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Cardiac disorders Cardiac Failure Congestive	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	1.5% 3/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Cardiac disorders Atrioventricular Block	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	1.0% 2/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Cardiac disorders Cardiac Failure	0.52% 1/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	1.0% 2/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Cardiac disorders Myocardial infarction	0.52% 1/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	1.0% 2/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Cardiac disorders Acute myocardial infarction	0.52% 1/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Cardiac disorders Aortic Valve Disease	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Cardiac disorders Atrial Tachycardia	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Cardiac disorders Bradycardia	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Cardiac disorders Cardiac Arrest	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Cardiac disorders Myocardial Ischaemia	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Cardiac disorders Palpitations	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Cardiac disorders Pericardial Effusion	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Cardiac disorders Supraventricular Tachycardia	0.52% 1/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Cardiac disorders Sinus Tachycardia	0.52% 1/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.00% 0/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Ear and labyrinth disorders Hypoacusis	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Eye disorders Vitreous Haemorrhage	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Diarrhoea	0.52% 1/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	3.1% 6/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Vomiting	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	2.6% 5/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Abdominal Pain	0.52% 1/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	2.1% 4/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Nausea	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	1.5% 3/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Umbilical Hernia	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	1.0% 2/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Upper Gastrointestinal Haemorrhage	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	1.0% 2/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Abdominal Pain Upper	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Anorectal Discomfort	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Duodenal Perforation	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Dysphagia	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Enteritis	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Intestinal Obstruction	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Large Intestinal Obstruction	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	0.51% 1/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.

Other adverse events
Measure	Ofatumumab (Arm A) n=191 participants at risk An anti-CD20 monoclonal antibody ofatumumab: The ofatumumab (IV) dosage and schedule is 12 doses administered over 24 weeks or until disease progression, unacceptable toxicity. Week 1: 300 mg initial dose Week 2 through 8: 2,000 mg (once weekly) Week 12, 16, 20 and 24: 2,000 mg (every 4 weeks)	Ibrutinib (Arm B) n=195 participants at risk A Bruton Tyrosine Kinase Inhibitor ibrutinib: ibrutinib 420 mg (3 x 140-mg capsules) will be administered orally once daily until disease progression or unacceptable toxicity
Blood and lymphatic system disorders Anaemia	16.8% 32/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	31.8% 62/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Blood and lymphatic system disorders Neutropenia	13.1% 25/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	30.8% 60/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Blood and lymphatic system disorders Increased Tendency to Bruise	2.1% 4/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	23.1% 45/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Blood and lymphatic system disorders Thrombocytopenia	11.5% 22/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	23.1% 45/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Blood and lymphatic system disorders Lymphocytosis	2.6% 5/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	5.1% 10/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Cardiac disorders Atrial Fibrillation	0.00% 0/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	9.7% 19/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Eye disorders Dry Eye	5.2% 10/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	16.9% 33/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Eye disorders Vision Blurred	3.1% 6/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	15.4% 30/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Eye disorders Lacrimation Increased	2.6% 5/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	13.8% 27/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Eye disorders Cataract	1.0% 2/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	13.3% 26/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Eye disorders Visual Acuity Reduced	0.52% 1/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	9.7% 19/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Eye disorders Eye Irritation	1.6% 3/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	8.7% 17/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Eye disorders Eye Pain	2.6% 5/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	7.7% 15/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Eye disorders Photophobia	2.1% 4/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	7.2% 14/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Eye disorders Vitreous Floaters	1.6% 3/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	7.2% 14/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Diarrhoea	17.3% 33/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	61.5% 120/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Nausea	19.9% 38/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	35.4% 69/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Constipation	9.9% 19/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	23.1% 45/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Vomiting	5.8% 11/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	20.0% 39/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Abdominal Pain	9.9% 19/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	15.4% 30/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Stomatitis	2.6% 5/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	15.4% 30/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Dyspepsia	3.1% 6/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	11.3% 22/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Gastrooesophageal Reflux Disease	1.6% 3/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	10.8% 21/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Dry Mouth	0.52% 1/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	9.7% 19/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Abdominal Pain Upper	1.6% 3/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	8.2% 16/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Flatulence	1.0% 2/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	5.1% 10/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Gastrointestinal disorders Haemorrhoids	1.6% 3/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	5.1% 10/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
General disorders Fatigue	29.8% 57/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	42.1% 82/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
General disorders Pyrexia	14.1% 27/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	33.8% 66/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
General disorders Oedema Peripheral	8.4% 16/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	23.6% 46/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
General disorders Asthenia	4.2% 8/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	11.3% 22/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
General disorders Chills	3.1% 6/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	8.2% 16/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
General disorders Influenza Like Illness	2.6% 5/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	8.2% 16/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
General disorders Malaise	0.52% 1/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	5.1% 10/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Infections and infestations Upper Respiratory Tract Infection	8.9% 17/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	39.5% 77/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Infections and infestations Sinusitis	6.3% 12/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	25.6% 50/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Infections and infestations Urinary Tract Infection	5.2% 10/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	23.6% 46/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Infections and infestations Bronchitis	1.0% 2/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	14.4% 28/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Infections and infestations Nasopharyngitis	3.7% 7/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	11.3% 22/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.
Infections and infestations Conjunctivitis	1.0% 2/191 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.	10.8% 21/195 • From first dose of study drug to within 30 days of last dose. 196 subjects were randomized to the Ofa arm with 191 received drug thus 5 patients were not included in the number of participants at risk.